atlas genet cytogenet oncol haematol. 2010;...

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)

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The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and educational items in the various related topics for students in Medicine and in Sciences.

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Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]

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The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008. The Atlas is hosted by INIST-CNRS (http://www.inist.fr)

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Editor

Jean-Loup Huret (Poitiers, France)

Editorial Board Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section Alessandro Beghini (Milan, Italy) Genes Section Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections Judith Bovée (Leiden, The Netherlands) Solid Tumours Section Vasantha Brito-Babapulle (London, UK) Leukaemia Section Charles Buys (Groningen, The Netherlands) Deep Insights Section Anne Marie Capodano (Marseille, France) Solid Tumours Section Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections Antonio Cuneo (Ferrara, Italy) Leukaemia Section Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section Louis Dallaire (Montreal, Canada) Education Section Brigitte Debuire (Villejuif, France) Deep Insights Section François Desangles (Paris, France) Leukaemia / Solid Tumours Sections Enric Domingo-Villanueva (London, UK) Solid Tumours Section Ayse Erson (Ankara, Turkey) Solid Tumours Section Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections Anne Hagemeijer (Leuven, Belgium) Deep Insights Section Nyla Heerema (Colombus, Ohio) Leukaemia Section Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections Sakari Knuutila (Helsinki, Finland) Deep Insights Section Lidia Larizza (Milano, Italy) Solid Tumours Section Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section Edmond Ma (Hong Kong, China) Leukaemia Section Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section Fredrik Mertens (Lund, Sweden) Solid Tumours Section Konstantin Miller (Hannover, Germany) Education Section Felix Mitelman (Lund, Sweden) Deep Insights Section Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section Mariano Rocchi (Bari, Italy) Genes Section Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section Albert Schinzel (Schwerzenbach, Switzerland) Education Section Clelia Storlazzi (Bari, Italy) Genes Section Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections Dan Van Dyke (Rochester, Minnesota) Education Section Roberta Vanni (Montserrato, Italy) Solid Tumours Section Franck Viguié (Paris, France) Leukaemia Section José Luis Vizmanos (Pamplona, Spain) Leukaemia Section Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections




Volume 14, Number 11, November 2010

Table of contents

Gene Section

MAPK12 (mitogen-activated protein kinase 12) 1007 Maria Isabel Cerezo-Guisado, Ana Cuenda

MAPK3 (mitogen-activated protein kinase 3) 1011 Seda Tuncay, Sreeparna Banerjee

MRC1 (mannose receptor, C type 1) 1016 Silvia Rasi, Alessio Bruscaggin, Gianluca Gaidano

MUC13 (mucin 13, cell surface associated) 1020 Diane Maher, Brij Gupta, Mara Ebeling, Satoshi Nagata, Meena Jaggi, Subhash C Chauhan

OLFM4 (olfactomedin 4) 1024 Wenli Liu, Griffin P Rodgers

PDE11A (phosphodiesterase 11A) 1027 Rossella Libé, Jérôme Bertherat

PTPN7 (protein tyrosine phosphatase, non-receptor type 7) 1032 Marie Fridberg, Helena Tassidis, Anette Gjörloff Wingren

RAP1GAP (RAP1 GTPase activating protein) 1034 Zixing Chen, Xuejun Shao

RGS2 (regulator of G-protein signaling 2, 24kDa) 1036 Chau H Nguyen

SOX11 (SRY (sex determining region Y)-box 11) 1039 Xiao Wang, Birgitta Sander

THY1 (Thy-1 cell surface antigen) 1042 John E Bradley, James S Hagood

TYRO3 (TYRO3 protein tyrosine kinase) 1050 Kristen M Jacobsen, Rachel MA Linger, Douglas K Graham

YAP1 (Yes-associated protein 1, 65kDa) 1054 Silvia Di Agostino, Sabrina Strano, Giovanni Blandino

ALK (anaplastic lymphoma receptor tyrosine kinase) 1059 Michèle Allouche

AXL (AXL receptor tyrosine kinase) 1065 Justine Migdall, Douglas K Graham

BAK1 (BCL2-antagonist/killer 1) 1070 Grant Dewson, Ruth Kluck

t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL




Leukaemia Section

t(3;12)(q27;p13) 1075 Jean-Loup Huret

t(3;3)(q25;q27) 1077 Jean-Loup Huret

dic(7;9)(p11-12;p12-13) PAX5/LOC392027 1078 Jean-Loup Huret

dic(9;12)(p13;p12) PAX5/SLCO1B3 1080 Jean-Loup Huret

t(2;14)(p13-16;q32) 1082 Adriana Zamecnikova

Solid Tumour Section

t(6;22)(p21;q12) in hidradenoma of the skin 1085 Jean-Loup Huret

t(6;22)(p21;q12) in mucoepidermoid carcinoma of the salivary glands 1086 Jean-Loup Huret

t(6;22)(p21;q12) in undifferentiated sarcoma 1087 Jean-Loup Huret

Deep Insight Section

Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer 1088 Ioannis A Voutsadakis

Gene Section Review

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1007



MAPK12 (mitogen-activated protein kinase 12) Maria Isabel Cerezo-Guisado, Ana Cuenda

Centro Nacional de Biotecnologia-CSIC, Department of Immunology and Oncology, Madrid, Spain (MICG, AC)

Published in Atlas Database: January 2010

Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPK12ID41290ch22q13.html DOI: 10.4267/2042/44881

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: EC 2.7.11.24; ERK3; ERK5; ERK-6; ERK6; p38gamma; PRKM12; SAPK-3; SAPK3

HGNC (Hugo): MAPK12

Location: 22q13.33

DNA/RNA Description The MAPK12 entire gene spans 8.46 kb on the long arm of chromosome 22. It contains 12 exons.

Transcription The MAPK12 gene encodes a 367 amino-acid protein of about 42 kDa. MAPK12 mRNA is 1457 bp. No splice variants have been reported.

Pseudogene No human or mouse pseudogene known.

Protein Note p38gamma (MAPK12), also known as Stress-activated protein kinase 3 (SAPK3) belongs to the p38 subfamily of MAPKs. The p38MAPK subfamily is composed by four members encoded by different genes, which share high sequence homologies and are designated as p38alpha (MAPK14, or SAPK2a), p38beta (MAPK11 or SAPK2b), p38gamma (MAPK12 or SAPK3) and p38delta (MAPK13 or SAPK4). They are about 60% identical in their amino acid sequence but differ in their expresion patterns, substrate specificities and sensitivities to chemical inhibitors (Iñesta-Vaquera et al., 2008). All p38 MAPKs are strongly activated in vivo by environmental stresses and inflammatory cytokines, and less by serum and growth factors.

MAPK12 genomic context (Chromosome 22, location 22q13.33).

Genomic organization of MAPK12 gene on chromosome 22q13.33. The boxes indicate coding regions (exon 1-12) of the gene.

MAPK12 (mitogen-activated protein kinase 12) Cerezo-Guisado MI, Cuenda A


Schematic representation of the p38gamma (MAPK12) protein structure. Kinase Domain, catalytic kinase domain; TGY, sequence motif containing the regulatory phosphorylation residues. p38gamma (MAPK12) possesses at the C-terminal a sequence that binds to PDZ domain of several proteins.

Description p38gamma (MAPK12) is a Serine/Threonine protein kinase of 367 amino acids with a predicted molecular mass of 42 kDa. It possesses the conserved amino acid domains (I-XI) characteristic of protein kinases (Mertens et al., 1996). The Thr183 and Tyr185 residues in subdomain VIII are in an equivalent position to the TXY sequence in known MAPKs. The activation of p38gamma (MAPK12) occurs via dual phosphorylation of its TGY motif, in the activation loop, by MKK3 and MKK6 (Cuenda et al., 1997; Goedert et al., 1997).

Expression p38gamma (MAPK12) mRNA is widely expressed with high levels of expression in skeletal muscle.

Localisation p38gamma (MAPK12) localizes to the cytoplasm and nucleus of cultured cells.

Function p38gamma (MAPK12) regulates many cellular functions by phosphorylating several proteins. A feature that makes p38gamma unique among the p38 MAPKs is its short C-terminal sequence -KETXL, an amino acid sequence ideal for binding PDZ domains in proteins. SAPK3/p38gamma binds to a variety of these proteins, such as alpha1-syntrophin, SAP90/PSD95 and SAP97/hDlg, and under stress conditions is able to phosphorylate them and modulate their activity (Hasegawa et al., 1999; Sabio et al., 2004; Sabio et al., 2005). These proteins are scaffold proteins usually targeted to the plasma membrane cytoskeleton at specialised sites such as the neuromuscular junction and gap junctions through protein-protein interactions. In the case of SAP97/hDlg its phosphorylation by SAPK3/p38gamma provided a mechanism of dissociating SAP97/hDlg from the cytoskeleton (Sabio et al., 2005). p38gamma can also phosphorylate typical p38 MAPK substrates such as the transcription factors ATF2, Elk-1 or SAP1. However, it cannot phosphorylate MAPKAPK2 or MAPKAPK3, which are good substrates for other p38 MAPK isoforms (Cuenda et al., 1997; Goedert et al., 1997). Another p38gamma substrates that do not require PDZ domain binding interactions are the mitochondrial protein Sab (Court et al., 2004) and the microtubule-associated protein Tau (Feijoo et al., 2005).

Since p38gamma expression is very high in skeletal muscle in comparison to other tissues, it is not surprising that it may play a fundamental role in skeletal muscle differentiation. Thus, p38gamma protein level increases when myoblast differentiate into myotubes endogenous (Tortorella et al., 2003; Cuenda and Cohen, 1999). Moreover, it has been shown that over-expression of p38gamma in skeletal muscle cells leads to differentiation from myoblast to myotubes, and that a dominant-negative mutant of p38gamma prevented this differentiation process (Lechner et al., 1996). Recently, Gillespie et al. (2009) reported that p38gamma phosphorylates the transciption factor MyoD, which results in a decrease in its transcriptional activity. p38gamma plays a cardinal role in blocking the premature differentiation of skeletal muscle stem cells, the satellite cells. Additionally, p38gamma regulates mitochondrial biogenesis and angiogenesis, and it is required for endurance exercise-induced skeletal muscle adaptation (Pogozelski et al., 2009). Most of the work published on cellular transformation regulation by p38MAPK pathway has been focused on studying the role of the isoforms p38alpha and beta, but there are a number of recent publications providing evidences for the role of p38gamma (MAPK12) in cellular transformation. Overexpression of the active form of Rit, a Ras family member, in NIH3T3 cells, causes transformation and stimulates p38gamma, but not other isoforms of p38MAPKs, ERK1, ERK2 or ERK5 (Sakabe et al., 2002). In rat intestinal epithelial cells, Ras oncogene was found to increase p38gamma RNA and protein expression with concurrently stimulated p38alpha phosphorylation and decreased p38gamma phosphorylation (Tang et al., 2005; Loesch and Chen, 2008). These results indicate that increased p38gamma gene expression is required for Ras oncogene activity but the mechanism by which p38gamma may promote Ras transformation is not clear. Recent studies show that phospho-p38alpha can down-regulate p38gamma protein expression through c-jun dependent ubiquitin/proteasome pathways (Qi et al., 2007; Loesch and Chen, 2008). On the other hand other recent study shows that whereas p38gamma mediates Ras-induced senescence at least partly by stimulating the transcriptional activity of p53 through direct phosphorylation, p38alpha appears to regulate senescence in a p53-independent, p16INK4A dependent manner (Kwong et al., 2009).



Homology p38gamma (MAPK12) shows 70% identity with p38delta (MAPK13), 60% sequence identity with p38alpha (MAPK14) and p38beta (MAPK11), 45% identity with HOG1 from S. cerevisiae, 47% identity with human SAP kinase-1 (JNK1) and 42% identity with p42 MAP kinase (ERK2).

Mutations Note No mutation reported yet.

Implicated in Breast cancer Oncogenesis In human MCF-7 breast cancer cells, MKK6 expression inhibits DNA synthesis. This inhibitory effect is enhanced by the co-expressed p38gamma (Pramanik et al., 2003; Loesch and Chen, 2008). Ras also increases p38gamma protein expression in human breast cancer (Qi et al., 2006).

Skin cancer Oncogenesis p38gamma isoform is specifically implicated in melanoma death induced by UV radiation, cisplatin treatment (Pillaire et al., 2000). Moreover, melanoma cells overexpressing PDGF-Ralpha show a marked increase of p38gamma (Faraone et al., 2009).

Hepatoma Oncogenesis p38gamma expression is increased in hepatoma cell line HLE (Liu et al., 2003).

Ovarian cancer Oncogenesis p38gamma expression is regulated by the TNF-related apoptosis inducing ligand (TRIAL) and IL-8 in cellular lines from ovarian cancer (Abdollahi et al., 2003).

Pancreatic cancer Oncogenesis The levels of p38gamma seem to be decreased in pancreatic cancer cells (Crnogorac-Jurcevic et al., 2001).

References Lechner C, Zahalka MA, Giot JF, Møller NP, Ullrich A. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4355-9

Mertens S, Craxton M, Goedert M. SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases. FEBS Lett. 1996 Apr 1;383(3):273-6

Cuenda A, Cohen P, Buée-Scherrer V, Goedert M. Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and

cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO J. 1997 Jan 15;16(2):295-305

Goedert M, Cuenda A, Craxton M, Jakes R, Cohen P. Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO J. 1997 Jun 16;16(12):3563-71

Goedert M, Hasegawa J, Craxton M, Leversha MA, Clegg S. Assignment of the human stress-activated protein kinase-3 gene (SAPK3) to chromosome 22q13.3 by fluorescence in situ hybridization. Genomics. 1997 May 1;41(3):501-2

Cuenda A, Cohen P. Stress-activated protein kinase-2/p38 and a rapamycin-sensitive pathway are required for C2C12 myogenesis. J Biol Chem. 1999 Feb 12;274(7):4341-6

Hasegawa M, Cuenda A, Spillantini MG, Thomas GM, Buée-Scherrer V, Cohen P, Goedert M. Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1-syntrophin. A mechanism for specific substrate recognition. J Biol Chem. 1999 Apr 30;274(18):12626-31

Pillaire MJ, Nebreda AR, Darbon JM. Cisplatin and UV radiation induce activation of the stress-activated protein kinase p38gamma in human melanoma cells. Biochem Biophys Res Commun. 2000 Nov 30;278(3):724-8

Crnogorac-Jurcevic T, Efthimiou E, Capelli P, Blaveri E, Baron A, Terris B, Jones M, Tyson K, Bassi C, Scarpa A, Lemoine NR. Gene expression profiles of pancreatic cancer and stromal desmoplasia. Oncogene. 2001 Nov 1;20(50):7437-46

Sakabe K, Teramoto H, Zohar M, Behbahani B, Miyazaki H, Chikumi H, Gutkind JS. Potent transforming activity of the small GTP-binding protein Rit in NIH 3T3 cells: evidence for a role of a p38gamma-dependent signaling pathway. FEBS Lett. 2002 Jan 30;511(1-3):15-20

Abdollahi T, Robertson NM, Abdollahi A, Litwack G. Identification of interleukin 8 as an inhibitor of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in the ovarian carcinoma cell line OVCAR3. Cancer Res. 2003 Aug 1;63(15):4521-6

Liu LX, Liu ZH, Jiang HC, Zhang WH, Qi SY, Hu J, Wang XQ, Wu M. Gene expression profiles of hepatoma cell line HLE. World J Gastroenterol. 2003 Apr;9(4):683-7

Pramanik R, Qi X, Borowicz S, Choubey D, Schultz RM, Han J, Chen G. p38 isoforms have opposite effects on AP-1-dependent transcription through regulation of c-Jun. The determinant roles of the isoforms in the p38 MAPK signal specificity. J Biol Chem. 2003 Feb 14;278(7):4831-9

Tortorella LL, Lin CB, Pilch PF. ERK6 is expressed in a developmentally regulated manner in rodent skeletal muscle. Biochem Biophys Res Commun. 2003 Jun 20;306(1):163-8

Court NW, Kuo I, Quigley O, Bogoyevitch MA. Phosphorylation of the mitochondrial protein Sab by stress-activated protein kinase 3. Biochem Biophys Res Commun. 2004 Jun 18;319(1):130-7

Sabio G, Reuver S, Feijoo C, Hasegawa M, Thomas GM, Centeno F, Kuhlendahl S, Leal-Ortiz S, Goedert M, Garner C, Cuenda A. Stress- and mitogen-induced phosphorylation of the synapse-associated protein SAP90/PSD-95 by activation of SAPK3/p38gamma and ERK1/ERK2. Biochem J. 2004 May 15;380(Pt 1):19-30

Feijoo C, Campbell DG, Jakes R, Goedert M, Cuenda A. Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly. J Cell Sci. 2005 Jan 15;118(Pt 2):397-408



Sabio G, Arthur JS, Kuma Y, Peggie M, Carr J, Murray-Tait V, Centeno F, Goedert M, Morrice NA, Cuenda A. p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP. EMBO J. 2005 Mar 23;24(6):1134-45

Tang J, Qi X, Mercola D, Han J, Chen G. Essential role of p38gamma in K-Ras transformation independent of phosphorylation. J Biol Chem. 2005 Jun 24;280(25):23910-7

Qi X, Tang J, Loesch M, Pohl N, Alkan S, Chen G. p38gamma mitogen-activated protein kinase integrates signaling crosstalk between Ras and estrogen receptor to increase breast cancer invasion. Cancer Res. 2006 Aug 1;66(15):7540-7

Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 2007 Aug;1773(8):1358-75

Qi X, Pohl NM, Loesch M, Hou S, Li R, Qin JZ, Cuenda A, Chen G. p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. J Biol Chem. 2007 Oct 26;282(43):31398-408

Inesta-Vaquera FA, Sabio G, Kuma Y, Cuenda A.. Alternative p38MAPK pathways. Stress activated protein kinases. Topics in Current Genetics. Springer-Verlag Berlin Heidelberg. 2008; 20:17-26.

Loesch M, Chen G. The p38 MAPK stress pathway as a tumor suppressor or more? Front Biosci. 2008 May 1;13:3581-93

Faraone D, Aguzzi MS, Toietta G, Facchiano AM, Facchiano F, Magenta A, Martelli F, Truffa S, Cesareo E, Ribatti D, Capogrossi MC, Facchiano A. Platelet-derived growth factor-receptor alpha strongly inhibits melanoma growth in vitro and in vivo. Neoplasia. 2009 Aug;11(8):732-42

Kwong J, Hong L, Liao R, Deng Q, Han J, Sun P. p38alpha and p38gamma mediate oncogenic ras-induced senescence through differential mechanisms. J Biol Chem. 2009 Apr 24;284(17):11237-46

Pogozelski AR, Geng T, Li P, Yin X, Lira VA, Zhang M, Chi JT, Yan Z. p38gamma mitogen-activated protein kinase is a key regulator in skeletal muscle metabolic adaptation in mice. PLoS One. 2009 Nov 20;4(11):e7934

Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009 Aug;9(8):537-49

This article should be referenced as such:

Cerezo-Guisado MI, Cuenda A. MAPK12 (mitogen-activated protein kinase 12). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1007-1010.

Gene Section Review




MAPK3 (mitogen-activated protein kinase 3) Seda Tuncay, Sreeparna Banerjee

Department of Biological Sciences, Middle East Technical University, Ankara 06531, Turkey (ST, SB)


Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPK3ID425ch16p11.html DOI: 10.4267/2042/44882


Identity Other names: EC 2.7.11.24; ERK1; ERK-1; ERT2; HS44KDAP; HUMKER1A; MAPK 1; MGC20180; PRKM3; P44ERK1; P44MAPK; p44-ERK1; p44-MAPK

HGNC (Hugo): MAPK3

Location: 16p11.2

Local order: According to NCBI Map Viewer, genes flanking ERK1 (MAPK3) in centromere to telomere direction on 16p11.2 are:

centromere

- Hypothetical LOC100271831, Location: 16p11.2

- YPEL3, yippee-like 3 (Drosophila), Location: 16p11.2

- GDPD3, glycerophosphodiester phosphodiesterase domain containing 3, Location: 16p11.2

- MAPK3, 16p11.2

- CORO1A, coronin, actin binding protein 1A, Location: 16p11.2

- BOLA2B, bolA homolog 2B (E. coli), Location: 16p11.2

- GIYD1, GIY-YIG domain containing 1, Location: 16p11.2

telomere.

DNA/RNA Description According to Entrez Gene MAPK3 gene maps to NC_000016.9 and spans a region of 9.21 kb. According to Spidey mRNA-to-genomic alignment program ERK1 (MAPK3) variant 1 (the most common variant) has 8 exons, the sizes being 170, 183, 190, 117, 115, 132, 110, 123 bps (mRNA coordinates).

Transcription The promoter analysis of the human MAPK3 has shown that the elements responsible for basal transcriptional activity are located within 200 bp upstream of the initiation codon in the 5' UTR and rich in G/C content (80.5%). The sequence has four SP1 sites and an E box as the most relevant motifs. Site-directed mutagenesis, EMSA, and DNase I footprinting experiments proved that all these elements are required to achieve a significant level of transcription. It has also been reported that the promoter activity is strongly repressed when the cells are grown under growth arrest conditions, such as confluence or serum withdrawal.

Pseudogene No pseudogenes have been reported for MAPK3.

Diagram of the ERK1 (MAPK3) gene (isoform 1). Exons are represented by open boxes (in scale). Exons 1 to 8 are from the 5' to 3' direction.

MAPK3 (mitogen-activated protein kinase 3) Tuncay S, Banerjee S


Protein Note ERK1 (MAPK3) is identified by the specific TEY (Thr-Glu-Tyr) sequence in its activation loop. ERK1 (MAPK3) is activated by dual phosphorylation of tyrosine (Tyr204) and threonine (Thr202) residues which is required for complete activation of the protein. Activated ERK1 (MAPK3) migrates into the nucleus and phosphorylates transcription factors.

Description ERK1 (MAPK3) is a 43 kDa protein consisting of 379 amino acids. ERK1 (MAPK3) protein is 85% identical to ERK2 (MAPK1) (another MAP kinase family member) and the two proteins have even higher levels of similarity in their substrate binding regions. ERK1 (MAPK3) and ERK2 (MAPK1) both possess 2 DXXD docking sites that provide interaction sites with a Kinase Interaction Motif (KIM), which can be found on activators (MAPKK), inhibitors (PTP-SL (PTPRR) and dual specificity phosphatases) and substrates (ELK-1).

Expression Ubiquitously expressed with varying levels in different tissues.

Localisation Subcellular location of ERK1 (MAPK3) protein is the cytoplasm, and the nucleus. Upon activation by dual phosphorylation on its Tyr and Thr residues by upstream kinases, ERK1 (MAPK3) is translocated into the nucleus from cytoplasm where it phosphorylates its nuclear targets.

Function Being one of the most studied cytoplasmic signaling pathways, the ERK pathway is activated via GTP-loading of RAS at the plasma membrane and sequential activation of a series of protein kinases. Activated RAS recruits the RAF family of kinases such as RAF1 to the plasma membrane which in turn acts as a MAPKKK and activates MAP kinase/ERK kinase 1 and 2 (MEK1 (MAP2K1) and MEK2 (MAP2K2)) by serine phosphorylation. MEK1/2 catalyze the phosphorylation of ERK1 (MAPK3) and ERK2 (MAPK1). Activated ERK1/2 (MAPK3/1) phosphorylates many different substrates involved in various cellular responses from cytoskeletal changes to gene transcription. ERK1 (MAPK3) was initially identified as an insulin-stimulated protein kinase which has an activity towards microtubule-associated protein-2. Today, it is well known that ERK1/2 (MAPK3/1) is especially involved in the control of cell proliferation, cell differentiation and cell survival. It has been shown that activation of ERK1/2 (MAPK3/1) is crucial for cyclin D1 induction, providing a molecular link between ERK signaling and

cell cycle control as cyclin D1 gene is essential for G1 to S-phase progression. In response to Angiotensin II, ERK1/2 (MAPK3/1) regulates cell proliferation by either one of two signaling pathways which are heterotrimeric G protein/PKC zeta-dependent signaling and SRC/YES1/FYN signaling. ERK1/2 (MAPK3/1) phosphorylates specific transcription factors ELK-1 (leading to c-FOS transcriptional activity) following its translocation into the nucleus due to heterotrimeric G protein/PKC zeta-dependent signaling. Due to its phosphorylation in the cytoplasm by SRC/YES1/FYN signaling, ERK1/2 (MAPK3/1) complexes with RSK2 (RPS6KA), which in turn become activated and translocates into the nucleus to modulate c-FOS transcription and c-FOS protein activity. The ERK pathway has been found to be responsible for the phosphorylation of BCL2 that contributes to cell survival, the suppression of the apoptotic effect of BAD, the up-regulation of the antiapoptotic protein MCL-1. Moreover, it has been also shown that ERK1/2 (MAPK3/1) is one of the regulators of TP53 protein accumulation and activation during the DNA damage response. ERK1/2 (MAPK3/1) induces expression of PAI-1 (plasminogen activator type-1 inhibitor) which is closely associated with dynamic changes in cellular morphology and shape-altering physiologic processes. ERK1/2 (MAPK3/1) has been shown to regulate PPARg1 following EGF stimulation. CIITA is a critical transcription factor that initiates the expression of MHC class II genes and the subsequent induction of the immune response. Studies have indicated that ERK1/2 (MAPK3/1) negatively regulates CIITA by blocking expression of the CIITA gene and/or by phosphorylating CIITA at residues including serine 288, resulting in the loss of CIITA transactivation potential by enabling it to interact with CRM1 (XPO1) which causes export of CIITA protein from the nucleus.

Homology - P. troglodytes, MAPK3, mitogen-activated protein kinase 3 - C. lupus familiaris, MAPK3, mitogen-activated protein kinase 3 - B. taurus, MAPK3, mitogen-activated protein kinase 3 - M. musculus, MAPK3, mitogen-activated protein kinase 3 - R. norvegicus, MAPK3, mitogen activated protein kinase 3 - D. rerio, MAPK3, mitogen-activated protein kinase 3 - S. pombe, spk1, MAP kinase Spk1 - S. cerevisiae, FUS3, Fus3p - K. lactis, KLLA0E10527g, hypothetical protein - E. gossypii, AGOS_AFR019W, AFR019Wp - M. grisea, MGG_09565, mitogen-activated protein kinase



- N. crassa, NCU02393.1, hypothetical protein ((AF348490) MAP kinase [Neurospora crassa OR74A]) - A. thaliana, ATMPK13, ATMPK13; MAP kinase/ kinase

Implicated in Various diseases Disease Although both ERK1 (MAPK3) and ERK2 (MAPK1) have very similar functions, ERK2-/- mice are embryonic lethal while ERK1-/- mice are viable and show normal size and fertility. Thus each isoform may have a unique role, or there may be threshold of total ERK activity for normal viability. Although viable, ERK1-/- mice have reduced ability for thymocyte maturation and proliferation when T cell receptors are activated. These mice also show an enhancement of long term memory that was shown to be dependent on the striatum. Additionally, the loss of ERK1 results in a loss of adipocity, with the mice having fewer adipocytes than the wild type counterparts.

Oncogenesis Elevated and constitutive activation of ERK1/2 has been detected in a large number of human tumors; including colon, kidney, gastric, prostate, breast, non-small cell lung cancer, bladder, chondrosarcomas and glioblastoma multiforme which show especially high frequencies of kinase activation. The reason for constitutive activation of the ERK pathway in the majority of tumor cells seems to be due to a disorder in RAF, RAS, EGFR or other upstream signaling molecules. In addition, several studies have shown that the ERK-MAPK pathway can directly promote cell motility and the migration of tumor cells.

Gastric cancer Note Epidermal growth factor (EGF) and urokinase plasminogen activator receptor (uPAR (PLAUR)) are elevated in human gastric cancers and it has been shown that uPAR expression is induced by EGF via ERK1/2 as well as AP-1 (JUN) and NF-kB signaling pathways which in turn, stimulates cell invasiveness in human gastric cancer AGS cells.

Breast cancer Note In breast cancer patients, ERK1/2 has been found to be heavily phosphorylated on tyrosyl residues and have a 5-10 fold elevated activity compared to benign conditions (fibroadenoma and fibrocystic disease). Localization studies showed that hyperexpressed ERK1/2 mRNA localized to malignant epithelial cells. Furthermore, hyperexpression of ERK1/2 mRNA (5-20 fold) was also observed in metastatic cells within the lymph nodes of breast cancer patients. In addition, in a

recent study it was also shown that phosphorylated ERK1/2 levels were significantly high in breast cancer cell lines with high metastatic potential compared to non metastatic breast cancer cell lines. beta-catenin, cyclin D1, and survivin have been shown to be downstream effectors of pERK1/2, while G1/0 proteins, phospholipase C, and protein kinase C serve as upstream activators of pERK1/2 in those cells.

Colorectal cancer Note Several lines of evidence indicate that overexpression and activation of ERK-MAPK pathway play an important part in progression of colorectal cancer. The constitutive activation of the RAF/MEK/ERK has been shown to be necessary for RAS-induced transformation of HT1080 human colon carcinoma cell line.

Non-small-cell lung cancer Note It has been found that nuclear and cytoplasmic ERK1/2 activation positively correlates with the stage and lymph node metastases in lung cancer. Therefore ERK1/2 is associated with advanced and aggressive NSCLC tumors.

Bladder cancer Note ERK1/2 has been shown to mediate TNF-alpha-induced MMP-9 expression by regulating the binding activity of the transcription factors, NF-kB, AP-1 and SP-1, in urinary bladder cancer HT1376 cells.

Glioblastoma multiforme Note The activation of ERK1/2 has been implicated in different pathobiological processes of GBM which is the most common and malignant brain tumor. The ERK1/2 activation has been linked to EGFR overexpression and hypermethylation of 9p21 locus.

Prostate cancer Note In prostate tumors, the level of activated MAP kinase were found to be increased with increasing Gleason score and tumor stage while nonneoplastic prostate tissue showed little or no staining with activated MAP kinase antiserum.

Kidney cancer Note In a high number of human renal cancers ERK1/2 has been found to be constitutively activated. Moreover, ERK1/2 activation was observed more frequently with high-grade renal cancer cells (RCC) compared to low-grade RCC.

Chondrosarcomas Note Activation of the JNK (MAPK8) and ERK signal



transduction pathways have been shown to increase the activity and expression levels of their downstream effectors, transcription factors AP-1 and RUNX2. These transcription factors, in turn, stimulate genes that are involved in chondroblast cell biology, ultimately inducing chondroblastic tumorigenesis.

Cardiac hypertrophy Note It has been implicated that ERK1/2 mediate cardiac hypertrophy, which is a major risk factor for the development of arrhythmias, heart failure and sudden death.

References Boulton TG, Gregory JS, Cobb MH. Purification and properties of extracellular signal-regulated kinase 1, an insulin-stimulated microtubule-associated protein 2 kinase. Biochemistry. 1991 Jan 8;30(1):278-86

Oka H, Chatani Y, Hoshino R, Ogawa O, Kakehi Y, Terachi T, Okada Y, Kawaichi M, Kohno M, Yoshida O. Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma. Cancer Res. 1995 Sep 15;55(18):4182-7

Seger R, Krebs EG. The MAPK signaling cascade. FASEB J. 1995 Jun;9(9):726-35

Lavoie JN, L'Allemain G, Brunet A, Müller R, Pouysségur J. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem. 1996 Aug 23;271(34):20608-16

Camp HS, Tafuri SR. Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase. J Biol Chem. 1997 Apr 18;272(16):10811-6

Sivaraman VS, Wang H, Nuovo GJ, Malbon CC. Hyperexpression of mitogen-activated protein kinase in human breast cancer. J Clin Invest. 1997 Apr 1;99(7):1478-83

Mandell JW, Hussaini IM, Zecevic M, Weber MJ, VandenBerg SR. In situ visualization of intratumor growth factor signaling: immunohistochemical localization of activated ERK/MAP kinase in glial neoplasms. Am J Pathol. 1998 Nov;153(5):1411-23

Gioeli D, Mandell JW, Petroni GR, Frierson HF Jr, Weber MJ. Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res. 1999 Jan 15;59(2):279-84

Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M. Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene. 1999 Jan 21;18(3):813-22

Pagès G, Guérin S, Grall D, Bonino F, Smith A, Anjuere F, Auberger P, Pouysségur J. Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science. 1999 Nov 12;286(5443):1374-7

Persons DL, Yazlovitskaya EM, Pelling JC. Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin. J Biol Chem. 2000 Nov 17;275(46):35778-85

Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001 Apr;22(2):153-83

Mazzucchelli C, Vantaggiato C, Ciamei A, Fasano S, Pakhotin P, Krezel W, Welzl H, Wolfer DP, Pagès G, Valverde O, Marowsky A, Porrazzo A, Orban PC, Maldonado R, Ehrengruber MU, Cestari V, Lipp HP, Chapman PF, Pouysségur J, Brambilla R. Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory. Neuron. 2002 May 30;34(5):807-20

Samarakoon R, Higgins PJ. MEK/ERK pathway mediates cell-shape-dependent plasminogen activator inhibitor type 1 gene expression upon drug-induced disruption of the microfilament and microtubule networks. J Cell Sci. 2002 Aug 1;115(Pt 15):3093-103

Tárrega C, Blanco-Aparicio C, Muñoz JJ, Pulido R. Two clusters of residues at the docking groove of mitogen-activated protein kinases differentially mediate their functional interaction with the tyrosine phosphatases PTP-SL and STEP. J Biol Chem. 2002 Jan 25;277(4):2629-36

Saba-El-Leil MK, Vella FD, Vernay B, Voisin L, Chen L, Labrecque N, Ang SL, Meloche S. An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep. 2003 Oct;4(10):964-8

Hernández R, García F, Encío I, De Miguel C. Promoter analysis of the human p44 mitogen-activated protein kinase gene (MAPK3): transcriptional repression under nonproliferating conditions. Genomics. 2004 Jul;84(1):222-6

Vicent S, López-Picazo JM, Toledo G, Lozano MD, Torre W, Garcia-Corchón C, Quero C, Soria JC, Martín-Algarra S, Manzano RG, Montuenga LM. ERK1/2 is activated in non-small-cell lung cancer and associated with advanced tumours. Br J Cancer. 2004 Mar 8;90(5):1047-52

Bost F, Aouadi M, Caron L, Even P, Belmonte N, Prot M, Dani C, Hofman P, Pagès G, Pouysségur J, Le Marchand-Brustel Y, Binétruy B. The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis. Diabetes. 2005 Feb;54(2):402-11

Fang JY, Richardson BC. The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 2005 May;6(5):322-7

Papachristou DJ, Papachristou GI, Papaefthimiou OA, Agnantis NJ, Basdra EK, Papavassiliou AG. The MAPK-AP-1/-Runx2 signalling axes are implicated in chondrosarcoma pathobiology either independently or via up-regulation of VEGF. Histopathology. 2005 Dec;47(6):565-74

Godeny MD, Sayeski PP. ERK1/2 regulates ANG II-dependent cell proliferation via cytoplasmic activation of RSK2 and nuclear activation of elk1. Am J Physiol Cell Physiol. 2006 Dec;291(6):C1308-17

Nikodemova M, Watters JJ, Jackson SJ, Yang SK, Duncan ID. Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)alpha/betaII. J Biol Chem. 2007 May 18;282(20):15208-16

Baek MK, Kim MH, Jang HJ, Park JS, Chung IJ, Shin BA, Ahn BW, Jung YD. EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-kappaB signaling in human gastric carcinoma cells. Oncol Rep. 2008 Dec;20(6):1569-75

Kinoshita T, Yoshida I, Nakae S, Okita K, Gouda M, Matsubara M, Yokota K, Ishiguro H, Tada T. Crystal structure of human mono-phosphorylated ERK1 at Tyr204. Biochem Biophys Res Commun. 2008 Dec 26;377(4):1123-7

Lopez-Gines C, Gil-Benso R, Benito R, Mata M, Pereda J, Sastre J, Roldan P, Gonzalez-Darder J, Cerdá-Nicolás M. The activation of ERK1/2 MAP kinases in glioblastoma



pathobiology and its relationship with EGFR amplification. Neuropathology. 2008 Oct;28(5):507-15

Voong LN, Slater AR, Kratovac S, Cressman DE. Mitogen-activated protein kinase ERK1/2 regulates the class II transactivator. J Biol Chem. 2008 Apr 4;283(14):9031-9

Lorenz K, Schmitt JP, Vidal M, Lohse MJ. Cardiac hypertrophy: targeting Raf/MEK/ERK1/2-signaling. Int J Biochem Cell Biol. 2009 Dec;41(12):2351-5


Tuncay S, Banerjee S. MAPK3 (mitogen-activated protein kinase 3). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1011-1015.

Gene Section Mini Review




MRC1 (mannose receptor, C type 1) Silvia Rasi, Alessio Bruscaggin, Gianluca Gaidano

Division of Hematology, Department of Clinical and Experimental Medicine & Center of Biotechnologies for Applied Medical Research, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy (SR, AB, GG)


Online updated version : http://AtlasGeneticsOncology.org/Genes/MRC1ID44561ch10p12.html DOI: 10.4267/2042/44883


Identity Other names: CD206; CLEC13D; MMR

HGNC (Hugo): MRC1

Location: 10p12.33

Local order: MRC1 is located on chromosome 10 on the short arm (forward strand), and lies between the FAM23B (family with sequence similarity 23, member B) and SLC39A12 (solute carrier family 39 - zinc transporter, member 12) genes.

The gene loci including MRC1, MRC1L1 (mannose receptor, C type 1-like 1), FAM23B and

LOC340893 consists of two nearly identical genomic regions, that probably are a part of a duplicated region.

Note MRC1 belongs to the mannose receptor (MR) family; all members of the MR family share a common extracellular domain structure but distinct ligand-binding properties and cell type expression patterns. The MR family comprises 4 members in mammals: MRC1, MRC2 (mannose receptor C, type 2), LY75 (lymphocyte antigen 75) and PLA2R1 (phospholipase A2 receptor 1).

A. Chromosomal location of MRC1 gene. B. Mapping of MRC1 gene and local order on genomic context of the chromosome 10.

MRC1 (mannose receptor, C type 1) Rasi S, et al.


Exon-intron structure of MRC1 gene. The blue boxes correspond to protein coding sequences, while the white boxes correspond to non coding regions.

Representation of the MRC1 protein with localization of recognized domains. The ricin b-type lectin domain (RICIN) is shown in green, the fibronectin type-II domain (FN2) in yellow, the C-type lectin-like domains (CTLDs) in blue, while the transmembrane domain (TM) in red (UniProtKB/Swiss-Prot entry P22897).

DNA/RNA Description MRC1 is a functional gene of 101.74 kb comprising 30 exons and 29 introns. The 5' part of exon 1 and the 3' part of exon 30 are non coding.

Transcription Length of the transcript is 5171 bp. Coding sequence: CDS 104-4474. mRNA is mainly expressed in thyroid, spleen and blood.

Protein Description Protein length of the unprocessed precursor: 1456 amino acids. Molecular weight of the unprocessed precursor: 166 kDa. The protein encoded by the MRC1 gene is classified as a type I transmembrane receptor since the protein COOH terminus is located on the cytoplasmic side of the membrane. MRC1 is a membrane receptor containing: - a ricin b-type lectin domain (RICIN), that is a cystein-rich (CysR) domain located at the extreme N-terminus and that can bind specific sulphated glycoproteins, - a fibronectin type-II domain (FN2), that is the most conserved of the extracellular domains of the MR family and can bind several forms of collagen, - 8 C-type lectin-like domains (CTLDs), that are Ca(2+)-dependent structural motifs. The fourth of these domains, CTLD4, is the only functional domain. In cooperation with CTLD5, CTLD4 is central to ligand binding by the receptor, - a single transmembrane domain (TM), - a short cytosolic domain that contains motifs capable

of recognizing components of the endocytic pathway. The first 3 exons of MRC1 gene encode the signal sequence, the RICIN domain and the FN2 domain, while exon 30 encodes the TM anchor and the cytoplasmic tail. The other 26 exons encode the 8 CTLD domains and intervening spacer elements. Probably the MRC1 receptor acts with an alternation between bent and extended conformations that might serve as a "conformational switch" to regulate ligand binding and receptor activity. MRC1 interacts with CHEK2 (CHK2 checkpoint homolog - S. pombe) protein. Expression MRC1 is commonly expressed on macrophages and endothelial cells.

Localisation Plasma membrane.

Function - MRC1 mediates the endocytosis of glyproteins by macrophages binding both sulfated and non-sulfated polysaccharide chains. - MRC1 acts as a phagocytic receptor binding a range of pathogens, such as bacteria, viruses and fungi, through high-mannose structures that are in their surface. - MRC1 is required for rapid clearance of a subset of mannose-bearing serum glycoproteins that are normally elevated during inflammation. - MRC1 binds and internalises collagen and gelatin in a carbohydrate-independent mechanism. - MRC1 can function as an antigen-acquisition system in a subset of dendritic cells. - MRC1 is implicated in the regulation of macrophage migration during different stages of pathogenesis. - MRC1 has an important role in binding and transmission of HIV-1 by macrophages.



Homology Ortholog to murine Mrc1, rat Mrc1, cow LOC787578, chimpanzee MLR1L1, canine LOC487114. Paralog to MRC1L1, CD302, PLA2R1, MRC2.

Mutations Note No mutations have been reported for MRC1 gene.

Implicated in Pediatric acute lymphoblastic leukemia (ALL) Disease ALL is a form of leukemia characterized by excess of lymphoblastic cells that is most common in childhood. The rate of cure in children is of nearly 80%, while only 30/40% of adults with ALL are cured. It is a heterogeneous disease consisting of a number of genetically distinct leukemia subtypes that differ in the response to chemotherapy. These include B-lineage leukemias that contain t(9;22)[BCR-ABL], t(1;19)[E2A-PBX1], t(12;21)[TEL-AML1], rearrangements in the MLL gene on chromosome 11q23, or a hyperdiploid karyotype, and T-lineage leukemias (T-ALL).

Prognosis ALL is a heterogeneous disease and patients are assigned to specific risk groups. In fact, ALL prognosis differs among individuals and depends on several factors: sex, age and white blood cell count at diagnosis, leukemia spread to the central nervous system, morphological, immunological, and genetic subtypes, patient's response to initial treatment. Various genetic alterations are correlated with prognosis in ALL. In particular ALLs with the presence of t(12;21)[TEL-AML1] and hyperdiploid karyotype have favorable prognosis, while ALLs with t(9;22)[BCR-ABL], t(1;19)[E2A-PBX1] or rearrangements in MLL (11q23) have a poor prognosis.

Oncogenesis In cases having ALL with MLL rearrangements, expression of MRC1 is lower than in normal cells, suggesting a putative involvement of MRC1 in MLL-mediated growth of leukemic cells.

Acute monocytic leukemia (M5-AML) Note In acute monocytic leukemia, a trimannose conjugate (TMC), with a high affinity for mannose-specific lectins, binds to MRC1 and this concatenation may play an important role in the activation of monocytic leukemia cells. TMC may be a good candidate to target MRC1 in leukemia cells.

Disease Acute monocytic leukemia is a type of acute myeloid leukemias (AML), characterized by a dominance of monocytes in the bone marrow.

Cancer Note MRC1 on lymphatic endothelial cells is involved in leukocyte trafficking and contributes to the metastatic behavior of cancer cells. Moreover, expression of the MRC1 gene is up-regulated in vascular endothelial cells during early development indicating that this gene is a potential regulator of vasculature formation. Blocking of MRC1 may provide a new approach to controlling inflammation and cancer metastasis by targeting the lymphatic vasculature.

Kaposi's sarcoma (KS) Note KS cells express MRC1, since MRC1 is detected in more than 95% of KS cells in all of the major clinical forms of the disease. It is likely that KS lesions derive from tissue accumulation and local proliferation of a subset of macrophages with endotelial features.

Disease KS is a multicentric proliferative disease, involving cutaneous and visceral tissues. The etiology is unknown and the pathogenesis is unclear. KS lesions derive from local proliferation of spindleshaped cells (KS cells), that represent the histological hallmark of this disease.

References Taylor ME, Conary JT, Lennartz MR, Stahl PD, Drickamer K. Primary structure of the mannose receptor contains multiple motifs resembling carbohydrate-recognition domains. J Biol Chem. 1990 Jul 25;265(21):12156-62

Kim SJ, Ruiz N, Bezouska K, Drickamer K. Organization of the gene encoding the human macrophage mannose receptor (MRC1). Genomics. 1992 Nov;14(3):721-7

Eichbaum Q, Clerc P, Bruns G, McKeon F, Ezekowitz RA. Assignment of the human macrophage mannose receptor gene (MRC1) to 10p13 by in situ hybridization and PCR-based somatic cell hybrid mapping. Genomics. 1994 Aug;22(3):656-8

Uccini S, Sirianni MC, Vincenzi L, Topino S, Stoppacciaro A, Lesnoni La Parola I, Capuano M, Masini C, Cerimele D, Cella M, Lanzavecchia A, Allavena P, Mantovani A, Baroni CD, Ruco LP. Kaposi's sarcoma cells express the macrophage-associated antigen mannose receptor and develop in peripheral blood cultures of Kaposi's sarcoma patients. Am J Pathol. 1997 Mar;150(3):929-38

Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med. 1998 Aug 27;339(9):605-15

Kanbe E, Emi N, Abe A, Tanaka H, Kobayashi K, Saito H. Novel synthesized trimannose conjugate induces endocytosis and expression of immunostimulatory molecules in monocytic leukemia cells. Int J Hematol. 2001 Oct;74(3):309-15



East L, Isacke CM. The mannose receptor family. Biochim Biophys Acta. 2002 Sep 19;1572(2-3):364-86

Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J, Risteli L, Lee YC, Feizi T, Langen H, Nussenzweig MC. Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science. 2002 Mar 8;295(5561):1898-901

Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, Behm FG, Raimondi SC, Relling MV, Patel A, Cheng C, Campana D, Wilkins D, Zhou X, Li J, Liu H, Pui CH, Evans WE, Naeve C, Wong L, Downing JR. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 2002 Mar;1(2):133-43

Nguyen DG, Hildreth JE. Involvement of macrophage mannose receptor in the binding and transmission of HIV by macrophages. Eur J Immunol. 2003 Feb;33(2):483-93

Martinez-Pomares L, Wienke D, Stillion R, McKenzie EJ, Arnold JN, Harris J, McGreal E, Sim RB, Isacke CM, Gordon S. Carbohydrate-independent recognition of collagens by the macrophage mannose receptor. Eur J Immunol. 2006 May;36(5):1074-82

McKenzie EJ, Taylor PR, Stillion RJ, Lucas AD, Harris J, Gordon S, Martinez-Pomares L. Mannose receptor expression and function define a new population of murine dendritic cells. J Immunol. 2007 Apr 15;178(8):4975-83

Sturge J, Todd SK, Kogianni G, McCarthy A, Isacke CM. Mannose receptor regulation of macrophage cell migration. J Leukoc Biol. 2007 Sep;82(3):585-93

Llorca O. Extended and bent conformations of the mannose receptor family. Cell Mol Life Sci. 2008 May;65(9):1302-10

Marttila-Ichihara F, Turja R, Miiluniemi M, Karikoski M, Maksimow M, Niemelä J, Martinez-Pomares L, Salmi M, Jalkanen S. Macrophage mannose receptor on lymphatics controls cell trafficking. Blood. 2008 Jul 1;112(1):64-72

Wong KS, Proulx K, Rost MS, Sumanas S. Identification of vasculature-specific genes by microarray analysis of Etsrp/Etv2 overexpressing zebrafish embryos. Dev Dyn. 2009 Jul;238(7):1836-50


Rasi S, Bruscaggin A, Gaidano G. MRC1 (mannose receptor, C type 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1016-1019.

Gene Section Review




MUC13 (mucin 13, cell surface associated) Diane Maher, Brij Gupta, Mara Ebeling, Satoshi Nagata, Meena Jaggi, Subhash C Chauhan

Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, SD 57105, USA (DM, BG, ME, SN, MJ, SCC); Department of OB/GYN, and Basic Biomedical Science Division, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA (MJ, SCC)


Online updated version : http://AtlasGeneticsOncology.org/Genes/MUC13ID41454ch3q21.html

DOI: 10.4267/2042/44884


Identity Other names: DRCC1; FLJ20063; MUC-13; RECC

HGNC (Hugo): MUC13

Location: 3q21.2

Note: MUC13 is a membrane bound mucin exhibiting abundant O- and N-glycosylation. The aberrant expression and localization of MUC13 may be involved in cancer pathobiology and could be a potential diagnostic/prognostic biomarker of cancer as well as a target for antibody guided therapy for cancer treatment.

DNA/RNA Description Human MUC13 was originally identified as a ortholog of the previously identified murine MUC13 (Williams et al., 2001). Based on fluorescence in situ hybridization, MUC13 was originally identified at location 3q13.3 (Williams et al., 2001); however, MUC13 is now reported to be located on chromosome 3; location 3q21.2, MUC13 is flanked by ITGB5 (beta 5 integrin) and HEG-1 (Heart of Glass), each transcribed from the reverse strand.

Schematic diagram of the genomic MUC13 DNA (including neighboring genes) and the transcript of MUC13. MUC13 is located on chromosome 3 between ITGB5 and HEG-1. These 3 genes are transcribed from the reverse strand. The MUC13 transcript contains 12 exons and the final mRNA consists of 2,876 base pairs (Figure modified from Ensembl).

MUC13 (mucin 13, cell surface associated) Maher D, et al.


Interestingly, HEG and MUC13 share some molecular features, suggesting they may be evolutionarily related (Lang et al., 2006).

Transcription The predominate MUC13 transcript (exact match between Ensembl and Havana) contains 12 exons and encodes 511 amino acids. Splice variants have been detected and may alter the length of the tandem repeat domain (Lang et al., 2006); however they have not been well studied for MUC13.

Protein Note Members of the mucin family are characterized by a hallmark feature: the presence of a tandem repeat domain, consisting of a protein backbone which acts as a scaffold for a large number of complex O-linked carbohydrate side chains (Williams et al., 2001). In general, mucins have important biological roles in the lubrication and protection of normal epithelial tissues. In normal tissue, mucins are expressed in a tissue type dependent manner; however, for many types of cancer, mucin expression becomes altered (down-regulated, up-regulated or newly expressed). The mucin's ectodomain may protrude more than 200-2000 nm above the cell surface and can effectively block cell-cell adhesion. Therefore, the over-expression of mucins may be implicated in the exfoliation, dissemination and

invasion of the cancer cells (Hollingsworth and Swanson, 2004).

Description MUC13 is a recently identified membrane bound mucin (Williams et al., 2001). At the N-terminus, a signal peptide shuttles the protein into the secretary pathway. The signal peptide is followed by a large serine-threonine rich tandem repeat domain (TD). Composed of 10 degenerate tandem repeats, the tandem repeat domain provides a scaffold on which cells build oligosaccharide structures. O-glycosylation with complex oligosaccharides is crucial to mucin structure and function. The central region of MUC13 contains three epidermal growth factor (EGF)-like domains (EGF1, EGF2 and EGF3), suggesting that MUC13 may play an important role in a signaling cascade. A sea urchin sperm protein enterokinase arginine (SEA) module is present between EGF1 and EGF2 like domains, providing a cleavage site which separates MUC13 into an extracellular a subunit and a transmembrane beta subunit. It is expected that the SEA domain is cleaved while in transport to the cell surface and that after cleavage, the alpha and beta subunits are covalently bound together. Adjacent to the EGF3-like domain is a short transmembrane domain (TM), followed by a 69 amino acid long cytoplasmic domain (CD) (Williams et al., 2001; Shimamura et al., 2005).

Schematic diagram and annotated amino acid sequence of MUC13. Left: a schematic diagram shows the structural features of MUC13, highlighting the signal peptide, mucin repeat domain, SEA module, EGF-like domains, transmembrane region and the cytoplasmic domain. Right: The annotated amino acid sequence shows the extensive post-translation modifications that MUC13 undergoes (O-glycosylation, N-glycosylation and predicted disulfide bonds). The signal peptide, SEA module and Transmembrane sequences are indicated by pink, red and green font, respectively.



Within the cytoplasmic domain of MUC13, there are several potential phosphorylation sites (8 serine and 2 tyrosine residues) and a protein kinase C consensus phosphorylation motif, further supporting the hypothesis that MUC13 may be involved in cell signaling pathways.

Expression Among normal tissues, MUC13 mRNA and/or protein has been detected in the large intestine, trachea, kidney, small intestine, gastric epithelium and esophagus (Williams et al., 2001). MUC13 is normally localized to the apical surface of epithelial cells lining the mucosal surface. In ovarian, gastric and colon cancers, MUC13 expression (determined by immunohistochemical analysis) is increased compared to expression levels of non-neoplastic tissues (Shimamura et al., 2005; Walsh et al., 2007; Chauhan et al., 2009).

Localisation MUC13 is a transmembrane glycoprotein present at the apical surface in normal cells. In cancer cells, MUC13 is over-expressed and aberrantly located in the cytoplasm and occasionally in the nucleus (Williams et al., 2001; Chauhan et al., unpublished data).

Function Under normal physiological conditions, mucins, including MUC13, protect the epithelial surface of mucosal surfaces (gastrointestinal tract, respiratory tract and reproductive tract). Mucins create a physical barrier from the extracellular environment and protect epithelial tissues from noxious and toxic substances. When aberrantly expressed, MUC13 has oncogenic functions which are described below.

Homology MUC13 is known to have orthologs in mice, rats, chickens, dogs, cows, chimpanzees and even fish (Williams et al., 2001; Lang et al., 2006; NCBI: homologene). Additional putative orthologs are likely in a variety of different species and can be viewed via Ensembl.

Mutations Note While a variety of Single Nucleotide Polymorphisms (SNPs) have been identified, the clinical significance has not yet been determined (NCBI: SNPs).

Implicated in Ovarian cancer Disease Ovarian cancer is the most lethal gynecological cancer and the fifth most common cause of cancer mortality in women in the United States (Jemal et al., 2009). In 2009, it is estimated that 21550 women will be

diagnosed with ovarian cancer and 14600 women will die due to this disease (Jemal et al., 2009). A high percent of women with ovarian cancer are diagnosed at an advanced stage (67%) and have a 5 year survival rate of only 46% (Jemal et al., 2009).

Oncogenesis In a recently published report, we analyzed the expression profile and functions of MUC13 to elucidate its potential role in ovarian cancer diagnosis and pathogenesis. We determined the expression profile of MUC13 by immunohistochemistry, using ovarian cancer tissue microarrays and 56 additional epithelial ovarian cancer (EOC) samples. The expression of MUC13 was significantly (p<0.005) higher in cancer samples compared to the normal ovary/benign tissues. Among all ovarian cancer types, MUC13 expression was highest in EOC. Exogenous expression of full length MUC13 induced morphological changes, including scattering of cells, marked reduction in cell-cell adhesion and significant (p<0.05) increases in cell motility and proliferation. Additionally, we observed increased tumorigenesis in a xenograft mouse model system. These cellular characteristics were correlated with up-regulation of HER2, p21-activated kinase1 (PAK1) and p38 protein expression. These changes were abrogated through c-jun NH2-terminal kinase (JNK) chemical inhibitor (SP600125) or JNK2 siRNA. Our findings demonstrate the aberrant expression of MUC13 in ovarian cancer and show that its expression alters the cellular characteristics of SKOV-3 cells. This implies a significant role of MUC13 in ovarian cancer.

Colon cancer Disease Colon cancer is the third leading cause of cancer related deaths among men and women worldwide, with an estimated 639000 deaths in 2004 (WHO, 2009). In the United States in 2009, approximately 106000 people were diagnosed with colon cancer and 49900 people died, making colon cancer the second leading cause of deaths among all cancers (Jemal et al., 2009). Colon cancer has an overall survival rate of 49%, which is drastically dependent on the stage of diagnosis (Jemal, et al., 2009). For example, if colon cancer is detected in an early stage, prior to metastasis, survival is 90%; however, if colon cancer is not treated until an advanced stage (with metastasis to distant organs), survival decreases to approximately 10% (Jemal et al., 2009).

Oncogenesis Walsh et al studied the expression of MUC13 in various stages of colon cancer (99 samples) (Walsh et al., 2007). Using immunohistochemical analysis, MUC13 was detected predominantly on the apical surface, with some cytoplasmic staining, of glands in normal colon. Scoring of the normal tissue was not done for this study, so it is difficult to state a comparison of MUC13 staining between normal and



cancer cells. However, MUC13 was highly expressed in most of the colon tumors, with 81% of well differentiated adenocarcinomas exhibiting strong MUC13 staining. Interestingly, although the significance is not yet known, this study also found that tumors originating from the left side of the patient's body had a higher proportion of MUC13-positive cancer cells. Mucinous tumors expressed MUC13, but at a lower staining intensity (50% indicating strong staining) compared to adenocarcinomas. While MUC13 was most intense on the apical surface, it was also detected in the cytoplasm. Basolateral staining was detected in 24% of the cases, most frequently in poorly differentiated tumors (55% of poorly differentiated tumors showed basolateral staining). Although not statistically significant, there was a trend toward poorer survival in patients with tumors showing basolateral MUC13 expression. Taken together, these observations suggest aberrant expression of MUC13 may affect colon cancer pathogenesis. In contrast to these results, Packer et al reported that the RNA level of MUC13 was decreased in colon cancer; however this was a small study with only 23 samples of colon cancer and 6 normal colon tissues (Packer et al., 2004). In our own studies, we have observed the over-expression of MUC13 in colon and pancreatic cancer compared to normal colon and pancreas (unpublished data). Taken together, these data suggest that MUC13 may be a potential diagnostic/prognostic biomarker for colon, pancreatic and ovarian cancers. Additionally, due to its cell surface expression, MUC13 may be a suitable target for antibody guided therapy for cancer treatment.

Gastric cancer Disease Gastric cancer is the second most common cause of cancer related deaths worldwide, accounting for approximately 803000 deaths each year (WHO, 2009). In the United States, 21130 people were diagnosed with gastric cancer and 10620 died due to gastric cancer (Jemal et al., 2009). When diagnosed with localized gastric cancer, the survival rate is approximately 60%; however, if gastric cancer has metastasized to distant sites, the survival rate is very low (4%) (Jemal et al., 2009).

Oncogenesis Shimamura et al detected an increased expression of MUC13 at both mRNA and protein levels (Shimamura et al., 2005). In normal tissue, MUC13 protein was detected at the luminal surface of crypts in both the small and large intestines, but not in normal gastric

tissues. However, MUC13 staining in gastric cancer tissue was positive in 64.9% of cases and the cellular localization of MUC13 was dependent upon the histological type of gastric cancer. MUC13 was also detected in 9 out of 10 cases of intestinal metaplasia (precancerous lesions of intestinal type gastric cancer). When correlated with clinicopathological factors, MUC13 expression only correlated significantly with intestinal types of gastric cancer. MUC13 expression did not correlate with the expression of other mucins (MUC2, MUC5AC, MUC6 and CD10), suggesting that MUC13 may be regulated in a different manner then other mucins markers for gastric cancer (Shimamura et al., 2005).

References Williams SJ, Wreschner DH, Tran M, Eyre HJ, Sutherland GR, McGuckin MA. Muc13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells. J Biol Chem. 2001 May 25;276(21):18327-36

Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004 Jan;4(1):45-60

Packer LM, Williams SJ, Callaghan S, Gotley DC, McGuckin MA. Expression of the cell surface mucin gene family in adenocarcinomas. Int J Oncol. 2004 Oct;25(4):1119-26

Shimamura T, Ito H, Shibahara J, Watanabe A, Hippo Y, Taniguchi H, Chen Y, Kashima T, Ohtomo T, Tanioka F, Iwanari H, Kodama T, Kazui T, Sugimura H, Fukayama M, Aburatani H. Overexpression of MUC13 is associated with intestinal-type gastric cancer. Cancer Sci. 2005 May;96(5):265-73

Lang T, Hansson GC, Samuelsson T. An inventory of mucin genes in the chicken genome shows that the mucin domain of Muc13 is encoded by multiple exons and that ovomucin is part of a locus of related gel-forming mucins. BMC Genomics. 2006 Aug 3;7:197

Walsh MD, Young JP, Leggett BA, Williams SH, Jass JR, McGuckin MA. The MUC13 cell surface mucin is highly expressed by human colorectal carcinomas. Hum Pathol. 2007 Jun;38(6):883-92

Chauhan SC, Vannatta K, Ebeling MC, Vinayek N, Watanabe A, Pandey KK, Bell MC, Koch MD, Aburatani H, Lio Y, Jaggi M. Expression and functions of transmembrane mucin MUC13 in ovarian cancer. Cancer Res. 2009 Feb 1;69(3):765-74

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49


Maher D, Gupta B, Ebeling M, Nagata S, Jaggi M, Chauhan SC. MUC13 (mucin 13, cell surface associated). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1020-1023.





OLFM4 (olfactomedin 4) Wenli Liu, Griffin P Rodgers

Molecular and Clinical Hematology Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9N115, 10 Center Drive, Bethesda, MD 20892, USA (WL, GPR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/OLFM4ID49730ch13q14.html DOI: 10.4267/2042/44885


Identity Other names: bA209J19.1; GC1; GW112; hGC-1; hOLfD; KIAA4294; OlfD; OLM4; UNQ362

HGNC (Hugo): OLFM4

Location: 13q14.3

Note: OLFM4 is a member of olfactomedin-related protein family. This gene was originally cloned from human myeloblasts and constitutively expressed in normal bone marrow, stomach, small intestine, colon, prostate and pancreas.

DNA/RNA Description OLFM4 gene locus was mapped to chromosome 13q14.3 with five exons spanning 23220 bp.

Transcription OLFM4 is transcribed to 2861 bp mRNA with an open

reading frame of 1530 nucleotides. There is no alternative mRNA splicing. mRNA expression: highly in bone marrow and small intestine; lowly expressed in stomach, colon, pancreas and prostate; no expression is detected in other tissues determined by Northern blot. OLFM4 transcription is regulated by transcription factors, PU1 and NF-kB.

Protein Description OLFM4 encodes a 510 amino acid protein with a molecular weight of 55 kD. OLFM4 has a signal peptide and six N-linked glycosylation motifs and forms disulfide-bonded multimers. It has an N-terminal coil-coil domain and C-terminal olfactomedin domain.

Expression OLFM4 protein is endogenously expressed in mature neutrophils and gastric and intestinal epithelial cells.

OLFM4 (olfactomedin 4) Liu W, Rodgers GP


Its expression in bone marrow neutrophils is significantly higher than peripheral blood neutrophils. OLFM4 is more abundantly expressed in intestinal crypts than in surface epithelial cells.

Localisation OLFM4 is localized in multiple subcellular compartments including cytoplasm, mitochondria and membrane. It is also secreted extracellularly.

Function OLFM4 binds to cadherins and lectins and mediates cell adhesion. OLFM4 is a robust marker for stem cells in human intestine.

Homology Human OLFM4 is highly homologous to its mouse homologue (pDP4) with 93% amino acid identity. OLFM4 C-terminal olfactomedin domain has significant homology with other olfactomedin-related proteins including olfactomedin, TIGR, Noelin-1, Noeline-2 and latrophilin-1, etc.

Mutations Note No known genetic mutation in normal or cancer tissues.

Implicated in Stomach cancer Note OLFM4 mRNA expression is upregulated in gastric cancer patients. OLFM4 protein staining by immunohistochemistry was observed more frequently in well-differentiated cancer tissues and more frequently in stage I/II cases than in stage III/IV cases. Serum OLFM4 is a useful marker for gastric cancer patients.

Colon cancer Note OLFM4 mRNA is upregulated in colon cancer patients. OLFM4 protein expression is correlated with prognosis for colon cancer patients. Lower or lost OLFM4 protein expression is correlated with more malignancy and poor survival.

Prostate cancer Note OLFM4 mRNA expression is upregulated in prostate cancer patients. OLFM4 interacts with GRIM-19, a mitochondria pro-apoptosis protein and has an anti-apoptotic function in prostate cancer cells when it is overexpressed.

Pancreatic cancer Note OLFM4 mRNA is upregulated in pancreatic cancer patients. OLFM4 promotes S-phase transition in proliferation of pancreatic cancer cells.

Breast cancer Note OLFM4 mRNA is upregulated in breast cancer patients.

Chronic bowel disease (Crohn's disease and ulcerative colitis) Note OLFM4 mRNA expression is upregulated in the intestines of chronic bowel disease patients including Crohn's disease and ulcerative colitis.

H. pylori gastritis Note OLFM4 mRNA expression is upregulated in the gastric mucosa of H. pylori infected patients than normal individuals.

References Shinozaki S, Nakamura T, Iimura M, Kato Y, Iizuka B, Kobayashi M, Hayashi N. Upregulation of Reg 1alpha and GW112 in the epithelium of inflamed colonic mucosa. Gut. 2001 May;48(5):623-9

Zhang J, Liu WL, Tang DC, Chen L, Wang M, Pack SD, Zhuang Z, Rodgers GP. Identification and characterization of a novel member of olfactomedin-related protein family, hGC-1, expressed during myeloid lineage development. Gene. 2002 Jan 23;283(1-2):83-93

Rosenbauer F, Wagner K, Zhang P, Knobeloch KP, Iwama A, Tenen DG. pDP4, a novel glycoprotein secreted by mature granulocytes, is regulated by transcription factor PU.1. Blood. 2004 Jun 1;103(11):4294-301

OLFM4 (olfactomedin 4) Liu W, Rodgers GP


Zhang X, Huang Q, Yang Z, Li Y, Li CY. GW112, a novel antiapoptotic protein that promotes tumor growth. Cancer Res. 2004 Apr 1;64(7):2474-81

Oue N, Aung PP, Mitani Y, Kuniyasu H, Nakayama H, Yasui W. Genes involved in invasion and metastasis of gastric cancer identified by array-based hybridization and serial analysis of gene expression. Oncology. 2005;69 Suppl 1:17-22

Yasui W, Oue N, Aung PP, Matsumura S, Shutoh M, Nakayama H. Molecular-pathological prognostic factors of gastric cancer: a review. Gastric Cancer. 2005;8(2):86-94

Aung PP, Oue N, Mitani Y, Nakayama H, Yoshida K, Noguchi T, Bosserhoff AK, Yasui W. Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metalloproteinase-10 are novel prognostic factors in patients with gastric cancer. Oncogene. 2006 Apr 20;25(17):2546-57

Liu W, Chen L, Zhu J, Rodgers GP. The glycoprotein hGC-1 binds to cadherin and lectins. Exp Cell Res. 2006 Jun 10;312(10):1785-97

Kobayashi D, Koshida S, Moriai R, Tsuji N, Watanabe N. Olfactomedin 4 promotes S-phase transition in proliferation of pancreatic cancer cells. Cancer Sci. 2007 Mar;98(3):334-40

Koshida S, Kobayashi D, Moriai R, Tsuji N, Watanabe N. Specific overexpression of OLFM4(GW112/HGC-1) mRNA in colon, breast and lung cancer tissues detected using quantitative analysis. Cancer Sci. 2007 Mar;98(3):315-20

Liu W, Zhu J, Cao L, Rodgers GP. Expression of hGC-1 is correlated with differentiation of gastric carcinoma. Histopathology. 2007 Aug;51(2):157-65

Chin KL, Aerbajinai W, Zhu J, Drew L, Chen L, Liu W, Rodgers GP. The regulation of OLFM4 expression in myeloid precursor cells relies on NF-kappaB transcription factor. Br J Haematol. 2008 Nov;143(3):421-32

Conrotto P, Roesli C, Rybak J, Kischel P, Waltregny D, Neri D, Castronovo V. Identification of new accessible tumor antigens in human colon cancer by ex vivo protein biotinylation and comparative mass spectrometry analysis. Int J Cancer. 2008 Dec 15;123(12):2856-64

Liu W, Liu Y, Zhu J, Wright E, Ding I, Rodgers GP. Reduced hGC-1 protein expression is associated with malignant progression of colon carcinoma. Clin Cancer Res. 2008 Feb 15;14(4):1041-9

Oue N, Sentani K, Noguchi T, Ohara S, Sakamoto N, Hayashi T, Anami K, Motoshita J, Ito M, Tanaka S, Yoshida K, Yasui W. Serum olfactomedin 4 (GW112, hGC-1) in combination with Reg IV is a highly sensitive biomarker for gastric cancer patients. Int J Cancer. 2009 Nov 15;125(10):2383-92

van der Flier LG, Haegebarth A, Stange DE, van de Wetering M, Clevers H. OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology. 2009 Jul;137(1):15-7


Liu W, Rodgers GP. OLFM4 (olfactomedin 4). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1024-1026.

Gene Section Review




PDE11A (phosphodiesterase 11A) Rossella Libé, Jérôme Bertherat

INSERM U567, CNRS 8104, Institut Cochin, Service de Maladies Endocriniennes et Metabolique, Hopital Cochin, Paris, France (RL, JB)


Online updated version: http://AtlasGeneticsOncology.org/Genes/PDE11AID44448ch2q31.html DOI: 10.4267/2042/44886


Identity Other names: FLJ23693; MGC133355; MGC133356; PDE11A1; PDE11A2; PDE11A3; PPNAD2

HGNC (Hugo): PDE11A

Location: 2q31.2

DNA/RNA Description PDE11A is the most recently discovered PDE enzyme family. In this family, only one gene, PDE11A, has been identified. It is a dual phosphodiesterase that hydrolyzes both cAMP and cGMP.

Transcription Four different isoforms of PDE11A (PDE11A1→A4) have been identified. The longest variant, PDE11A4 is composed of 20 coding exons of varying length, separated by introns, giving the gene a total length of 4441 bps.

Protein Description PDE11A4 is a protein of 104 kDa: it contains two N-terminal GAF domains (between exons 3-12) and one C-terminal catalytic domain (between exons 14-22).

Expression Isoform 1 is present in prostate, pituitary, heart, liver and skeletal muscle. Isoform 2 and 3 are expressed in the testis. Isoform 4 is the only isoform of the enzyme expressed in the adrenal cortex, where it is expressed substantially less than in the prostate.

Localisation Cytoplasm > cytosol.

Function PDE11A enzymes catalyze the hydrolysis of both cAMP and cGMP to 5'-AMP and 5'-GMP, respectively. This takes part in the down-regulation of the cAMP and cGMP signaling.

PDE11A (phosphodiesterase 11A) Libé R, Bertherat J


Inactive mutations of the isoform PDE11A4 gene have been identified in patients with adrenal Cushing syndrome due to micronodular adrenocortical hyperplasia. An association of PDE11A4 variants and other neoplasms is suggested since a higher frequency of PDE11A4 missense mutations is observed in patients with macronodular adrenal hyperplasia and testicular tumors than in the controls.

Homology The catalytic domain is conserved among the 4 isoforms of PDE11A. A high sequence similarity of 42-51% is found within the amino acid sequences of the catalytic regions of PDEs containing a Gaf sequence (i.e. PDE2A, PDE5A, PDE6B, PDE6C, PDE10A and PDE11A). Gene conserved among species: Pan troglodytes: 98.6%; Canis lupus familiaris: 96.4%; Bos taurus: 95.9%; Mus musculus: 94.6%; Rattus norvegicus: 94.5%; Gallus gallus: 90%; Danio rerio: 90%.

Mutations Germinal Non sense. Three PDE11A nonsense mutations leading to a premature stop codon were identified in 3 kindreds with adrenal Cushing syndrome due to micronodular adrenocortical hyperplasia. Other missense mutations (genetic variants) are described in adrenocortical tumor, as macronodular adrenal hyperplasia (AIMAH), adrenocortical adenoma (ACA), adrenocortical carcinoma (ACC) and testicular tumors.

Somatic Loss of heterozygosity with loss of wild type allele has been reported in adrenocortical tumor (benign and malignant) with PDE11A4 missense mutations.

Implicated in Adrenal Cushing syndrome due to micronodular adrenocortical hyperplasia

Disease ACTH-independant chronic oversecretion of cortisol due to bilateral adrenal involvement. Pathological examination demonstrates diffuse micronodular hyperaplasia of the cortex of both adrenal. These nodules can be pigmented as observed in primary pigmented nodular adrenocortical disease (PPNAD).

Prognosis Morbidity and mortality of non treated Cushing syndrome is high. However after treatment (bilateral adrenalectomy in most cases) there is a clear improvement and the overall prognosis is good, the main side effect of the treatment being adrenal deficiency.

Oncogenesis In the patients with non-sense mutations a loss of the wild type allele was demonstrated in the adrenal nodes, supporting the hypothesis that PDE11A4 is a tumor suppressor gene.

ACTH-independent macronodular adrenal hyperplasia (AIMAH) Disease AIMAH is a rare form of benign bilateral adrenocortical tumor. It can be associated to an overt Cushing's syndrome (CS). Nowadays, the most frequent clinical presentation is that of bilateral adrenal incidentalomas. The initial endocrine evaluation usually demonstrates subtle abnormalities of cortisol secretion, suggesting a subclinical CS.

Prognosis Morbidity and mortality of non treated Cushing syndrome is high. However after treatment (bilateral adrenalectomy in most cases) there is a clear improvement and the overall prognosis is good, the main side effect of the treatment being adrenal deficiency.

Cytogenetics A higher frequency of missense PDE11A mutations (genetic variants) than in healthy subjects is found.

Oncogenesis The higher frequency of PDE11A missense mutations suggests a role of PDE11A in the genetic predisposition to adrenal tumors.



Non-sense mutations (yellow) and missense mutations (green) described in adrenocortical tumor (PPNAD, AIMAH, ACA and ACC).

Testicular germ cells tumors (TGCT) Disease It is the most common malignancy in Caucasian men aged from 15 to 45 years old. A genetic basis for TGCT is supported by familial clustering, younger-than-usual age at diagnosis, and an increased risk of bilateral disease.

Prognosis More than 90% of patients with newly diagnosed TGCT are cured, and delay in diagnosis correlates with a higher stage at presentation for treatment.

Cytogenetics Recently, PDE11A missense mutations (genetic variants) have been reported in TGCT. The frequency was significantly higher in patients with TGCT than in healthy subjects.

Oncogenesis PDE11A variants are involved in the testicular tumorigenesis and may modify the risk of familial and bilateral TGCT.

Adrenocortical carcinoma (ACC) Disease ACC is a rare malignant tumor, with an estimated prevalence between 4 and 12 per million in adults.

Prognosis The overall survival varies according to tumor stage. However the overall survival is poor and below 30% at 5 years in most series.

Cytogenetics A higher frequency of a polymorphism in exon 6 (E421E) and of three associated polymorphisms located in intron 10-exon 11-intron 11 is found in ACCs than in healthy subjects. Oncogenesis The synonymous E421E variant and the intron 10/intron 11 variants could play a role in the predisposition to ACC development.

References Fawcett L, Baxendale R, Stacey P, McGrouther C, Harrow I, Soderling S, Hetman J, Beavo JA, Phillips SC. Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3702-7

Hetman JM, Robas N, Baxendale R, Fidock M, Phillips SC, Soderling SH, Beavo JA. Cloning and characterization of two splice variants of human phosphodiesterase 11A. Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12891-5

Yuasa K, Kotera J, Fujishige K, Michibata H, Sasaki T, Omori K. Isolation and characterization of two novel phosphodiesterase PDE11A variants showing unique structure and tissue-specific expression. J Biol Chem. 2000 Oct 6;275(40):31469-79

Yuasa K, Kanoh Y, Okumura K, Omori K. Genomic organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF domains. Eur J Biochem. 2001 Jan;268(1):168-78

Yuasa K, Ohgaru T, Asahina M, Omori K. Identification of rat cyclic nucleotide phosphodiesterase 11A (PDE11A): comparison of rat and human PDE11A splicing variants. Eur J Biochem. 2001 Aug;268(16):4440-8

Zoraghi R, Kunz S, Gong K, Seebeck T. Characterization of TbPDE2A, a novel cyclic nucleotide-specific phosphodiesterase from the protozoan parasite Trypanosoma brucei. J Biol Chem. 2001 Apr 13;276(15):11559-66

Ahlström M, Pekkinen M, Huttunen M, Lamberg-Allardt C. Dexamethasone down-regulates cAMP-phosphodiesterase in human osteosarcoma cells. Biochem Pharmacol. 2005 Jan 15;69(2):267-75

D'Andrea MR, Qiu Y, Haynes-Johnson D, Bhattacharjee S, Kraft P, Lundeen S. Expression of PDE11A in normal and malignant human tissues. J Histochem Cytochem. 2005 Jul;53(7):895-903

Francis SH. Phosphodiesterase 11 (PDE11): is it a player in human testicular function? Int J Impot Res. 2005 Sep-Oct;17(5):467-8

Loughney K, Taylor J, Florio VA. 3',5'-cyclic nucleotide phosphodiesterase 11A: localization in human tissues. Int J Impot Res. 2005 Jul-Aug;17(4):320-5



Pomara G, Morelli G. Inhibition of phosphodiesterase 11 (PDE11) impacts on sperm quality. Int J Impot Res. 2005 Jul-Aug;17(4):385-6; author reply 387

Seftel AD. 3',5'-Cyclic nucleotide phosphodiesterase 11A: localization in human tissues. J Urol. 2005 Sep;174(3):1044

Seftel AD. Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology. J Urol. 2005 Sep;174(3):1043-4

Wayman C, Phillips S, Lunny C, Webb T, Fawcett L, Baxendale R, Burgess G. Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology. Int J Impot Res. 2005 May-Jun;17(3):216-23

Weeks JL, Zoraghi R, Beasley A, Sekhar KR, Francis SH, Corbin JD. High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients. Int J Impot Res. 2005 Jan-Feb;17(1):5-9

Cazabat L, Ragazzon B, Groussin L, Bertherat J. PRKAR1A mutations in primary pigmented nodular adrenocortical disease. Pituitary. 2006;9(3):211-9

Gross-Langenhoff M, Hofbauer K, Weber J, Schultz A, Schultz JE. cAMP is a ligand for the tandem GAF domain of human phosphodiesterase 10 and cGMP for the tandem GAF domain of phosphodiesterase 11. J Biol Chem. 2006 Feb 3;281(5):2841-6

Horvath A, Boikos S, Giatzakis C, Robinson-White A, Groussin L, Griffin KJ, Stein E, Levine E, Delimpasi G, Hsiao HP, Keil M, Heyerdahl S, Matyakhina L, Libè R, Fratticci A, Kirschner LS, Cramer K, Gaillard RC, Bertagna X, Carney JA, Bertherat J, Bossis I, Stratakis CA. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet. 2006 Jul;38(7):794-800

Horvath A, Giatzakis C, Robinson-White A, Boikos S, Levine E, Griffin K, Stein E, Kamvissi V, Soni P, Bossis I, de Herder W, Carney JA, Bertherat J, Gregersen PK, Remmers EF, Stratakis CA. Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population. Cancer Res. 2006 Dec 15;66(24):11571-5

Wong ML, Whelan F, Deloukas P, Whittaker P, Delgado M, Cantor RM, McCann SM, Licinio J. Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response. Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15124-9

Horvath A, Stratakis C. Primary pigmented nodular adrenocortical disease and Cushing's syndrome. Arq Bras Endocrinol Metabol. 2007 Nov;51(8):1238-44

Pomara G, Morelli G, Canale D, Turchi P, Caglieresi C, Moschini C, Liguori G, Selli C, Macchia E, Martino E, Francesca F. Alterations in sperm motility after acute oral administration of sildenafil or tadalafil in young, infertile men. Fertil Steril. 2007 Oct;88(4):860-5

Stratakis CA. Adrenocortical tumors, primary pigmented adrenocortical disease (PPNAD)/Carney complex, and other bilateral hyperplasias: the NIH studies. Horm Metab Res. 2007 Jun;39(6):467-73

Teranishi KS, Slager SL, Garriock H, Kraft JB, Peters EJ, Reinalda MS, Jenkins GD, McGrath PJ, Hamilton SP. Variants in PDE11A and PDE1A are not associated with citalopram response. Mol Psychiatry. 2007 Dec;12(12):1061-3

Weeks JL 2nd, Zoraghi R, Francis SH, Corbin JD. N-Terminal domain of phosphodiesterase-11A4 (PDE11A4) decreases affinity of the catalytic site for substrates and tadalafil, and is

involved in oligomerization. Biochemistry. 2007 Sep 11;46(36):10353-64

Boikos SA, Horvath A, Heyerdahl S, Stein E, Robinson-White A, Bossis I, Bertherat J, Carney JA, Stratakis CA. Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other corticotropin-independent lesions. Horm Metab Res. 2008 May;40(5):347-53

Gross-Langenhoff M, Stenzl A, Altenberend F, Schultz A, Schultz JE. The properties of phosphodiesterase 11A4 GAF domains are regulated by modifications in its N-terminal domain. FEBS J. 2008 Apr;275(8):1643-50

Horvath A, Giatzakis C, Tsang K, Greene E, Osorio P, Boikos S, Libè R, Patronas Y, Robinson-White A, Remmers E, Bertherat J, Nesterova M, Stratakis CA. A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex. Eur J Hum Genet. 2008 Oct;16(10):1245-53

Horvath A, Stratakis CA. Unraveling the molecular basis of micronodular adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2008 Jun;15(3):227-33

Libé R, Fratticci A, Coste J, Tissier F, Horvath A, Ragazzon B, Rene-Corail F, Groussin L, Bertagna X, Raffin-Sanson ML, Stratakis CA, Bertherat J. Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors. Clin Cancer Res. 2008 Jun 15;14(12):4016-24

Tadjine M, Lampron A, Ouadi L, Horvath A, Stratakis CA, Bourdeau I. Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease (PPNAD). Clin Endocrinol (Oxf). 2008 Sep;69(3):367-73

Tissier F. [Sporadic adrenocortical tumors: genetics and perspectives for the pathologist]. Ann Pathol. 2008 Oct;28(5):409-16

Waddleton D, Wu W, Feng Y, Thompson C, Wu M, Zhou YP, Howard A, Thornberry N, Li J, Mancini JA. Phosphodiesterase 3 and 4 comprise the major cAMP metabolizing enzymes responsible for insulin secretion in INS-1 (832/13) cells and rat islets. Biochem Pharmacol. 2008 Oct 1;76(7):884-93

Alevizaki M, Stratakis CA. Multiple endocrine neoplasias: advances and challenges for the future. J Intern Med. 2009 Jul;266(1):1-4

Bimpaki EI, Nesterova M, Stratakis CA. Abnormalities of cAMP signaling are present in adrenocortical lesions associated with ACTH-independent Cushing syndrome despite the absence of mutations in known genes. Eur J Endocrinol. 2009 Jul;161(1):153-61

Cabanero M, Laje G, Detera-Wadleigh S, McMahon FJ. Association study of phosphodiesterase genes in the Sequenced Treatment Alternatives to Relieve Depression sample. Pharmacogenet Genomics. 2009 Mar;19(3):235-8

Horvath A, Korde L, Greene MH, Libe R, Osorio P, Faucz FR, Raffin-Sanson ML, Tsang KM, Drori-Herishanu L, Patronas Y, Remmers EF, Nikita ME, Moran J, Greene J, Nesterova M, Merino M, Bertherat J, Stratakis CA. Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors. Cancer Res. 2009 Jul 1;69(13):5301-6

Hsiao HP, Kirschner LS, Bourdeau I, Keil MF, Boikos SA, Verma S, Robinson-White AJ, Nesterova M, Lacroix A, Stratakis CA. Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropin-independent macronodular adrenal hyperplasia compared with other adrenocortical tumors. J Clin Endocrinol Metab. 2009 Aug;94(8):2930-7



Kruse LS, Møller M, Tibaek M, Gammeltoft S, Olesen J, Kruuse C. PDE9A, PDE10A, and PDE11A expression in rat trigeminovascular pain signalling system. Brain Res. 2009 Jul 24;1281:25-34

Laje G, Perlis RH, Rush AJ, McMahon FJ. Pharmacogenetics studies in STAR*D: strengths, limitations, and results. Psychiatr Serv. 2009 Nov;60(11):1446-57

Luo HR, Wu GS, Dong C, Arcos-Burgos M, Ribeiro L, Licinio J, Wong ML. Association of PDE11A global haplotype with major depression and antidepressant drug response. Neuropsychiatr Dis Treat. 2009;5:163-70

Matthiesen K, Nielsen J. Binding of cyclic nucleotides to phosphodiesterase 10A and 11A GAF domains does not stimulate catalytic activity. Biochem J. 2009 Oct 12;423(3):401-9

Owen DR, Walker JK, Jon Jacobsen E, Freskos JN, Hughes RO, Brown DL, Bell AS, Brown DG, Phillips C, Mischke BV, Molyneaux JM, Fobian YM, Heasley SE, Moon JB, Stallings WC, Joseph Rogier D, Fox DN, Palmer MJ, Ringer T, Rodriquez-Lens M, Cubbage JW, Blevis-Bal RM, Benson AG, Acker BA, Maddux TM, Tollefson MB, Bond BR, Macinnes A, Yu Y. Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 inhibitors. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4088-91

Peverelli E, Ermetici F, Filopanti M, Elli FM, Ronchi CL, Mantovani G, Ferrero S, Bosari S, Beck-Peccoz P, Lania A,

Spada A. Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients. Eur J Endocrinol. 2009 Nov;161(5):687-94

Stratakis CA. New genes and/or molecular pathways associated with adrenal hyperplasias and related adrenocortical tumors. Mol Cell Endocrinol. 2009 Mar 5;300(1-2):152-7

Weeks JL 2nd, Corbin JD, Francis SH. Interactions between cyclic nucleotide phosphodiesterase 11 catalytic site and substrates or tadalafil and role of a critical Gln-869 hydrogen bond. J Pharmacol Exp Ther. 2009 Oct;331(1):133-41

Louiset E, Gobet F, Libé R, Horvath A, Renouf S, Cariou J, Rothenbuhler A, Bertherat J, Clauser E, Grise P, Stratakis CA, Kuhn JM, Lefebvre H. ACTH-independent Cushing's syndrome with bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma. J Clin Endocrinol Metab. 2010 Jan;95(1):18-24


Libé R, Bertherat J. PDE11A (phosphodiesterase 11A). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1027-1031.





PTPN7 (protein tyrosine phosphatase, non-receptor type 7) Marie Fridberg, Helena Tassidis, Anette Gjörloff Wingren

Department of Tumor Biology, Lund University, Malmo University Hospital, Malmo, Sweden (MF, HT); Department of Laboratory Science, Health and Society, Malmo University and Malmo University Hospital, Malmo, Sweden (AGW)


Online updated version : http://AtlasGeneticsOncology.org/Genes/PTPN7ID41921ch1q32.html DOI: 10.4267/2042/44887


Identity Other names: BPTP-4; HEPTP; LC-PTP; LPTP; PTPNI

HGNC (Hugo): PTPN7

Location: 1q32.1

DNA/RNA Description The premessenger has 10 exons and covers 14.59 kb on the genome.

Transcription The complete mRNA is 3784 bp long. 2 alternatively spliced transcript variants encoding different isoforms have been found, but it has also been reported that transcription produces 16 different mRNAs, 15 alternatively spliced variants and 1 unspliced form. Of the 2 described variants, variant 1 (2,805 bp linear mRNA) contains a different 5' region, which includes a part of the coding sequence when compared to variant 2. Variant 2 (3,263 bp linear mRNA) contains an alternate 5' region, which includes an additional in-frame translation start codon, as compared to variant 1. It thus encodes a protein that is 39 aa longer at the N-terminus.

Pseudogene No pseudogenes have been found.

Protein Description The hematopoietic protein tyrosine phosphatase (HePTP) protein is a 40,5 kDa protein of 360 amino acids. It is a class I non-receptor PTP that is strongly expressed in T cells. It is composed of a C-terminal classical PTP domain (residues 44-339) and a short N-terminal extension (residues 1-43) that functions to direct HePTP to its physiological substrates.

Expression Thymus, spleen, leukocytes.

Localisation Cytoplasmic.

Function Protein tyrosine phosphatase activity, hydrolase activity, phosphoric monoester hydrolase activity, receptor activity- participation in MAPK signaling pathways, T cell receptor signaling pathway and protein amino acid dephosphorylation. The protein can interact with tyrosine-phosphorylated MAPK1, MAPK3 and several other MAP kinases and suppress the MAP kinase activities. Plays a role in the regulation of T and B-lymphocyte development and signal transduction.

Homology HePTP has high homologies with striatal-enriched

PTPN7 (protein tyrosine phosphatase, non-receptor type 7) Fridberg M, et al.


phosphatase (STEP) and PCPTP (PC12 protein Tyr phosphatase).

Mutations Germinal No germline mutations are described.

Somatic Mutations have not been observed.

Implicated in Acute leukemia Disease Myelodysplastic syndrome and myelogenous leukemia; HePTP often is dysregulated in the preleukemic disorder myelodysplastic syndrome and myelogenous leukemia (elevated expression of HePTP). The first indication of a role of HePTP in cell proliferation or differentiation came from the finding that the HePTP gene is located on the long arm of chromosome 1, which is often found in extra copies (trisomy) in bone marrow cells from patients with myelodysplastic syndrome, which is characterized by reduced hematopoiesis and increased risk of acute leukemia.

Non-Hodgkin Lymphoma Disease Pediatric lymphoma; HePTP is down-regulated in pediatric lymphoma compared to control lymphoid cells. Loss of HePTP might indicate increased cell proliferation and/or survival of lymphoma cells.

References Zanke B, Suzuki H, Kishihara K, Mizzen L, Minden M, Pawson A, Mak TW. Cloning and expression of an inducible lymphoid-specific, protein tyrosine phosphatase (HePTPase). Eur J Immunol. 1992 Jan;22(1):235-9

Adachi M, Miyachi T, Sekiya M, Hinoda Y, Yachi A, Imai K. Structure of the human LC-PTP (HePTP) gene: similarity in genomic organization within protein-tyrosine phosphatase genes. Oncogene. 1994 Oct;9(10):3031-5

Zanke B, Squire J, Griesser H, Henry M, Suzuki H, Patterson B, Minden M, Mak TW. A hematopoietic protein tyrosine phosphatase (HePTP) gene that is amplified and overexpressed in myeloid malignancies maps to chromosome 1q32.1. Leukemia. 1994 Feb;8(2):236-44

Shiozuka K, Watanabe Y, Ikeda T, Hashimoto S, Kawashima H. Cloning and expression of PCPTP1 encoding protein tyrosine phosphatase. Gene. 1995 Sep 11;162(2):279-84

Saxena M, Williams S, Gilman J, Mustelin T. Negative regulation of T cell antigen receptor signal transduction by hematopoietic tyrosine phosphatase (HePTP). J Biol Chem. 1998 Jun 19;273(25):15340-4

Mustelin T, Brockdorff J, Rudbeck L, Gjörloff-Wingren A, Han S, Wang X, Tailor P, Saxena M. The next wave: protein tyrosine phosphatases enter T cell antigen receptor signalling. Cell Signal. 1999 Sep;11(9):637-50

Oh-hora M, Ogata M, Mori Y, Adachi M, Imai K, Kosugi A, Hamaoka T. Direct suppression of TCR-mediated activation of extracellular signal-regulated kinase by leukocyte protein tyrosine phosphatase, a tyrosine-specific phosphatase. J Immunol. 1999 Aug 1;163(3):1282-8

Saxena M, Williams S, Brockdorff J, Gilman J, Mustelin T. Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP). J Biol Chem. 1999 Apr 23;274(17):11693-700

Gjörloff-Wingren A, Saxena M, Han S, Wang X, Alonso A, Renedo M, Oh P, Williams S, Schnitzer J, Mustelin T. Subcellular localization of intracellular protein tyrosine phosphatases in T cells. Eur J Immunol. 2000 Aug;30(8):2412-21

Pettiford SM, Herbst R. The MAP-kinase ERK2 is a specific substrate of the protein tyrosine phosphatase HePTP. Oncogene. 2000 Feb 17;19(7):858-69

Mustelin T, Tautz L, Page R. Structure of the hematopoietic tyrosine phosphatase (HePTP) catalytic domain: structure of a KIM phosphatase with phosphate bound at the active site. J Mol Biol. 2005 Nov 18;354(1):150-63

Fridberg M, Kjellström S, Anagnostaki L, Skogvall I, Mustelin T, Wiebe T, Persson JL, Dictor M, Wingren AG. Immunohistochemical analyses of phosphatases in childhood B-cell lymphoma: lower expression of PTEN and HePTP and higher number of positive cells for nuclear SHP2 in B-cell lymphoma cases compared to controls. Pediatr Hematol Oncol. 2008 Sep;25(6):528-40


Fridberg M, Tassidis H, Gjörloff Wingren A. PTPN7 (protein tyrosine phosphatase, non-receptor type 7). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1032-1033.





RAP1GAP (RAP1 GTPase activating protein) Zixing Chen, Xuejun Shao

Jiangsu Institute of Hematology, 1st Affiliated Hospital, Soochow University, Suzhou 215006 JS, China (ZC, XS)


Online updated version : http://AtlasGeneticsOncology.org/Genes/RAP1GAPID42043ch1p36.html DOI: 10.4267/2042/44888


Identity Other names: RAPGAP; RAP1GA1; KIAA0474; RAP1GAP1; RAP1GAPII

HGNC (Hugo): RAP1GAP

Location: 1p36.12

Local order: From centromere to telomere: NBPF3, ALPL, RAP1GAP, USP48, HSPG2.

DNA/RNA Description 25 exons encompassing about 73 kb of genomic DNA.

Transcription About 3.334 kb mRNA, and has three transcript variant, RAP1 GTPase activating protein isoform a, b, c.

Protein Description 663 amino acids; homodimer and heterodimer with RAP1B.

Expression Significant expression seen in the brain, kidney and pancreas. Abundant in the cerebral cortex and expressed at much lower levels in the spinal cord. Not detected in the lymphoid tissues. (according to Swiss-Prot).

Localisation Golgi apparatus membrane; Peripheral membrane protein (according to Swiss-Prot).

Function GTPase activator for the nuclear Ras-related regulatory protein Rap1, converting it to the putatively inactive GDP-bound state (according to Swiss-Prot); Regulation of small GTPase-mediated signal transduction.

Homology The RAP1GAP gene is conserved in cow, mouse, rat, zebrafish, fruit fly, mosquito, and C. elegans.

Implicated in Solid tumors Disease Papillary thyroid cancer, pancreatic cancer, prostate cancer, melanoma tumors

Oncogenesis Rap1GAP, which acts as a GTPase activator for the nuclear Ras-related regulatory protein Rap1, was a specific negative regulator of Rap1, and the monomeric G protein Rap1 has been implicated in cancer tumorigenesis. It signals to pathways involved in cell adhesion, migration, and survival. Loss of Rap1GAP was discovered in papillary thyroid cancer, pancreatic cancer, prostate cancer, melanoma tumors, and their cell lines, all of them exhibited increased Rap1 activity, that activation of Rap1 promotes cell proliferation and migration potentiality through the mitogen-activated protein kinase pathway and integrin activation. As a putative tumor suppressor gene, Rap1GAP inhibits tumor growth but induces MMP2- and MMP9-mediated squamous cell carcinoma invasion and tumor progression, suggesting a role for this protein as a biomarker for early N-stage, aggressive squamous cell carcinomas.

RAP1GAP (RAP1 GTPase activating protein) Chen Z, Shao X


Myelodysplastic syndrome (MDS) Disease The expression level of Rap1GAP in MDS patients significantly increased as compared with patients with non-malignant blood diseases or acute myeloid leukemia (AML). Among MDS patients, the expression level of Rap1GAP in MDS-refractory anemia (RA) was significantly higher than that in MDS-refractory anemia with excess of blasts (RAEB). On the other hand, inhibiting Rap1 activity by expression of Rap1GAP increased leukocyte transendothelial migration, providing physiological relevance to the hypothesis that Rap1 augments barrier function of inter-endothelial cell junctions, implying the relevance of Rap1GAP in the regulation of haematogenesis.

References Wittchen ES, Worthylake RA, Kelly P, Casey PJ, Quilliam LA, Burridge K. Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function. J Biol Chem. 2005 Mar 25;280(12):11675-82

Zhang L, Chenwei L, Mahmood R, van Golen K, Greenson J, Li G, D'Silva NJ, Li X, Burant CF, Logsdon CD, Simeone DM. Identification of a putative tumor suppressor gene Rap1GAP in pancreatic cancer. Cancer Res. 2006 Jan 15;66(2):898-906

Zhang Z, Mitra RS, Henson BS, Datta NS, McCauley LK, Kumar P, Lee JS, Carey TE, D'Silva NJ. Rap1GAP inhibits tumor growth in oropharyngeal squamous cell carcinoma. Am J Pathol. 2006 Feb;168(2):585-96

Mitra RS, Goto M, Lee JS, Maldonado D, Taylor JM, Pan Q, Carey TE, Bradford CR, Prince ME, Cordell KG, Kirkwood KL, D'Silva NJ. Rap1GAP promotes invasion via induction of matrix metalloproteinase 9 secretion, which is associated with poor survival in low N-stage squamous cell carcinoma. Cancer Res. 2008 May 15;68(10):3959-69

Qi X, Chen Z, Qian J, Cen J, Gu M. Expression of Rap1GAP in human myeloid disease following microarray selection. Genet Mol Res. 2008 Apr 29;7(2):379-87

Bailey CL, Kelly P, Casey PJ. Activation of Rap1 promotes prostate cancer metastasis. Cancer Res. 2009 Jun 15;69(12):4962-8

Ika SA, Qi XF, Chen ZX. Protein RAP1GAP in human myelodysplastic syndrome detected by flow cytometry and its clinical relevance. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009 Jun;17(3):612-7

Nellore A, Paziana K, Ma C, Tsygankova OM, Wang Y, Puttaswamy K, Iqbal AU, Franks SR, Lv Y, Troxel AB, Feldman MD, Meinkoth JL, Brose MS. Loss of Rap1GAP in papillary thyroid cancer. J Clin Endocrinol Metab. 2009 Mar;94(3):1026-32

Zheng H, Gao L, Feng Y, Yuan L, Zhao H, Cornelius LA. Down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration. Cancer Res. 2009 Jan 15;69(2):449-57


Chen Z, Shao X. RAP1GAP (RAP1 GTPase activating protein). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1034-1035.

Gene Section Review




RGS2 (regulator of G-protein signaling 2, 24kDa) Chau H Nguyen

Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1, Canada (CHN)


Online updated version : http://AtlasGeneticsOncology.org/Genes/RGS2ID42102ch1q31.html DOI: 10.4267/2042/44889


Identity Other names: G0S8

HGNC (Hugo): RGS2

Location: 1q31.2

Note: RGS2 is a member of the RGS protein family of GTPase accelerating proteins (GAPs) for heterotrimeric G proteins. It is classified into the B/R4 subfamily.

DNA/RNA Description The gene spans 3,233 bases.

Transcription 6 alternatively spliced mRNA variants have been reported; 1 unspliced form. The best characterized mRNA variant is 1355bp long arising from 5 exons: 32bp 5' UTR, 636bp coding sequence, 687 bp 3' UTR.

Protein

MTS = Membrane Targeting Sequence (residues 33-53). RGS = Regulator of G protein Signaling Domain (residues 80-205).

Description Primary protein product is a 211 amino acid hydrophilic, basic protein (pI 9.6) with a calculated molecular weight of 24.4 kD (Siderovski et al., 1994). Possibly three additional functional proteins arising from alternative translation initiation of AUG codons corresponding to amino acid residues 5, 16, and 33 of full-length protein (Gu et al., 2008). RGS2 can be phosphorylated by PKC and PKGIalpha (Cunningham et al., 2001; Tang et al., 2003).

Expression RGS2 is ubiquitously expressed and its mRNA is found at medium to high levels in brain, heart, lung, kidney, intestine, lymphocytes, placenta, and testis (Larminie et al., 2004). RGS2 expression (mRNA and protein) can be upregulated in response to Gs- and Gq-mediated signals (Song et al., 1999; Miles et al., 2000; Roy et al., 2006b; Zou et al., 2006), as well as a variety of stressful stimuli including heat shock (Zmijewski et al., 2001), oxidative stress (Zmijewski et al., 2001), DNA damage (Song and Jope, 2006), and infection (McCaffrey et al., 2004).

Localisation RGS2 is localized to the nucleus and the plasma membrane (Roy et al., 2003; Gu et al., 2007).

Function Canonical functions: RGS proteins bind to heterotrimeric G proteins by way of their RGS domain and act as GAPs (GTPase accelerating protein) to turn off G protein coupled receptor (GPCR) signals (Ross and Wilkie, 2000). RGS2 is unique in its selective GAP activity toward Galphaq and its low affinity for Galphai/o subunits (Heximer et al., 1997; Heximer et al., 1999; Cladman and Chidiac, 2002). RGS2 has also been shown to regulate Galphas-mediated signals in a GAP-independent manner, which likely reflects its ability to interact with other components of the G protein signaling machinery to interfere with G protein-effector interactions. These include adenylyl cyclase (Salim et al., 2003; Roy et al., 2006a), select GPCRs (Bernstein et al., 2004; Hague et al., 2005; Roy et al., 2006a), and the GPCR-scaffolding protein, spinophilin (Wang et al., 2005). RGS2 has been implicated in the control of vascular and neurological functions (Ingi et al., 1998; Kammermeier and Ikeda, 1999; Oliveira-

RGS2 (regulator of G-protein signaling 2, 24kDa) Nguyen CH


Dos-Santos et al., 2000; Heximer et al., 2003; Tang et al., 2003). Noncanonical functions: RGS2 has been shown to bind and regulate the activity of proteins outside the realm of GPCR signaling networks including tubulin (Heo et al., 2006), the TRPV6 calcium channel (Schoeber et al., 2006), and the eukaryotic initation factor, eIF2B (Nguyen et al., 2009).

Homology All RGS proteins share a homologous (45-80%) 120 amino acid RGS domain that confers their binding to heterotrimeric G protein alpha subunits. RGS2 shares highest homology to other members of the B/R4 subfamily (Ross and Wilkie, 2000; Sierra et al., 2002).

Implicated in Colorectal cancer Note The correlation between RGS2 expression and survival time of patients with colorectal cancer was studied (Jiang et al., 2009). The authors determined that RGS2 mRNA levels were lower in tissues from patients with recurring colorectal cancer in comparison to those patients without recurrence; however, this study did not identify any causal relationship between RGS2 expression and colorectal cancer.

Breast cancer Note RGS2 mRNA expression was examined in a number of breast cancer cell lines and solid breast cancers (Smalley et al., 2007). The authors found that RGS2 was expressed at higher levels in the majority of solid breast cancers in comparison to control mammary cells. No causal relationship between RGS2 expression and breast cancer was identified.

Prostate cancer Note RGS2 expression was found to be selectively decreased in androgen-independent prostate cancer cells compared to androgen-dependent cancer cells, as well as in human prostate tumor samples (Cao et al., 2006). The authors show that exogenous RGS2 is sufficient to inhibit androgen-independent receptor signaling and clonogenic growth of androgen-independent prostate cancer cells.

Acute myeloid leukemia Note RGS2 expression was found to be repressed by an activating mutation of the fetal liver tyrosine kinase 3 (Flt3-ITD), which is associated with acute myeloid leukemia (Schwable et al., 2005). The authors demonstrate that exogenous RGS2 is sufficient to modulate Flt3-ITD-mediated signaling in myeloid cells. Further, RGS2 is able to reverse the Flt3-ITD-induced

alterations in proliferation and differentiation in these cells.

Hypertension Note Studies using RGS2 knockout mice have identified a role for RGS2 in vascular function and blood pressure regulation (Heximer et al., 2003; Tang et al., 2003).

References Siderovski DP, Heximer SP, Forsdyke DR. A human gene encoding a putative basic helix-loop-helix phosphoprotein whose mRNA increases rapidly in cycloheximide-treated blood mononuclear cells. DNA Cell Biol. 1994 Feb;13(2):125-47

Heximer SP, Watson N, Linder ME, Blumer KJ, Hepler JR. RGS2/G0S8 is a selective inhibitor of Gqalpha function. Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14389-93

Ingi T, Krumins AM, Chidiac P, Brothers GM, Chung S, Snow BE, Barnes CA, Lanahan AA, Siderovski DP, Ross EM, Gilman AG, Worley PF. Dynamic regulation of RGS2 suggests a novel mechanism in G-protein signaling and neuronal plasticity. J Neurosci. 1998 Sep 15;18(18):7178-88

Heximer SP, Srinivasa SP, Bernstein LS, Bernard JL, Linder ME, Hepler JR, Blumer KJ. G protein selectivity is a determinant of RGS2 function. J Biol Chem. 1999 Nov 26;274(48):34253-9

Kammermeier PJ, Ikeda SR. Expression of RGS2 alters the coupling of metabotropic glutamate receptor 1a to M-type K+ and N-type Ca2+ channels. Neuron. 1999 Apr;22(4):819-29

Song L, De Sarno P, Jope RS. Muscarinic receptor stimulation increases regulators of G-protein signaling 2 mRNA levels through a protein kinase C-dependent mechanism. J Biol Chem. 1999 Oct 15;274(42):29689-93

Miles RR, Sluka JP, Santerre RF, Hale LV, Bloem L, Boguslawski G, Thirunavukkarasu K, Hock JM, Onyia JE. Dynamic regulation of RGS2 in bone: potential new insights into parathyroid hormone signaling mechanisms. Endocrinology. 2000 Jan;141(1):28-36

Oliveira-Dos-Santos AJ, Matsumoto G, Snow BE, Bai D, Houston FP, Whishaw IQ, Mariathasan S, Sasaki T, Wakeham A, Ohashi PS, Roder JC, Barnes CA, Siderovski DP, Penninger JM. Regulation of T cell activation, anxiety, and male aggression by RGS2. Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12272-7

Ross EM, Wilkie TM. GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem. 2000;69:795-827

Cunningham ML, Waldo GL, Hollinger S, Hepler JR, Harden TK. Protein kinase C phosphorylates RGS2 and modulates its capacity for negative regulation of Galpha 11 signaling. J Biol Chem. 2001 Feb 23;276(8):5438-44

Zmijewski JW, Song L, Harkins L, Cobbs CS, Jope RS. Oxidative stress and heat shock stimulate RGS2 expression in 1321N1 astrocytoma cells. Arch Biochem Biophys. 2001 Aug 15;392(2):192-6

Cladman W, Chidiac P. Characterization and comparison of RGS2 and RGS4 as GTPase-activating proteins for m2 muscarinic receptor-stimulated G(i). Mol Pharmacol. 2002 Sep;62(3):654-9

Sierra DA, Gilbert DJ, Householder D, Grishin NV, Yu K, Ukidwe P, Barker SA, He W, Wensel TG, Otero G, Brown G,

RGS2 (regulator of G-protein signaling 2, 24kDa) Nguyen CH


Copeland NG, Jenkins NA, Wilkie TM. Evolution of the regulators of G-protein signaling multigene family in mouse and human. Genomics. 2002 Feb;79(2):177-85

Heximer SP, Knutsen RH, Sun X, Kaltenbronn KM, Rhee MH, Peng N, Oliveira-dos-Santos A, Penninger JM, Muslin AJ, Steinberg TH, Wyss JM, Mecham RP, Blumer KJ. Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J Clin Invest. 2003 Feb;111(4):445-52

Roy AA, Lemberg KE, Chidiac P. Recruitment of RGS2 and RGS4 to the plasma membrane by G proteins and receptors reflects functional interactions. Mol Pharmacol. 2003 Sep;64(3):587-93

Salim S, Sinnarajah S, Kehrl JH, Dessauer CW. Identification of RGS2 and type V adenylyl cyclase interaction sites. J Biol Chem. 2003 May 2;278(18):15842-9

Tang KM, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer SP, Kaltenbronn KM, Blumer KJ, Siderovski DP, Zhu Y, Mendelsohn ME. Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med. 2003 Dec;9(12):1506-12

Bernstein LS, Ramineni S, Hague C, Cladman W, Chidiac P, Levey AI, Hepler JR. RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11alpha signaling. J Biol Chem. 2004 May 14;279(20):21248-56

Larminie C, Murdock P, Walhin JP, Duckworth M, Blumer KJ, Scheideler MA, Garnier M. Selective expression of regulators of G-protein signaling (RGS) in the human central nervous system. Brain Res Mol Brain Res. 2004 Mar 17;122(1):24-34

McCaffrey RL, Fawcett P, O'Riordan M, Lee KD, Havell EA, Brown PO, Portnoy DA. A specific gene expression program triggered by Gram-positive bacteria in the cytosol. Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11386-91

Hague C, Bernstein LS, Ramineni S, Chen Z, Minneman KP, Hepler JR. Selective inhibition of alpha1A-adrenergic receptor signaling by RGS2 association with the receptor third intracellular loop. J Biol Chem. 2005 Jul 22;280(29):27289-95

Schwäble J, Choudhary C, Thiede C, Tickenbrock L, Sargin B, Steur C, Rehage M, Rudat A, Brandts C, Berdel WE, Müller-Tidow C, Serve H. RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation. Blood. 2005 Mar 1;105(5):2107-14

Wang X, Zeng W, Soyombo AA, Tang W, Ross EM, Barnes AP, Milgram SL, Penninger JM, Allen PB, Greengard P, Muallem S. Spinophilin regulates Ca2+ signalling by binding the N-terminal domain of RGS2 and the third intracellular loop of G-protein-coupled receptors. Nat Cell Biol. 2005 Apr;7(4):405-11

Cao X, Qin J, Xie Y, Khan O, Dowd F, Scofield M, Lin MF, Tu Y. Regulator of G-protein signaling 2 (RGS2) inhibits

androgen-independent activation of androgen receptor in prostate cancer cells. Oncogene. 2006 Jun 22;25(26):3719-34

Heo K, Ha SH, Chae YC, Lee S, Oh YS, Kim YH, Kim SH, Kim JH, Mizoguchi A, Itoh TJ, Kwon HM, Ryu SH, Suh PG. RGS2 promotes formation of neurites by stimulating microtubule polymerization. Cell Signal. 2006 Dec;18(12):2182-92

Roy AA, Baragli A, Bernstein LS, Hepler JR, Hébert TE, Chidiac P. RGS2 interacts with Gs and adenylyl cyclase in living cells. Cell Signal. 2006 Mar;18(3):336-48

Roy AA, Nunn C, Ming H, Zou MX, Penninger J, Kirshenbaum LA, Dixon SJ, Chidiac P. Up-regulation of endogenous RGS2 mediates cross-desensitization between Gs and Gq signaling in osteoblasts. J Biol Chem. 2006 Oct 27;281(43):32684-93

Schoeber JP, Topala CN, Wang X, Diepens RJ, Lambers TT, Hoenderop JG, Bindels RJ. RGS2 inhibits the epithelial Ca2+ channel TRPV6. J Biol Chem. 2006 Oct 6;281(40):29669-74

Song L, Jope RS. Cellular stress increases RGS2 mRNA and decreases RGS4 mRNA levels in SH-SY5Y cells. Neurosci Lett. 2006 Jul 24;402(3):205-9

Zou MX, Roy AA, Zhao Q, Kirshenbaum LA, Karmazyn M, Chidiac P. RGS2 is upregulated by and attenuates the hypertrophic effect of alpha1-adrenergic activation in cultured ventricular myocytes. Cell Signal. 2006 Oct;18(10):1655-63

Gu S, He J, Ho WT, Ramineni S, Thal DM, Natesh R, Tesmer JJ, Hepler JR, Heximer SP. Unique hydrophobic extension of the RGS2 amphipathic helix domain imparts increased plasma membrane binding and function relative to other RGS R4/B subfamily members. J Biol Chem. 2007 Nov 9;282(45):33064-75

Smalley MJ, Iravani M, Leao M, Grigoriadis A, Kendrick H, Dexter T, Fenwick K, Regan JL, Britt K, McDonald S, Lord CJ, Mackay A, Ashworth A. Regulator of G-protein signalling 2 mRNA is differentially expressed in mammary epithelial subpopulations and over-expressed in the majority of breast cancers. Breast Cancer Res. 2007;9(6):R85

Gu S, Anton A, Salim S, Blumer KJ, Dessauer CW, Heximer SP. Alternative translation initiation of human regulators of G-protein signaling-2 yields a set of functionally distinct proteins. Mol Pharmacol. 2008 Jan;73(1):1-11

Nguyen CH, Ming H, Zhao P, Hugendubler L, Gros R, Kimball SR, Chidiac P. Translational control by RGS2. J Cell Biol. 2009 Sep 7;186(5):755-65

Jiang Z, Wang Z, Xu Y, Wang B, Huang W, Cai S. Analysis of RGS2 expression and prognostic significance in stage II and III colorectal cancer. Biosci Rep. 2010 Dec;30(6):383-90


Nguyen CH. RGS2 (regulator of G-protein signaling 2, 24kDa). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1036-1038.





SOX11 (SRY (sex determining region Y)-box 11) Xiao Wang, Birgitta Sander

Department of Pathology, F46, Karolinska Institutet, SE 141 86 Stockholm, Sweden (XW), Department of Pathology, F46, Karolinska University Hospital and Karolinska Institutet, SE 141 86 Stockholm, Sweden (BS)


Online updated version : http://AtlasGeneticsOncology.org/Genes/SOX11ID42357ch2p25.html DOI: 10.4267/2042/44890


Identity HGNC (Hugo): SOX11

Location: 2p25.2

DNA/RNA

The human SOX11 gene. The only exon is indicated by the red box. The number above the box shows the size of the exon.

Description The intronless gene encompasses 8718 base pairs and is located at 2p25.2.

Transcription The mRNA SOX11 transcript contains one exon with 8718 base pairs.

Protein

The human SOX11 protein and functional domains. Numbers indicate the amino acid positions at the beginning and the end of each domain. The grey bar shows the High-Mobility-Group (HMG) box DNA-binding domain; and the dark blue bar shows the TransActivation Domain (TAD).

Description The human SOX11 protein has 441 amino acids and 46.7 kDa molecular weight. It contains two functional

domains: a Sry-related high-mobility group (HMG) box (Sox) DNA-binding domain, located in the N-terminal third (47-122), and a transactivation domain (TAD), located at the C-terminus (408-441) (Dy et al., 2008; Penzo-Méndez, 2009).

Expression SOX11 is widely expressed during organogenesis in the embryo and is highly expressed in the central and peripheral nervous system of the human fetus (Jay et al., 1995; Sock et al., 2004). SOX11 expression is more restricted by birth, and low transcript levels of SOX11 were detected in adult colon, small intestine, heart and brain (Weigle et al., 2005). High level of SOX11 mRNA is only present in normal prostate tissue (Brennan et al., 2009).

Localisation Nucleus.

Function SOX11 contains domains that may function as transcriptional activators or repressors and is a member of the group C SOX transcription factor family. It appears to have critical roles in embryonic neurogenesis and development of many organ systems including heart, palate and eyelids (Sock et al., 2004). SOX11 can, together with SOX4, regulate the differentiation of neuronal progenitors (Bergsland et al., 2006). SOX11 is involved in the transcriptional regulation of specific gene expression programs in adult neurogenesis at the stage of the immature neuron (Haslinger et al., 2009). SOX11 controls morphological maturation such as neurite growth (Jankowski et al., 2006) and modulates the regeneration following peripheral nerve injury (Jankowski et al., 2009). The class-III beta-tubulin gene TUBB3 is the first and still

SOX11 (SRY (sex determining region Y)-box 11) Wang X, Sander B


the unique gene to be identified as a direct target of SOX11 (Dy et al., 2008). SOX11 has been suggested to bind and regulate LINE retrotransposons (Tchénio, 2000).

Homology The two domains are highly conserved regions between species (from human to fly). In the SOX C group, consisting of SOX4, SOX11 and SOX12, the HMG box and C33 domains are more highly conserved among Sox4 orthologues and SOX11 orthologues than among SOX12.

Implicated in Malignant glioma Note SOX11 was identified by screening an expression database for genes highly expressed in glioblastoma multiforme (Weigle et al., 2005). Overexpression of SOX11 can prevent tumorigenesis of glioma-initiating cells by inducing their neuronal differentiation (Hide et al., 2009).

Disease Malignant glioma comprises of the majority of primary brain tumors with 16800 new cases reported each year in USA.

Prognosis SOX11 can serve as a target antigen for glioma-directed cytotoxic T lymphocytes (CTLs), and this novel CTL epitope may serve as a suitable candidate for a T cell-based immunotherapy of glioma patients (Schmitz et al., 2007).

Medulloblastoma Note SOX11 has been shown to be overexpressed in most classical medulloblastomas (Lee et al., 2002).

Disease Medulloblastomas are brain tumors occurred in the cerebellum.

Haematological malignancies Note Overexpression of SOX11 was first described as a unique marker for a specific malignant B cell lymphoma, mantle cell lymphoma (Ek et al., 2008; Wang et al., 2008). Subsequent studies have demonstrated that Sox11 is also present in: - 50% of hairy cell leukemia (Chen et al., 2009; Dictor et al., 2009); - 25-50% of Burkitt lymphoma cases (Dictor et al., 2009; Mozos et al., 2009); - Almost all of B-cell lymphoblastic leukemia/lymphomas and T-cell lymphoblastic leukemia/lymphomas;

- 2/3 cases of T-cell prolymphocytic leukemia (Dictor et al., 2009; Mozos et al., 2009).

Prognosis Expression of SOX11 in mantle cell lymphoma is not only a new diagnostic marker but may also carry information related to the clinical and biological behaviour (Wang et al., 2008).

Ovarian cancer Note SOX11 is overexpressed in many epithelial ovarian cancers, and loss of Sox11 is associated with a decreased recurrence-free survival and a more aggressive phenotype (Brennan et al., 2009).

Prognosis SOX11 is differently expressed in epithelial ovarian cancer and is a prognostic marker.

References Jay P, Gozé C, Marsollier C, Taviaux S, Hardelin JP, Koopman P, Berta P. The human SOX11 gene: cloning, chromosomal assignment and tissue expression. Genomics. 1995 Sep 20;29(2):541-5

Tchénio T, Casella JF, Heidmann T. Members of the SRY family regulate the human LINE retrotransposons. Nucleic Acids Res. 2000 Jan 15;28(2):411-5

Lee CJ, Appleby VJ, Orme AT, Chan WI, Scotting PJ. Differential expression of SOX4 and SOX11 in medulloblastoma. J Neurooncol. 2002 May;57(3):201-14

Sock E, Rettig SD, Enderich J, Bösl MR, Tamm ER, Wegner M. Gene targeting reveals a widespread role for the high-mobility-group transcription factor Sox11 in tissue remodeling. Mol Cell Biol. 2004 Aug;24(15):6635-44

Weigle B, Ebner R, Temme A, Schwind S, Schmitz M, Kiessling A, Rieger MA, Schackert G, Schackert HK, Rieber EP. Highly specific overexpression of the transcription factor SOX11 in human malignant gliomas. Oncol Rep. 2005 Jan;13(1):139-44

Bergsland M, Werme M, Malewicz M, Perlmann T, Muhr J. The establishment of neuronal properties is controlled by Sox4 and Sox11. Genes Dev. 2006 Dec 15;20(24):3475-86

Jankowski MP, Cornuet PK, McIlwrath S, Koerber HR, Albers KM. SRY-box containing gene 11 (Sox11) transcription factor is required for neuron survival and neurite growth. Neuroscience. 2006 Dec 1;143(2):501-14

Schmitz M, Wehner R, Stevanovic S, Kiessling A, Rieger MA, Temme A, Bachmann M, Rieber EP, Weigle B. Identification of a naturally processed T cell epitope derived from the glioma-associated protein SOX11. Cancer Lett. 2007 Jan 8;245(1-2):331-6

Dy P, Penzo-Méndez A, Wang H, Pedraza CE, Macklin WB, Lefebvre V. The three SoxC proteins--Sox4, Sox11 and Sox12--exhibit overlapping expression patterns and molecular properties. Nucleic Acids Res. 2008 May;36(9):3101-17

Ek S, Dictor M, Jerkeman M, Jirström K, Borrebaeck CA. Nuclear expression of the non B-cell lineage Sox11 transcription factor identifies mantle cell lymphoma. Blood. 2008 Jan 15;111(2):800-5

SOX11 (SRY (sex determining region Y)-box 11) Wang X, Sander B


Wang X, Asplund AC, Porwit A, Flygare J, Smith CI, Christensson B, Sander B. The subcellular Sox11 distribution pattern identifies subsets of mantle cell lymphoma: correlation to overall survival. Br J Haematol. 2008 Oct;143(2):248-52

Brennan DJ, Ek S, Doyle E, Drew T, Foley M, Flannelly G, O'Connor DP, Gallagher WM, Kilpinen S, Kallioniemi OP, Jirstrom K, O'Herlihy C, Borrebaeck CA. The transcription factor Sox11 is a prognostic factor for improved recurrence-free survival in epithelial ovarian cancer. Eur J Cancer. 2009 May;45(8):1510-7

Dictor M, Ek S, Sundberg M, Warenholt J, György C, Sernbo S, Gustavsson E, Abu-Alsoud W, Wadström T, Borrebaeck C. Strong lymphoid nuclear expression of SOX11 transcription factor defines lymphoblastic neoplasms, mantle cell lymphoma and Burkitt's lymphoma. Haematologica. 2009 Nov;94(11):1563-8

Haslinger A, Schwarz TJ, Covic M, Chichung Lie D. Expression of Sox11 in adult neurogenic niches suggests a stage-specific role in adult neurogenesis. Eur J Neurosci. 2009 Jun;29(11):2103-14

Hide T, Takezaki T, Nakatani Y, Nakamura H, Kuratsu J, Kondo T. Sox11 prevents tumorigenesis of glioma-initiating cells by inducing neuronal differentiation. Cancer Res. 2009 Oct 15;69(20):7953-9

Jankowski MP, McIlwrath SL, Jing X, Cornuet PK, Salerno KM, Koerber HR, Albers KM. Sox11 transcription factor modulates peripheral nerve regeneration in adult mice. Brain Res. 2009 Feb 23;1256:43-54

Mozos A, Royo C, Hartmann E, De Jong D, Baró C, Valera A, Fu K, Weisenburger DD, Delabie J, Chuang SS, Jaffe ES, Ruiz-Marcellan C, Dave S, Rimsza L, Braziel R, Gascoyne RD, Solé F, López-Guillermo A, Colomer D, Staudt LM, Rosenwald A, Ott G, Jares P, Campo E. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica. 2009 Nov;94(11):1555-62

Chen YH, Gao J, Fan G, Peterson LC. Nuclear expression of sox11 is highly associated with mantle cell lymphoma but is independent of t(11;14)(q13;q32) in non-mantle cell B-cell neoplasms. Mod Pathol. 2010 Jan;23(1):105-12

Penzo-Méndez AI. Critical roles for SoxC transcription factors in development and cancer. Int J Biochem Cell Biol. 2010 Mar;42(3):425-8


Wang X, Sander B. SOX11 (SRY (sex determining region Y)-box 11). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1039-1041.

Gene Section Review




THY1 (Thy-1 cell surface antigen) John E Bradley, James S Hagood

Departments of Pediatrics, Biochemistry and Molecular Genetics, University of Alabama-Birmingham, AL, USA (JEB), Department of Pediatrics, University of California at San Diego, USA (JSH)


Online updated version : http://AtlasGeneticsOncology.org/Genes/THY1ID45672ch11q23.html DOI: 10.4267/2042/44891


Identity Other names: CD90; CDw90; FLJ33325

HGNC (Hugo): THY1

Location: 11q23.3

DNA/RNA Description 4 exons; DNA size: 5591.

Transcription Transcription of THY1 is initiated at multiple sites producing an approximately 5591 bp transcript. After splicing, the transcript is reduced to 2143 bp. Transcriptional regulation for tissue-specific expression of Thy-1, as well as for controlling expression in cell sub-populations, and in some cancers, is governed by a number of mechanisms. For tissue-specific transcriptional regulation, the regulatory elements are found exclusively downstream of the transcription initiation site within the gene itself. Differential tissue expression of Thy1 exists between species as closely related as mouse and rat.

For example, Thy1 is expressed in mouse thymocytes and splenocytes, but only thymocytes in rat. The absence of Thy1 in rat splenocytes is attributed to a three nucleotide difference in a conserved 36 bp region within the third intron. In mice, this 36 bp region can bind an Ets-l-like nuclear factor expressed by both mouse thymocytes and splenocytes. In rats, the three nucleotide difference renders the 36 bp region no longer capable of binding the similar Ets-l-like nuclear factor expressed by rats. However, rat thymocytes but not splenocytes express another nuclear factor which does recognize the 36 bp region and this is thought to account for the expression of Thy1 in rat thymocytes but not splenocytes. In humans, THY1 is detected in the brain, spleen, kidneys, but not thymus. In mouse, Thy1 is detected in the brain, spleen, thymus, but not kidneys. In transgenic mice, deletion of half the 3' end of intron 1 prevents expression of Thy1 in the brain but allows for its expression in the thymus. The control elements within the first intron of Thy-1 are conserved in human and mouse, as replacement of the first intron in mouse with that from human causes no detectable change in Thy1 expression in the brain.

Organization of the human THY1 gene and control elements. There are sequences conferring tissue specificity for the brain in the first intron and kidney in the third intron.

THY1 (Thy-1 cell surface antigen) Bradley JE, Hagood JS


Differences between intron 3 of mouse and human Thy-1 seem to account for expression of Thy-1 in human but not mouse kidney and mouse but not human thymus. In transgenic mice, Thy1 is no longer expressed in the thymus but ectopically expressed in the kidney when the third intron of mouse Thy1 is replaced with the third intron of human THY1. The aforementioned downstream control elements require at a minimum 300 bp of the endogenous Thy1 promoter for transcription to occur. Interestingly, the endogenous Thy1 promoter in itself does not elicit transcription or tissue specificity absent the downstream elements. Conversely, the downstream elements are able to direct tissue-specific transcription of Thy1 with a heterologous promoter. Therefore, the downstream control elements are "promiscuous" with regard to a promoter, while the endogenous promoter is "monogamous" with the downstream control elements. The validity of these assertions is exemplified in the design of the murine thy1.2 genomic expression cassette for driving expression in the nervous system. In this cassette, the coding sequences, as well as the third intron of thy1.2 have all been removed, but the first intron is retained. Suppression of Thy-1 transcription within sub-populations of lung fibroblasts and the tumorigenic nasopharyngeal cell carcinoma (NPC) cell line HONE1 is shown to occur via hypermethylation of CpG (cytosine-guanine) islands in the Thy-1 gene promoter. Moreover, THY1 is thought to function as a tumor suppressor in NPC as microcell-mediated transfer of an

additional intact human chromosome 11 into HONE1 cells decreases colony formation with re-expression of THY1. Tumor segregants of the HONE1 microcell hybrids were all negative for THY1. Concurrently, the region 11q22-23 is shown to be critical for tumorigenicty in NPC. In both rat and human lung fibroblasts, CpG islands in the Thy-1 gene promoter are hypermethylated in the Thy-1 negative fibroblast subpopulation but not in the positive. Thy1 expression is induced in Thy1 (-) fibroblasts by treatment with 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor. Suppression of THY1 transcription via hypermethylation of its promoter in THY1 (-) lung fibroblasts has implications in the disease idiopathic pulmonary fibrosis (IPF). Fibroblastic foci are populated predominantly by THY1 (-) myofibroblasts and methylation-specific PCR-in situ hybridization has demonstrated THY1 promoters within these areas to be hypermethylated.

Protein Description Human and mouse Thy-1 are both initially translated as a 161 and 162 amino acid pro-form, respectively. In mouse, there are two alleles that encode two proteins distinguished by having either arginine or glutamine at position 89. Humans have only one allele of THY1. The first 19 aa of the pro-form are a localization signal that targets it into the ER. Initially, the c-terminal residues 131-161 function as a trans-membrane domain within the ER.

THY1 molecule and proposed soluble forms. THY1 is initially generated as a 161 aa pro form. The initial 19 aa signal peptide is removed, and the terminal 31 aa are replaced with a GPI anchor, generating the mature form, which is anchored to the outer leaflet of the cell membrane by the diacyl group of the GPI anchor. N-linked glycosylation sites depict conserved asparagines within murine Thy1 that are known to be glycosylated. Soluble Thy-1 could be generated either by cleavage of the GPI anchor by GPI-PLD, or by undefined proteases acting at as yet undetermined cleavage sites.



Thy-1 undergoes several post translation modifications, including proteolytic cleavage, N-linked glycosylation, and addition of a GPI moiety. The localization signal and trans-membrane domain are proteolytically cleaved away leaving a core protein composed of residues 20-131. The N-linked glycosylation sites of murine Thy1 are at asparagine residues 42, 94, and 118. Only two of these residues are conserved in human at positions 42 and 119. The carbohydrate content of THY1 accounts for nearly 30% of its molecular mass, which ranges from 25 to 37 kDa. Between species, tissue types, and cells in different stages of development: these carbohydrate moieties may vary dramatically. After removal of the trans-membrane domain, a GPI moiety is attached to the c-terminal residue of the core protein, cysteine 130. The GPI moiety contains two fatty-acyl groups that embed into the membrane thereby anchoring Thy-1 to the cell surface. Thus, Thy-1 has no intra-cellular domain. Thy-1 is a member of the immunoglobulin superfamily and as such possesses cysteine residues which form disulfide bonds. A soluble variety of Thy-1 exists and is presumably produced by a proteolytic and/or lipolytic cleavage at the cell surface. If the latter is the case, it is presumed to occur in close proximity to the c-terminus. Completely deglycosylated membranous and soluble THY1 have indistinguishable migration speeds through a polyacrylamide gel.

Expression In mouse and human, Thy-1 is expressed at the cell surface of mature neurons, a subset of fibroblasts, and activated natural killer cells. With the exception of these cell types, mouse and human each have unique Thy-1 expression profiles. Thy1 covers up to 10-20% of mouse thymocyte cell surface but levels diminish in locations of greater thymocyte maturation. Specifically, cortical thymocytes express higher levels of Thy1 than medullary thymocytes and Lymph node cells have levels less than both. The only human thymocytes to express THY1 are a small population of cortical thymocytes, whereas expression of Thy1 in the mouse is broader and also includes peripheral T cells. In humans, THY1 is also expressed by endothelial cells (conditionally), smooth muscle cells, some glial cells, a subset of CD34 (+) bone marrow cells, and umbilical cord blood- and fetal liver-derived hematopoietic stem cells. A soluble variety of THY1 is detectable in serum, cerebral spinal fluid, wound fluid from venous leg ulcers, and the synovial fluid from joints in rheumatoid arthritis. Cultured lung fibroblasts shed THY1 into the media when treated with pro-inflammatory cyokines, such as IL-1beta and TNF-alpha. The opposite effect is elicited in endothelial cells, in which pro-inflammatory cytokines stimulate increased THY1 expression. Relative to the neonatal and developing brain, the adult brain expresses far greater levels of THY1. Moreover, postnatal increase in Thy-1 expression coincides

strongly with histological and physiological indicators of brain maturation. Thus, expression of Thy-1 is developmentally regulated in the brain. As the brain develops, expression of Thy1 mRNA precedes detection of protein by several days, thereby suggesting post-transcription regulation of Thy-1 mRNA as a mechanism for controlling temporal expression of Thy-1 protein in the developing brain. This mode of regulation has been shown to be an intrinsic attribute of immature neurons. Mature Thy1.1-expressing neurons fused with immature Thy1.2-negative neurons to form heterokaryons become Thy1 negative within 16 h. As factors that maintained the immature condition of the Thy1.2 negative neuron counterpart presumably give way, the heterokaryons express both Thy1.1 and Thy1.2 within 3-4 days after becoming negative. This suggests that a developmentally regulated diffusible suppressor molecule inhibits translation of the Thy1 protein in immature neurons. This method of regulation is perhaps a means to forgo the time needed to transcribe Thy-1 mRNA and thereby prime the immature neuron for immediate expression of Thy-1 protein to coincide with maturation. In response to injury, Thy1 expression in mature neurons mimics that of a developing neuron. In young adult rats, Thy1 expression dramatically decreases in dorsal root ganglion neurons two days post a crush injury of the sciatic nerve reaching a low around day four. Thy1 expression gradually returns to pre-injury levels 1 week after the sciatic nerve crush and coincides with recovery of sensory function. Central nervous system neurons do not have the same potential to recover from traumatic injury as peripheral nervous system neurons do. Response to traumatic injury by central nervous system ganglion cells also differs with respect to Thy1 expression. Specifically, optic nerve crush results in cell loss due to apoptosis after 2 weeks. Prior to any cell loss, levels of Thy1 mRNA decrease over the course of 7 days with no change in the number of Thy1 expressing cells. This suggests the decrease in Thy1 mRNA is an injury response rather than a consequence of apoptosis. The optic ganglion cells of Bax knockout mice are resistant to cell death following optic nerve crush. Despite this, the same decrease in Thy1 mRNA is observed following optic nerve crush in Bax knockout mice. Additional means of optic nerve injury also cause a decrease in Thy1 mRNA levels including intravitreal injections of N-methyl-D-aspartate and induced elevated intraocular pressure.

Localisation At the cell surface, Thy-1, like many GPI anchored proteins, localizes to cholesterol-rich lipid rafts. Release of Thy-1 into the extracellular space and into body fluids, such as serum and cerebral spinal fluid, occurs via unknown mechanisms. In-vitro, both mammalian GPI-PLD and bacterial PLC are capable of separating the diacyl glycerol from the remainder of the GPI-moiety. When Thy-1 is released from the cell



surface by GPI-PLD the phosphate is not retained, but is when released by PLC. In order for Thy-1 to be susceptible to release by GPI-PLD, lipid rafts must be disrupted by detergents or saponins. PLC has no such requirement. However, Thy1 in certain cell types is more resistant to PLC. Thus, Thy-1 is thought to be afforded some protection from GPI-PLD catalyzed release by its localization within lipid rafts. For Thy-1 to signal, it must be localized to its native lipid raft microdomain. Thy1 (-) neurons grown on a monolayer of astrocytes and expressing exogenous human THY1 or mouse Thy1.2 experienced inhibited neurite outgrowth. Yet under the same conditions, Thy1 (-) neurons expressing a construct of Thy1 in which the GPI anchor is replaced by the transmembrane domain of CD8 have normal neurite outgrowth. The transmembrane domain of CD8 does not localize Thy1 to lipid raft microdomains. This same construct was later used in experiments to assess the role of the Thy1 GPI anchor in modulating fibroblast phenotypes. Not unlike the results in the neuron experiments, Thy1 (-) fibroblasts made to express the Thy1-CD8 construct maintained their "negative" phenotype in that they remained insensitive to thrombospondin-mediated transient phosphorylation of FAK and SFK, focal adhesion disassembly, and migration.

Function The Thy1 antigen was initially discovered in an attempt to raise antiserum against leukemia-specific antigens from the CH3 mouse strain in the AKR mouse strain and vice versa. The antibodies were found to strongly label thymocytes as well as peripheral T cells, hence the name Thy1. Thy-1 has several immunological functions, most mediated through interactions with integrins. In particular, Thy1 binds integrins alphaMbeta2 and alphaXbeta2 which are both expressed by leukocytes. In cell adhesion assays, monocytes and polymorphonuclear cells adhere to exogenous Thy1-expressing CHO cells and activated THY1-expressing Human Dermal Microvascular Endothelial Cells (HDMECs). This adherence was found to be mediated by the interaction between THY1 and alphaMbeta2. Antibodies against alphaMbeta2 blocked adherence, while exogenously expressing alphaMbeta2 but not control CHO cells are able to retain biotynilated purified THY1 at their cell surface. Moreover, the interaction of THY1 with alphaMbeta2 was found to be vital in transendothelial migration of the aforementioned leukocytes across a monolayer of HDMECs. Thereby, THY1 is implicated in the regulation of leukocyte recruitment to sites of inflammation. Early evidence showed surface Thy1 expression diminishes as thymocytes mature into T cells, suggesting a role for Thy-1 in regulating thymocyte lineage. Thymocytes from Thy1 null mice have a reduced maturation rate from the immature

CD4+CD8+ double-positive to the CD4+ or CD8+ single-positive mature T cell. Thy1 supports adhesion of thymocytes to thymic epithelial cells. Accordingly, the contacts between thymus cells of the Thy1 null mice are atypical as evaluated by electron microscopy. The role of Thy-1 in thymocyte adhesion and maturation may not be mutually exclusive. Thy1 seems to have a continued role in T cell activity beyond maturation from thymocytes. Cross-linking Thy1 using bivalent antibodies against Thy1 results in T cell activation as indicated by proliferation and IL-2 synthesis. It is important to note there is no known ligand for Thy-1 that the cross-linking antibody presumably mimics. Traditionally, activation of a T cell is thought to require two simultaneous signals. One is a B7 family member engaging T cell CD28 receptor and the other is the T cell receptor being presented its specific antigen by an MHC. Cross-linking Thy1 with antibodies partially supplies the latter signal to activate T cells when the CD28 receptor is engaged by anti-CD28 antibodies. The activation is only partial because, although the T cells adhere to target cells and express perforin, granzyme B, and Fas ligand, they are unable to kill target cells. The specific role Thy1 has in T cell activation and thymocyte maturation in vivo, and whether they are related is unknown. Thy-1 expression modulates fibroblast phenotype. Pulmonary fibroblasts sorted into Thy-1 (+) and (-) populations have dissimilar potential for differentiating into myofibroblasts, response to pro-inflammatory cytokines, and localization into areas of active fibrosis. Rat Thy1 (-) pulmonary fibroblasts have greater myofibroblastic differentiation relative to Thy1 (+) as assessed by contractility and myogenic gene expression of MyoD, myocardin, myf5, and myogenin, both at baseline and in response to fibrogenic mediators. In addition, Thy1 (-) fibroblasts resist apoptosis in a contracting collagen matrix. Thy1 (+) and (-) pulmonary fibroblasts have dissimilar production of and/or responses to various cytokines. In response to PDGF-BB, both populations undergo concentration-dependent proliferation. However, only the Thy1 (-) population proliferates in response to PDGF-AA. Consistent with the proliferation assays, both populations express PDGFR-beta. Only Thy1 (-) pulmonary fibroblast express PDGFR-alpha. Thrombospondin-1 or its N-terminal heparin-binding domain alone is a potent inducer of cell migration. Coordinated focal adhesion disassembly is critical for cell migration to occur. Thy1 (+) but not Thy1 (-) pulmonary fibroblasts respond to Thrombospondin-1/HEP-I with transient phosphorylation of FAK and SFK, focal adhesion disassembly, and migration. Exogenous expression of WT Thy1 by Thy1 (-) pulmonary fibroblasts creates sensitivity to Thrombospondin-1/HEP-I. It is important to note that as for other described functions of Thy-1, localization of Thy-1 within lipid rafts is required (see Localisation, above). Thy1 (-) pulmonary fibroblasts, in contrast to



Thy1 (+), are capable of activating latent TGF-beta. Only Thy1 (-) murine pulmonary fibroblasts produce IL-1 in response to TNF-alpha. Moreover, proliferation and IL-6 expression induced by IL-1beta treatment is greater in Thy1 (-) cells relative to Thy1 (+). Phenotypes attributed to the Thy1 (-) and Thy1 (+) fibroblast population of one tissue may be different or reversed in those from another tissue. Unlike in the lung, only THY1 (+) orbital fibroblasts appear capable of differentiating into myofibroblasts, whereas THY1 (-) are incapable of doing so but are unique in their ability to differentiate into mature adipocytes. Thus, the effects of THY1 on cell signaling are likely to be context-dependent. Purified Thy1 immobilized on microbeads has been shown to bind 3 on astrocytes causing them to form focal adhesion sites. However, inhibition of neurite outgrowth in Thy1 expressing neurons is not believed to require induced focal adhesion formation or factors emanating from the astrocytes. Thy1 (-) neurons expressing a construct of Thy1 at the cell surface that does not localize to lipid rafts and grown on a monolayer of astrocytes are capable of normal neurite outgrowth. Despite Thy1 being able to engage integrin beta3 on the astrocyte, neurite outgrowth is not inhibited. Thy1 requires correct localization to its native membrane micro domain to exert an inhibitory effect which suggests that Thy1 functions as a receptor of the neuron rather than a ligand for the astrocyte. Remarkably, Thy1 deficient mice have only subtle nervous system irregularities, including inhibition of hippocampal long-term potentiation in the dentate gyrus and failure to transmit social cues regarding food selection.

Implicated in Nasopharyngeal carcinoma Note In nasopharyngeal carcinoma, THY1 is believed to function as a tumor suppressor. The tumorigenic NPC cell line, HONE1, decrease colony formation with addition of an intact chromosome 11 via microcell-mediated transfer and coincides with reexpression of THY-1. The THY1 gene is located within region 11q22-23 which is critical for tumorigenicity in NPC. Additionally, tumor segregants of the HONE1 microcell hybrids were all negative for THY1. THY1 expression is decreased in more invasive/metastatic NPC and this is thought to occur via epigenetic silencing.

Ovarian cancer Note The loss of heterozygosity at 11q23.3-q24.3 for patients with ovarian cancer is associated with poor prognosis. This region of chromosome 11 contains the THY1 gene. THY1 expression in the tumorigenic ovarian cancer cell line, SKOV-3, induced by either

microcell-mediated chromosome 11 transfer or THY1 expression inducible system suppresses tumorigenicity.

Idiopathic pulmonary fibrosis (IPF) Note Evidence from both in vivo and in vitro experiments implicates loss of fibroblast THY1 is important in the disease Idiopathic Pulmonary Fibrosis (IPF). The most characteristic histopathologic feature of IPF is aggregates of proliferating fibroblasts and myofibroblasts called fibrotic foci. The number of FF directly correlates with severity of the disease. Though the vast majority of quiescent lung fibroblasts are THY1 positive, FF are exclusively occupied by THY1 (-) myofibroblasts. Thy1 (-) lung fibroblasts have a more fibrotic phenotype including response to profibrotic cytokines and propensity to differentiate into myofibroblasts. Moreover, the chemically induced model for lung fibrosis, intra-tracheal administered bleomycin, is more severe in Thy1 knockout mice with respect to accumulation of myofibroblasts, collagen, and increased activation of TGF-beta. THY1 expression has been shown to be epigenetically silenced by DNA hypermethylation in fibroblasts from IPF lesions in vivo and in vitro.

Prognosis The prognosis for a patient with IPF is almost universally poor, with a mean survival of only 2 to 4 years after diagnosis. Onset of the disease and subsequent diagnosis usually occur after the age of 50. Over the course of the disease, patients suffer severe dyspnea. For the estimated 40000 to 130000 IPF patients in the United States, there is no medical intervention that affords a survival benefit save for a lung transplant.

Experimental glomerulonephritis Note Intravenous administration of crosslinking anti-Thy1 antibodies to rats induces glumerulonephritis and serves as a model for study of the disease. The use of Thy1 antibodies for this purpose is supported by in vitro experiments. Cross linking Thy1 expressed on glomerular mesangial cells with anti-Thy1 antibodies induces apoptosis as confirmed by TdT-mediated dUTP nick-end labeling (TUNEL) and annexin V assays. Glumerulonephritis induced with anti-Thy1 antibodies in vivo has recently been shown to result from the combination of complement-mediated necrosis as well as apoptosis.

Graves'ophthalmopathy (GO) Note GO is characterized by an increase in volume of the extraocular muscles and/or the intraorbital adipose tissues which causes the eyeball to bulge from the orbit. Intraorbital fibroblasts, including those that reside around and within the extraocular muscles, have a pathogenic role in this disease. The THY1 (+), but not



the THY1 (-), orbital fibroblast subpopulation differentiates into myofibroblasts as indicated by alpha-smooth muscle actin expression. The opposite is true for differentiation into lipofibroblasts assessed by accumulation of cytoplasmic lipid droplets. The orbital adipose/connective tissue taken from GO patients was shown to have greater THY1 mRNA and protein expression relative to the same tissue retrieved from individuals with no history of Graves'disease whose corneas were being procured for transplantation. Fibroblasts cultured from these two tissue sources were examined for THY1 expression. As with total tissue levels, there was greater expression of THY1 by fibroblasts cultured from tissue obtained from GO patients.

References REIF AE, ALLEN JM. THE AKR THYMIC ANTIGEN AND ITS DISTRIBUTION IN LEUKEMIAS AND NERVOUS TISSUES. J Exp Med. 1964 Sep 1;120:413-33

Schlesinger M, Yron I. Antigenic changes in lymph-node cells after administration of antiserum to thymus cells. Science. 1969 Jun 20;164(886):1412-3

Barclay AN, Letarte-Muirhead M, Williams AF, Faulkes RA. Chemical characterisation of the Thy-1 glycoproteins from the membranes of rat thymocytes and brain. Nature. 1976 Oct 14;263(5578):563-7

Barclay AN. Localization of the Thy-1 antigen in the cerebellar cortex of rat brain by immunofluorescence during postnatal development. J Neurochem. 1979 Apr;32(4):1249-57

Hoessli D, Bron C, Pink JR. T-lymphocyte differentiation is accompanied by increase in sialic acid content of Thy-1 antigen. Nature. 1980 Feb 7;283(5747):576-8

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McKenzie JL, Fabre JW. Human thy-1: unusual localization and possible functional significance in lymphoid tissues. J Immunol. 1981 Mar;126(3):843-50

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Xue GP, Morris R. Expression of the neuronal surface glycoprotein Thy-1 does not follow appearance of its mRNA in developing mouse Purkinje cells. J Neurochem. 1992 Feb;58(2):430-40

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Bergman AS, Carlsson SR. Saponin-induced release of cell-surface-anchored Thy-1 by serum glycosylphosphatidylinositol-specific phospholipase D. Biochem J. 1994 Mar 15;298 Pt 3:661-8

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Nosten-Bertrand M, Errington ML, Murphy KP, Tokugawa Y, Barboni E, Kozlova E, Michalovich D, Morris RG, Silver J, Stewart CL, Bliss TV, Morris RJ. Normal spatial learning despite regional inhibition of LTP in mice lacking Thy-1. Nature. 1996 Feb 29;379(6568):826-9

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Ishizu A, Ishikura H, Nakamaru Y, Kikuchi K, Koike T, Yoshiki T. Interleukin-1alpha regulates Thy-1 expression on rat vascular endothelial cells. Microvasc Res. 1997 Jan;53(1):73-8

Killeen N. T-cell regulation: Thy-1 - hiding in full view. Curr Biol. 1997 Dec 1;7(12):R774-7

Tokugawa Y, Koyama M, Silver J. A molecular basis for species differences in Thy-1 expression patterns. Mol Immunol. 1997 Dec;34(18):1263-72

Devasahayam M, Catalino PD, Rudd PM, Dwek RA, Barclay AN. The glycan processing and site occupancy of recombinant Thy-1 is markedly affected by the presence of a glycosylphosphatidylinositol anchor. Glycobiology. 1999 Dec;9(12):1381-7

Hagood JS, Miller PJ, Lasky JA, Tousson A, Guo B, Fuller GM, McIntosh JC. Differential expression of platelet-derived growth factor-alpha receptor by Thy-1(-) and Thy-1(+) lung fibroblasts. Am J Physiol. 1999 Jul;277(1 Pt 1):L218-24

Saalbach A, Wetzig T, Haustein UF, Anderegg U. Detection of human soluble Thy-1 in serum by ELISA. Fibroblasts and activated endothelial cells are a possible source of soluble Thy-1 in serum. Cell Tissue Res. 1999 Nov;298(2):307-15

Schäfer H, Bartels T, Hahn G, Otto A, Burger R. T-cell-activating monoclonal antibodies, reacting with both leukocytes and erythrocytes, recognize the guinea pig Thy-1 differentiation antigen: characterization and cloning of guinea pig CD90. Cell Immunol. 1999 Nov 1;197(2):116-28

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Shimizu A, Masuda Y, Kitamura H, Ishizaki M, Ohashi R, Sugisaki Y, Yamanaka N. Complement-mediated killing of mesangial cells in experimental glomerulonephritis: cell death by a combination of apoptosis and necrosis. Nephron. 2000 Oct;86(2):152-60

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Schlamp CL, Johnson EC, Li Y, Morrison JC, Nickells RW. Changes in Thy1 gene expression associated with damaged retinal ganglion cells. Mol Vis. 2001 Aug 15;7:192-201

Campsall KD, Mazerolle CJ, De Repentingy Y, Kothary R, Wallace VA. Characterization of transgene expression and Cre recombinase activity in a panel of Thy-1 promoter-Cre transgenic mice. Dev Dyn. 2002 Jun;224(2):135-43

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Koumas L, Smith TJ, Feldon S, Blumberg N, Phipps RP. Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes. Am J Pathol. 2003 Oct;163(4):1291-300

Zhao Y, Ohdan H, Manilay JO, Sykes M. NK cell tolerance in mixed allogeneic chimeras. J Immunol. 2003 Jun 1;170(11):5398-405

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Barker TH, Pallero MA, MacEwen MW, Tilden SG, Woods A, Murphy-Ullrich JE, Hagood JS. Thrombospondin-1-induced focal adhesion disassembly in fibroblasts requires Thy-1 surface expression, lipid raft integrity, and Src activation. J Biol Chem. 2004 May 28;279(22):23510-6

Haeryfar SM, Hoskin DW. Thy-1: more than a mouse pan-T cell marker. J Immunol. 2004 Sep 15;173(6):3581-8

Wetzel A, Chavakis T, Preissner KT, Sticherling M, Haustein UF, Anderegg U, Saalbach A. Human Thy-1 (CD90) on activated endothelial cells is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Immunol. 2004 Mar 15;172(6):3850-9

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Lung HL, Bangarusamy DK, Xie D, Cheung AK, Cheng Y, Kumaran MK, Miller L, Liu ET, Guan XY, Sham JS, Fang Y, Li L, Wang N, Protopopov AI, Zabarovsky ER, Tsao SW, Stanbridge EJ, Lung ML. THY1 is a candidate tumour suppressor gene with decreased expression in metastatic nasopharyngeal carcinoma. Oncogene. 2005 Sep 29;24(43):6525-32

Rege TA, Hagood JS. Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis. FASEB J. 2006 Jun;20(8):1045-54

Rege TA, Hagood JS. Thy-1, a versatile modulator of signaling affecting cellular adhesion, proliferation, survival, and cytokine/growth factor responses. Biochim Biophys Acta. 2006 Oct;1763(10):991-9

Rege TA, Pallero MA, Gomez C, Grenett HE, Murphy-Ullrich JE, Hagood JS. Thy-1, via its GPI anchor, modulates Src family kinase and focal adhesion kinase phosphorylation and subcellular localization, and fibroblast migration, in response to thrombospondin-1/hep I. Exp Cell Res. 2006 Nov 15;312(19):3752-67



Sanders YY, Kumbla P, Hagood JS. Enhanced myofibroblastic differentiation and survival in Thy-1(-) lung fibroblasts. Am J Respir Cell Mol Biol. 2007 Feb;36(2):226-35

Scotton CJ, Chambers RC. Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest. 2007 Oct;132(4):1311-21

Surviladze Z, Harrison KA, Murphy RC, Wilson BS. FcepsilonRI and Thy-1 domains have unique protein and lipid compositions. J Lipid Res. 2007 Jun;48(6):1325-35

Khoo TK, Coenen MJ, Schiefer AR, Kumar S, Bahn RS. Evidence for enhanced Thy-1 (CD90) expression in orbital fibroblasts of patients with Graves' ophthalmopathy. Thyroid. 2008 Dec;18(12):1291-6

Sanders YY, Pardo A, Selman M, Nuovo GJ, Tollefsbol TO, Siegal GP, Hagood JS. Thy-1 promoter hypermethylation: a novel epigenetic pathogenic mechanism in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2008 Nov;39(5):610-8

Bradley JE, Ramirez G, Hagood JS. Roles and regulation of Thy-1, a context-dependent modulator of cell phenotype. Biofactors. 2009 May-Jun;35(3):258-65

Kusner LL, Young A, Tjoe S, Leahy P, Kaminski HJ. Perimysial fibroblasts of extraocular muscle, as unique as the muscle fibers. Invest Ophthalmol Vis Sci. 2010 Jan;51(1):192-200


Bradley JE, Hagood JS. THY1 (Thy-1 cell surface antigen). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1042-1049.

Gene Section Review




TYRO3 (TYRO3 protein tyrosine kinase) Kristen M Jacobsen, Rachel MA Linger, Douglas K Graham

Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA (KMJ, RMAL, DKG)


Online updated version : http://AtlasGeneticsOncology.org/Genes/TYRO3ID42739ch15q15.html DOI: 10.4267/2042/44892


Identity Other names: Brt; BYK; DTK; FLJ16467; RSE; SKY; Tif

HGNC (Hugo): TYRO3

Location: 15q15.1

DNA/RNA Description The human TYRO3 gene is located on chromosome 15q15.1 and contains 19 exons. By sequence analysis, exons 1-9 are predicted to encode the extracellular domain, exon 10 may encode the transmembrane domain and exons 11-19 are predicted to encode the intracellular domain. Within the extracellular domain, there are two immunoglobulin (Ig) domains (predicted to be

encoded by exons 2-5) and two fibronectin (FN) type III domains (predicted to be encoded by exons 6-9). Exons 12-19 are predicted to encode the tyrosine kinase domain, within the intracellular region (Hubbard et al., 2009).

Transcription A 4.2 kilobase mRNA transcript of TYRO3 has been identified in several tissues, including brain, placenta, lung, heart, kidney, pancreas, ovary and testis (Polvi et al., 1993; Dai et al., 1994). Alternative splicing results in three different splice variants. Isoform I contains exon 2A, Isoform II contains exon 2B, while exon 2C is found in Isoform III. All three splice variants encode a transmembrane TYRO3 protein, but differ in the signal peptide sequence at the amino terminus (Biesecker et al., 1995; Lewis et al., 1996; Lu et al., 1999).

The cartoon depicts the structure of the TYRO3 gene (bottom) roughly aligned with the corresponding functional protein domains (top). The genomic DNA is represented by boxes (exons) and connecting lines (introns). The exons are drawn approximately 10-fold larger than the introns to facilitate alignment with the protein domains. The open ended boxes for exons 1 and 19 indicate untranslated regions which are not shown here. Exon 2 can be alternatively spliced resulting in transcripts containing either exon 2A, 2B, or 2C.

TYRO3 (TYRO3 protein tyrosine kinase) Jacobsen KM, et al.


The cartoon on the top depicts the domain structure of the TYRO3 receptor tyrosine kinase. The conserved sequence within the kinase domain is shown. The amino acids at positions three and five within the conserved sequence are leucine (L) residues in TYRO3 and isoleucine (I) residues in the related receptor tyrosine kinases, AXL and MERTK. The cartoon on the bottom depicts the domain structure of the ligands, Gas6 and Protein S, which share 43% homology. Thrombin cleavage sites are present in the loop region of Protein S, but not Gas6. Gas6 and Protein S are rendered active by vitamin K-dependent carboxylation of the gamma-carboxyglutamic acid (Gla) domain.

Protein Description TYRO3 is synthesized as an 890 amino acid protein. The predicted molecular weight of TYRO3 is 97 kD, however, the extracellular domain contains sites for NH2-linked glycosylation. Due to the potential for post-translational modifications, TYRO3 proteins can range in size from 100 to 140 kD (Linger et al., 2008). The extracellular domain of the TYRO3 receptor contains two Ig domains (aa 60-117 for domain 1 and aa 156-203 for domain 2) and two FNIII domains (aa 224-313 for domain 1 and aa 322-409 for domain 2) (Ohashi et al., 1994). The two Ig domains and two FNIII domains define TYRO3 as a member of a family of receptor tyrosine kinases (RTKs), which also includes AXL and MERTK. TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases (Linger et al., 2008). The extracellular domain of TYRO3 is the ligand-binding region for the ligands GAS6 and Protein S. GAS6 has been shown to bind the TYRO3 receptor specifically in the Ig domains (Heiring et al., 2004). The tyrosine kinase domain (aa 525-776) is within the intracellular region of the TYRO3 receptor. This kinase domain contains a signature motif, KW(I/L)A(I/L)ES,

that is only found in the TAM receptor family members (Graham et al., 1994). Following ligand binding to the extracellular domain, the TYRO3 receptors dimerize and autophosphorylation of the tyrosine kinase domain occurs. In addition to ligand-dependent signaling, studies suggest that TYRO3 signaling can be initated through a ligand-independent mechanism (Taylor et al., 1995; Heiring et al., 2004). Three tyrosine residues (Y681, Y685, Y686) located within the activation loop of the kinase domain of the TYRO3 receptor correspond to three tyrosine residues in the MERTK receptor kinase domain, which have been identified as sites of autophosphorylation, however, there is no direct evidence that Y681, Y685, and Y686 are autophosphorylated in the TYRO3 receptor (Linger et al., 2008). TYRO3 phosphorylation has been linked to the activation of ERK1/ERK2 and AKT (Chen et al., 1997; Lan et al., 2000; Prieto et al., 2007), but the downstream signaling events following ligand binding of the TYRO3 receptor are poorly understood. Studies have shown potential interactions between TYRO3 and RanBMP, protein phosphatase 1 (PP1) and the p85 subunit of PI3K (via one of its SH2 domains), as well as members of the Src family kinases (Toshima et al., 1995; Lan et al., 2000; Hafizi et al., 2005).



Expression High levels of TYRO3 expression are detected in the nervous system, including the neocortex, hippocampus and cerebellum. TYRO3 is also expressed in monocytes, macrophages, platelets, dendritic cells and NK cells. TYRO3 has also been found in the breast, ovary, testis, lung, kidney, retinal pigment epithelium and osteoclasts (Linger et al., 2008). Upregulation of the TYRO3 receptor has been found in AML, CML, multiple myeloma, and melanoma, as well as uterine endometrial cancers (Sun et al., 2003; Linger et al., 2008; Zhu et al., 2009).

Localisation TYRO3 is a transmembrane receptor tyrosine kinase. Function TYRO3 activation and downstream signaling through MAPK/ERK and PI3K/AKT may facilitate the cellular functions of TYRO3, including actin reorganization/cell migration and cell survival. Within the brain, activation of MAPK and PI3K pathways via TYRO3 may lead to expression of genes involved in alterations in the consolidation of memories, addictive behaviors, and circadian rhythms, as well as modulating synaptic plasticity (Prieto et al., 2007). TYRO3 has also been shown to mediate the survival and migration of Gonadotropin-releasing hormone (GnRH) neurons within the forebrain (Pierce et al., 2008). There is evidence suggesting that TYRO3 plays a role in the clearance of apoptotic cells by dendritic cells, and to a lesser extent, macrophages and is essential for NK cell maturation and differentiation (Caraux et al., 2006; Seitz et al., 2007). TYRO3 is necessary for normal platelet aggregation and clot stabilization (Angelillo-Scherrer et al., 2005). TYRO3 may also mediate cell entry by filoviruses (Shimojima et al., 2006). In addition to its functions within the brain and immune cells, TYRO3 is also involved in the reabsorption of bone by osteoclasts (Nakamura et al., 1998).

Homology The two Ig domains and two FNIII domains within the extracelluar domain of TYRO3 are shared with the other members of the TAM family, AXL and MERTK. Within the extracellular regions, the TAM receptors share 31-36% sequence identity (52-57% similarity). The protein sequences in the intracellular domains are 54-59% identical (72-75% similar), with higher homology in the tyrosine kinase domains (Graham et al., 1995).

Mutations Note No mutations in TYRO3 have been documented.

Implicated in Malignancy Disease TYRO3, as well as the other TAM receptor family members have been implicated in several malignant diseases. Studies have shown that TYRO3 expression is upregulated in AML, CML, multiple myeloma, endometrial cancer and melanoma (Liu et al., 1988; Crosier et al., 1995; De Vos et al., 2001; Sun et al., 2003; Zhu et al., 2009). In addition to TYRO3 overexpression in many cancers, it has also been shown to have transforming abilities (Lan et al., 2000). TYRO3, like its family members, may function as a prosurvival factor in tumorigenesis. In melanoma cells, TYRO3 knockdown inhibits proliferation and leads to increased sensitivity to chemotherapeutic agents in vitro (Zhu et al., 2009).

Autoimmune disease Disease Triple mutant mice that lack all three TAM receptors (TYRO3, AXL and MERTK) have a lymphoproliferative disorder of broad-spectrum autoimmunity. Specifically, triple mutant mice have high titers of auto-antibodies to nucleoproteins, dsDNA and collagen, leading to the development of diseases resembling rheumatoid arthritis, pemphigus vulgaris and systemic lupus erythematosus (Lu et al., 2001). These finding suggest a role for TYRO3 in regulation of the immune system however, no human cases have been reported.

References Liu E, Hjelle B, Bishop JM. Transforming genes in chronic myelogenous leukemia. Proc Natl Acad Sci U S A. 1988 Mar;85(6):1952-6

Polvi A, Armstrong E, Lai C, Lemke G, Huebner K, Spritz RA, Guida LC, Nicholls RD, Alitalo K. The human TYRO3 gene and pseudogene are located in chromosome 15q14-q25. Gene. 1993 Dec 8;134(2):289-93

Dai W, Pan H, Hassanain H, Gupta SL, Murphy MJ Jr. Molecular cloning of a novel receptor tyrosine kinase, tif, highly expressed in human ovary and testis. Oncogene. 1994 Mar;9(3):975-9

Graham DK, Dawson TL, Mullaney DL, Snodgrass HR, Earp HS. Cloning and mRNA expression analysis of a novel human protooncogene, c-mer. Cell Growth Differ. 1994 Jun;5(6):647-57

Ohashi K, Mizuno K, Kuma K, Miyata T, Nakamura T. Cloning of the cDNA for a novel receptor tyrosine kinase, Sky, predominantly expressed in brain. Oncogene. 1994 Mar;9(3):699-705

Biesecker LG, Giannola DM, Emerson SG. Identification of alternative exons, including a novel exon, in the tyrosine kinase receptor gene Etk2/tyro3 that explain differences in 5' cDNA sequences. Oncogene. 1995 Jun 1;10(11):2239-42



Crosier PS, Hall LR, Vitas MR, Lewis PM, Crosier KE. Identification of a novel receptor tyrosine kinase expressed in acute myeloid leukemic blasts. Leuk Lymphoma. 1995 Aug;18(5-6):443-9

Graham DK, Bowman GW, Dawson TL, Stanford WL, Earp HS, Snodgrass HR. Cloning and developmental expression analysis of the murine c-mer tyrosine kinase. Oncogene. 1995 Jun 15;10(12):2349-59

Taylor IC, Roy S, Varmus HE. Overexpression of the Sky receptor tyrosine kinase at the cell surface or in the cytoplasm results in ligand-independent activation. Oncogene. 1995 Dec 21;11(12):2619-26

Toshima J, Ohashi K, Iwashita S, Mizuno K. Autophosphorylation activity and association with Src family kinase of Sky receptor tyrosine kinase. Biochem Biophys Res Commun. 1995 Apr 17;209(2):656-63

Lewis PM, Crosier KE, Wood CR, Crosier PS. Analysis of the murine Dtk gene identifies conservation of genomic structure within a new receptor tyrosine kinase subfamily. Genomics. 1996 Jan 1;31(1):13-9

Chen J, Carey K, Godowski PJ. Identification of Gas6 as a ligand for Mer, a neural cell adhesion molecule related receptor tyrosine kinase implicated in cellular transformation. Oncogene. 1997 May 1;14(17):2033-9

Nakamura YS, Hakeda Y, Takakura N, Kameda T, Hamaguchi I, Miyamoto T, Kakudo S, Nakano T, Kumegawa M, Suda T. Tyro 3 receptor tyrosine kinase and its ligand, Gas6, stimulate the function of osteoclasts. Stem Cells. 1998;16(3):229-38

Lu Q, Gore M, Zhang Q, Camenisch T, Boast S, Casagranda F, Lai C, Skinner MK, Klein R, Matsushima GK, Earp HS, Goff SP, Lemke G. Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Nature. 1999 Apr 22;398(6729):723-8

Lan Z, Wu H, Li W, Wu S, Lu L, Xu M, Dai W. Transforming activity of receptor tyrosine kinase tyro3 is mediated, at least in part, by the PI3 kinase-signaling pathway. Blood. 2000 Jan 15;95(2):633-8

De Vos J, Couderc G, Tarte K, Jourdan M, Requirand G, Delteil MC, Rossi JF, Mechti N, Klein B. Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays. Blood. 2001 Aug 1;98(3):771-80

Lu Q, Lemke G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science. 2001 Jul 13;293(5528):306-11

Sun WS, Fujimoto J, Tamaya T. Coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases Axl and Sky in human uterine endometrial cancers. Ann Oncol. 2003 Jun;14(6):898-906

Heiring C, Dahlbäck B, Muller YA. Ligand recognition and homophilic interactions in Tyro3: structural insights into the Axl/Tyro3 receptor tyrosine kinase family. J Biol Chem. 2004 Feb 20;279(8):6952-8

Angelillo-Scherrer A, Burnier L, Flores N, Savi P, DeMol M, Schaeffer P, Herbert JM, Lemke G, Goff SP, Matsushima GK, Earp HS, Vesin C, Hoylaerts MF, Plaisance S, Collen D,

Conway EM, Wehrle-Haller B, Carmeliet P. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J Clin Invest. 2005 Feb;115(2):237-46

Hafizi S, Gustafsson A, Stenhoff J, Dahlbäck B. The Ran binding protein RanBPM interacts with Axl and Sky receptor tyrosine kinases. Int J Biochem Cell Biol. 2005 Nov;37(11):2344-56

Caraux A, Lu Q, Fernandez N, Riou S, Di Santo JP, Raulet DH, Lemke G, Roth C. Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases. Nat Immunol. 2006 Jul;7(7):747-54

Shimojima M, Takada A, Ebihara H, Neumann G, Fujioka K, Irimura T, Jones S, Feldmann H, Kawaoka Y. Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J Virol. 2006 Oct;80(20):10109-16

Prieto AL, O'Dell S, Varnum B, Lai C. Localization and signaling of the receptor protein tyrosine kinase Tyro3 in cortical and hippocampal neurons. Neuroscience. 2007 Dec 5;150(2):319-34

Seitz HM, Camenisch TD, Lemke G, Earp HS, Matsushima GK. Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J Immunol. 2007 May 1;178(9):5635-42

Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008;100:35-83

Pierce A, Bliesner B, Xu M, Nielsen-Preiss S, Lemke G, Tobet S, Wierman ME. Axl and Tyro3 modulate female reproduction by influencing gonadotropin-releasing hormone neuron survival and migration. Mol Endocrinol. 2008 Nov;22(11):2481-95

Hubbard TJ, Aken BL, Ayling S, Ballester B, Beal K, Bragin E, Brent S, Chen Y, Clapham P, Clarke L, Coates G, Fairley S, Fitzgerald S, Fernandez-Banet J, Gordon L, Graf S, Haider S, Hammond M, Holland R, Howe K, Jenkinson A, Johnson N, Kahari A, Keefe D, Keenan S, Kinsella R, Kokocinski F, Kulesha E, Lawson D, Longden I, Megy K, Meidl P, Overduin B, Parker A, Pritchard B, Rios D, Schuster M, Slater G, Smedley D, Spooner W, Spudich G, Trevanion S, Vilella A, Vogel J, White S, Wilder S, Zadissa A, Birney E, Cunningham F, Curwen V, Durbin R, Fernandez-Suarez XM, Herrero J, Kasprzyk A, Proctor G, Smith J, Searle S, Flicek P. Ensembl 2009. Nucleic Acids Res. 2009 Jan;37(Database issue):D690-7

Zhu S, Wurdak H, Wang Y, Galkin A, Tao H, Li J, Lyssiotis CA, Yan F, Tu BP, Miraglia L, Walker J, Sun F, Orth A, Schultz PG, Wu X. A genomic screen identifies TYRO3 as a MITF regulator in melanoma. Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):17025-30


Jacobsen KM, Linger RMA, Graham DK. TYRO3 (TYRO3 protein tyrosine kinase). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1050-1053.

Gene Section Review




YAP1 (Yes-associated protein 1, 65kDa) Silvia Di Agostino, Sabrina Strano, Giovanni Blandino

Molecular Medicine Department, Regina Elena Cancer Institute, Rome 00144, Italy (SD, SS, GB)


Online updated version : http://AtlasGeneticsOncology.org/Genes/YAP1ID42855ch11q22.html DOI: 10.4267/2042/44893


Identity Other names: YAP; YAP2; YAP65; YKI

HGNC (Hugo): YAP1

Location: 11q22.1

Local order: Genes flanking YAP1 on 11q22.1 are:

- CNTN5, contactin-5, 11q22.1

- FLJ42335, Hypothetical protein LOC100128386, 11q22.1

- FLJ32810, Rho-type GTPase-activating protein FLJ32810, 11q22.1

- TMEM133, transmembrane protein 133, 11q22.1

- PGR, progesterone receptor, 11q22-q23

- TRPC6, transient receptor potential cation channel, subfamily C, member 6, 11q22.1

- ANGPTL5, angiopoietin-like 5, 11q22.1

- YAP1, Yes-associated protein 1, 11q22.1

- RPS6P17, ribosomal protein S6 pseudogene 17, 11q22.2

- BIRC3, baculoviral IAP repeat-containing protein 3, 11q22.2

- BIRC2, baculoviral IAP repeat-containing protein 2, 11q22.2

- MMP20, matrix metalloproteinase 20, 11q22.2

Note: YAP interacts with the SH3 domain of c-Yes (and also c-Src), through a stretch of proline residues. YAP protein contains a WW domain that is found in various structural, regulatory and signaling molecules in yeast, nematode, and mammals, and it is involved in protein-protein interaction.

DNA/RNA Description The genomic size is 122863 bases and the gene is located on plus strand. YAP1 gene is composed of 7 exons. The open reading frame of the coding region is 1364 bp. No polymorphism of YAP1 is known. SNP: 1590 single nucleotide polymorphisms are present in the human gene according to NCBI database.

Transcription The human YAP1 coding sequence consists of 1364 bp from the start codon to the stop codon. A differentially spliced isoform of YAP1 (9 exons), with two WW domains known as YAP2 also exists (Sudol et al., 1995).

Pseudogene No pseudogene of YAP1 is known.

YAP1 mRNA spans approximately 5218 bases and has 7 exons.

YAP1 (Yes-associated protein 1, 65kDa) Di Agostino S, et al.


Structure of human YAP isoforms. The protein domains and their length (indicated by number of limiting residues) are reported. YAP1 contains a proline-rich domain, a WW domain, a glutamine rich domain and portion of protein that regulates the transcription activation.

Protein Note The Yes-associated protein (YAP), a critical mediator of p73 function, binds p73 to regulate its transcriptional activity (Strano et al., 2001) and subsequent cell-death induction (Basu et al., 2003). This binding is negatively regulated by AKT-mediated YAP phosphorylation (Basu et al., 2003) and enhanced by DNA damage (Strano et al., 2005). In addition to increase p73 transcriptional activity via the p300 acetyltansferase (Strano et al., 2005), YAP can stabilize p73 protein in a posttranslational manner by competing with the ITCH E3-ligase for binding to p73 (Levy et al., 2007).

Description Structure: YAP protein consists of 454 amino acids, with a molecular weight of 65 kDa. It was identified as a protein that interacted with the non receptor tyrosine kinase c-Yes, which is a member of the Src family (Sudol, 1994). In fact, Yap is able to interact with the SH3 domain of c-Yes (and also c-Src), through a stretch of proline residues; this proline-rich region is able to interact with SH3 domains of many other proteins. In addition Yap contains another binding domain of a different nature. Due to the presence of two tryptophan residues, which appear to be conserved along evolution and that play an important role in the domain structure and function, it was named WW domain (Sudol et al., 1995; Sudol and Hunter, 2000). The WW domain binds to short stretches of prolines (PY motif), and therefore mediating the interaction between proteins. The WW domain of Yap belongs to the first of four different classes that differ in terms of the sequence of the interacting motif, a PPxY in the case of WW type I. Yap has been found to interact with many proteins, whose function often is quite substantially different, and the majority of these interactions are mostly mediated by the WW domain (Bertini et al., 2009). The interaction with PEBP2 (a RunX transcription factor) was the first example of Yap1 as a co-activator of transcription. The WW domain of Yap1 interacts with the PY motif present in the transcription activation domain of PEBP2 and in this occasion Yap1 was reported for the first time to have a strong intrinsic transactivation activity (Yagi et al., 1999). The transcriptional coactivator Yes-associated protein (YAP) was shown to interact with and to enhance p73-dependent apoptosis in response to DNA damage (Strano et al., 2001; Strano et al., 2005).

Interactors of YAP Reference

YES Sudol et al., 1995 WBP1 and WBP2 Chen and Sudol, 1995 NFE2 Gavva et al., 1997 RUNX1 and RUNX2 Yagi et al., 1999 EBP50 Mohler et al., 1999 TP53BP2 Espanel and Sudol, 2001 TP73 Strano et al., 2001 TEAD1, 2, 3, 4 Vassilev et al., 2001 SMAD7 Ferrigno et al., 2002 AKT Basu et al., 2003 ERBB4 Komuro et al., 2003 HNRNPU Howell et al., 2004 LATS1 Hao et al., 2008 ABL1 Levy et al., 2008 PML Lapi et al., 2008 EGR1 Zagurovskaya et al., 2009

Table 1: Modified by Bertini et al., 2009.

Expression By Northern blot analysis YAP1 expression shows a major transcript of approximately 5 kb in several human tissues. High expression was found in placenta, prostate, testis, ovary, and small intestine, and lower expression was found in brain, liver, and spleen. No expression was found in peripheral blood leukocytes (Sudol et al., 1995). YAP1 is the predominant isoform and is ubiquitously expressed in the major part of tissues for twelve normal human tissues (out of 28 tissues shown) hybridized against Affymetrix GeneChips HG-U95A-E (GeneNote data) and for 22 normal human tissues hybridized against HG-U133A (GNF Symatlas data) (Su et al., 2004).

Localisation Posttranslational modification of YAP determines its binding and localisation. Lapi et al. (2008) have shown Akt-mediated phosphorylation promotes YAP cytoplasmic retention, demonstrating that active Akt counters cisplatin-induced increases in PML transcription via the YAP-p73 complex. Recently, Levy et al. (2008) have also shown that cisplatin induces ABL1-mediated YAP phosphorylation, resulting in



YAP nuclear localization and increased p73 binding and activation of pro-apoptotic genes. YAP binding of p73 and its coordination of other binding proteins probably depend on an integration of phosphorylation by AKT, ABL1, and other kinases. However, the shuttling of Yap between nucleus and cytoplasm has emerged as an important means for regulating the activity of this protein.

Function Yap is a small protein that binds to many transcription factors and modulates their activity. Yap increases the ability of p73 to induce apoptosis as a consequence of damage to the DNA, and therefore its activity was thought to favor tumor suppression. However, other studies have recently shown a role for Yap in cell differentiation, cell transformation and in the regulation of organ size. It has been demonstrated that the Drosophila Hippo pathway has a mammalian equivalent, and that Yap is part of this pathway, where it could stimulate proliferation (Pan, 2007; Harvey et al., 2007). Apoptosis: The transcriptional coactivator Yes-associated protein (YAP) has demonstrated to interact with and to enhance p73-dependent apoptosis in response to DNA damage (Strano et al., 2001; Strano et al., 2005). It has been reported that YAP is phosphorylated by AKT, and such modification impairs YAP-nuclear translocation and attenuates p73-mediated apoptosis (Basu et al., 2003). Recently, it was demonstrated that p73 is required for the nuclear translocation of endogenous YAP in cells exposed to cisplatin and that YAP is recruited by PML into nuclear bodies to promote p73 transcriptional activity (Strano et al., 2005). It was found that YAP contributes to p73 stabilization in response to DNA damage and promotes p73-dependent apoptosis through the specific and selective coactivation of apoptotic p73 target genes and potentiation of p300-mediated acetylation of p73 (Strano et al., 2005). Then, it was described the existence of a proapoptotic autoregulatory feedback loop between p73, YAP, and the promyelocytic leukemia (PML) tumor suppressor gene (Lapi et al., 2008). PML is a direct transcriptional target of p73/YAP. PML contributes to the p73-dependent apoptotic response by regulating YAP stability. Importantly, PML and YAP physically interact through their PVPVY and WW domains, respectively, causing YAP stabilization upon cisplatin treatment, which occurs through PML mediated sumoylation (Lapi et al., 2008). Together with this proapoptotic role, YAP recently was identified as a tumor suppressor in breast cancer (Yuan et al., 2008). The findings that YAP plays opposing roles in tissue growth/development and DNA damage/apoptosis appear at first contradictory, but this can be explained if YAP binds and activates or inactivates different transcription factors to

differentially regulate either pro-growth or pro-apoptotic genes. Organ size and cell differentiation: Yap plays an important role in controlling organ growth. The works done on Drosophila show how a disrupted Hippo signalling pathway has a negative impact on the growth of imaginal discs (Pan et al., 2007) and how the presence of mutated forms of Yap in particular has an effect on size and shape of fly wings (Zhao et al., 2007). In addition Dong et al. (2007) reported that overexpression of Yap in mice increases liver size, and in the long term it induces nodules which present characteristics of HCC (Dong et al., 2007). This is in accordance with another important study where increased levels of Yap are shown to enlarge liver size in a reversible manner (Camargo et al., 2007). However, many questions are unsolved. For instance, it would be interesting to check whether the Hippo pathway plays a role in choices taken by Yap during cell differentiation; to verify whether activity of Yap could be extended to a cellular context beside intestine epithelium; to find the molecular mechanism used by Yap to control transcription of those genes that are in charge of cell differentiation; and obviously, a screen for these genes.

Homology Orthologs: YAP1 is evolutionarily principally conserved in 8 eukaryotes: Canis familiaris, Pan troglodytes, Bos taurus, Mus musculus, Galus gallus, Danio rerio, Xenopus laevis, Silurana tropicalis. Orthologies between human and Drosophyla melanogaster, Caenorabditis elegans and Saccaromyces cerevisiae are quite low. For details see: HomoloGene.

Mutations Note No mutations of YAP1 are known.

Implicated in Various cancers Note Overholtzer and collaborators identified a mouse mammary tumor with a small amplicon involving the Yap1 gene. They noted that amplification of the syntenic locus on human chromosome 11q22 is present in different cancers (breast, colon, prostate). Overexpression of human YAP1 in nontransformed mammary epithelial cells induced epithelial-to-mesenchymal transition, suppression of apoptosis, growth factor-independent proliferation, and anchorage-independent growth in soft agar (Overholtzer et al., 2006). They concluded that YAP1 contributes to malignant transformation in cancers harboring the 11q22 amplicon.



Tumor suppression Note As previously described, the regulation of p73 activity by YAP has been investigated in the context of DNA-damage signaling. As an activating cofactor for a proapoptotic transcription factor, it was assumed that YAP plays a tumor suppressor role in cancer. YAP has also been identified as an oncogenic progrowth, cell size regulator in both Drosophila melanogaster and mammalian cells (Dong et al., 2007; Zhao et al., 2007). The mechanism for the growth control role of YAP or its fly homolog, Yki, is the result of its inactivation by the MST2 (HIPPO in fly) pathway, where the tumor suppressor LATS1 kinase (WTS in fly) directly phosphorylates YAP (Yki), inhibiting its coactivation of the TEAD (Scalloped in fly) transcription factor to upregulate pro-growth genes (Zhao et al., 2008). The MST2/LATS1 pathway can also enhance YAP-p73 binding and activation of proapoptotic genes downstream of Fas signaling in breast cancer cells (Matallanas et al., 2007).

References Sudol M. Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene. 1994 Aug;9(8):2145-52

Chen HI, Sudol M. The WW domain of Yes-associated protein binds a proline-rich ligand that differs from the consensus established for Src homology 3-binding modules. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7819-23

Sudol M, Bork P, Einbond A, Kastury K, Druck T, Negrini M, Huebner K, Lehman D. Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain. J Biol Chem. 1995 Jun 16;270(24):14733-41

Gavva NR, Gavva R, Ermekova K, Sudol M, Shen CJ. Interaction of WW domains with hematopoietic transcription factor p45/NF-E2 and RNA polymerase II. J Biol Chem. 1997 Sep 26;272(39):24105-8

Espanel X, Sudol M. A single point mutation in a group I WW domain shifts its specificity to that of group II WW domains. J Biol Chem. 1999 Jun 11;274(24):17284-9

Mohler PJ, Kreda SM, Boucher RC, Sudol M, Stutts MJ, Milgram SL. Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50. J Cell Biol. 1999 Nov 15;147(4):879-90

Yagi R, Chen LF, Shigesada K, Murakami Y, Ito Y. A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J. 1999 May 4;18(9):2551-62

Sudol M, Hunter T. NeW wrinkles for an old domain. Cell. 2000 Dec 22;103(7):1001-4

Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A, Oren M, Sudol M, Cesareni G, Blandino G. Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem. 2001 May 4;276(18):15164-73

Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML. TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the

cytoplasm. Genes Dev. 2001 May 15;15(10):1229-41

Ferrigno O, Lallemand F, Verrecchia F, L'Hoste S, Camonis J, Atfi A, Mauviel A. Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Oncogene. 2002 Jul 25;21(32):4879-84

Basu S, Totty NF, Irwin MS, Sudol M, Downward J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell. 2003 Jan;11(1):11-23

Komuro A, Nagai M, Navin NE, Sudol M. WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem. 2003 Aug 29;278(35):33334-41

Howell M, Borchers C, Milgram SL. Heterogeneous nuclear ribonuclear protein U associates with YAP and regulates its co-activation of Bax transcription. J Biol Chem. 2004 Jun 18;279(25):26300-6

Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP, Walker JR, Hogenesch JB. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7

Strano S, Monti O, Pediconi N, Baccarini A, Fontemaggi G, Lapi E, Mantovani F, Damalas A, Citro G, Sacchi A, Del Sal G, Levrero M, Blandino G. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage. Mol Cell. 2005 May 13;18(4):447-59

Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12405-10

Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, Brummelkamp TR. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol. 2007 Dec 4;17(23):2054-60

Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan D. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007 Sep 21;130(6):1120-33

Harvey K, Tapon N. The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network. Nat Rev Cancer. 2007 Mar;7(3):182-91

Levy D, Adamovich Y, Reuven N, Shaul Y. The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73. Cell Death Differ. 2007 Apr;14(4):743-51

Matallanas D, Romano D, Yee K, Meissl K, Kucerova L, Piazzolla D, Baccarini M, Vass JK, Kolch W, O'neill E. RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein. Mol Cell. 2007 Sep 21;27(6):962-75

Pan D. Hippo signaling in organ size control. Genes Dev. 2007 Apr 15;21(8):886-97

Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, Zheng P, Ye K, Chinnaiyan A, Halder G, Lai ZC, Guan KL. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007 Nov 1;21(21):2747-61

Hao Y, Chun A, Cheung K, Rashidi B, Yang X. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem. 2008 Feb 29;283(9):5496-509



Lapi E, Di Agostino S, Donzelli S, Gal H, Domany E, Rechavi G, Pandolfi PP, Givol D, Strano S, Lu X, Blandino G. PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. Mol Cell. 2008 Dec 26;32(6):803-14

Levy D, Adamovich Y, Reuven N, Shaul Y. Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage. Mol Cell. 2008 Feb 15;29(3):350-61

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Gene Section Review




ALK (anaplastic lymphoma receptor tyrosine kinase) Michèle Allouche

INSERM U.563 CPTP, Bat. B, Pavillon Lefevre, CHU Purpan, BP 3028, 31024 Toulouse Cedex 3, France (MA)

Published in Atlas Database: February 2010

Online updated version : http://AtlasGeneticsOncology.org/Genes/ALK.html DOI: 10.4267/2042/44894

This article is an update of : Huret JL, Senon S. ALK (anaplastic lymphoma kinase). Atlas Genet Cytogenet Oncol Haematol 2003;7(4):217-220. Huret JL. ALK (anaplastic lymphoma kinase). Atlas Genet Cytogenet Oncol Haematol 2001;5(4):249-251. Huret JL. ALK (anaplastic lymphoma kinase). Atlas Genet Cytogenet Oncol Haematol 1997;1(1):4. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: anaplastic lymphoma kinase (Ki-1); CD246

HGNC (Hugo): ALK

Location: 2p23

ALK (2p23) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

DNA/RNA Description The gene is composed of 29 exons spanning in a region of 728793 bp.

Transcription 6226 bp cDNA; coding sequence: 4.9 kb.

Protein Description 1620 amino acids; 177 kDa; after glycosylation, produces a 200 kDa mature glycoprotein; type I transmembrane receptor; composed of an extracellular region (containing two MAM and one LDLa domains, and one glycin-rich region), a transmembrane, and an intracellular region (composed of a juxta-membrane domain, a tyrosine kinase domain (1122-1376), and a C-terminal domain; dimerization.

Expression Is tissue specific; mainly in: central and peripheral nervous system during development (less in adult), and testis; not in the lymphocytes.

Localisation Cell membrane.

ALK (anaplastic lymphoma receptor tyrosine kinase) Allouche M


Function ALK is a membrane associated tyrosine kinase receptor of the insulin receptor superfamily. The function of the full-length ALK receptor is poorly understood. It has a probable role in the central and peripheral nervous system development and maintenance. ALK is a dependence receptor, which may exert antagonist functions, proapoptotic or antiapoptotic, depending on the absence or presence of a ligand (Mourali et al., 2006). Dependence receptors have a potential role in cancer and development (Allouche, 2007). Ligands available for this demonstration were agonist anti-ALK antibodies (Motegi et al., 2004; Moog-Lutz et al., 2005). If a specific ALK ligand (jelly belly) has been clearly identified in Drosophila, it has no homologue in vertebrates (Palmer et al., 2009). ALK is still an orphan receptor, given the high level of controversy about pleiotrophin and midkine, which have been proposed as ligands by Stoica et al. (2001, 2002) (see review by Chiarle et al., 2008).

Homology Homologies with the insulin receptor super family: LTK (leucocyte tyrosine kinase), IGF1-R, IRb, TRKA, ROS (homolog of the drosophila Sevenless).

Implicated in ALK+ anaplastic large cell lymphoma (ALCL) Disease ALCL are high grade non Hodgkin lymphomas. ALK+ ALCL are ALCL where ALK is involved in a fusion gene; systemic ALK+ ALCL (as opposed to cutaneous ALCL, which are usually ALK negative) represent 60 to 80 % of ALCL cases (they are CD30+, ALK+); 70 to 80% of ALK+ ALCL cases bear a t(2;5); the remaining ALK+ ALCL cases bear variant translocations "X-ALK", where X designates a partner gene.

Prognosis Although presenting as a high grade tumour, an 80% five year survival is associated with this anomaly, but recurrence is a concern.

Cytogenetics The prototype anomaly is the t(2;5)(p23;q35) generating the NPM1-ALK fusion. Alternative anomalies involving the ALK gene in ALCL are described below as "cytoplasmic ALK+ ALCL" cases, among which the t(1;2) TPM3-ALK is found in 20% of ALK+ ALCL. Complex karyotypes may also be found.

Hybrid/Mutated gene 5' NPM1 - 3' ALK on the der(5).

Abnormal protein 680 amino acids, 80 kDa; N-term 117 amino acids from NPM1 fused to the 563 C-term amino acids of ALK

(i.e. composed of the oligomerization domain and the metal binding site of NPM1, and the entire cytoplasmic portion of ALK); no apparent expression of the ALK/NPM1 counterpart. Characteristic localisation in the cytoplasm, nucleus and nucleolus, due to heterooligomerization of NPM1-ALK and normal NPM1 whereas the normal NPM1 protein is confined to the nucleus and nucleolus; constitutive activation of the catalytic domain of ALK.

Oncogenesis Via the kinase function activated by oligomerization of NPM1-ALK mediated by the NPM1 part.

Cytoplasmic ALK+ anaplasic large cell lymphoma (ALCL) Prognosis Present a favourable prognosis comparable to the one found in t(2;5) ALK+ ALCL.

Cytogenetics Either t(X;2)(q11;p23), t(1;2)(q25;p23), inv(2)(p23q35), t(2;3)(p23;q21), t(2;17)(p23;q23), t(2;17)(p23;q25), t(2;19)(p23;p13.1) or t(2;22)(p23;q11.2).

Hybrid/Mutated gene 5' MSN, TPM3, ATIC, TFG, CLTC, ALO17, TPM4 or MYH9 - 3' ALK.

Abnormal protein N-term amino acids from the partner gene fused to the 563 C-term amino acids (in the great majority of cases) from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); cytoplasmic/membraneous localisation only.

Oncogenesis The partner gene seems to provoke the dimerization of the fused X-ALK, which should lead to constitutive autophosphorylation and activation of the ALK tyrosine kinase, as for NPM1-ALK (see t(2;5)(p23;q35)).

Inflammatory myofibroblastic tumours with 2p23 rearrangements Disease Rare soft tissue tumour found in children and young adults about one third to half of inflammatory myofibroblastic tumour cases present with a 2p23 rearrangement involving ALK.

Prognosis Good prognosis.

Cytogenetics t(1;2)(q25;p23), t(2;2)(p23;q13) or inv(2)(p23;q11-13), inv(2)(p23;q35), t(2;4)(p23;q21), t(2;11)(p23;p15), t(2;17)(p23;q23), or t(2;19)(p23;p13.1) so far.

Hybrid/Mutated gene 5' TPM3 in the t(1;2), RANBP2 in the t(2;2) or inv(2)(p23;q11-13), 5' ATIC in inv(2)(p23;q35), 5'



SEC31L1 in t(2;4), 5' CARS in the t(2;11), 5' CLTC in the t(2;17), or 5' TPM4 in the t(2;19) - 3' ALK.

Abnormal protein N-term amino acids from the partner gene fused to the 563 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); homodimerization of the fusion protein is known or suspected.

Oncogenesis Fused-ALK is constitutively activated.

ALK+ diffuse large B-cell lymphoma (DLBCL) Disease Very rare form of DLBCL (40 cases described) expressing either ALK in fusion with CLTC (cytoplasmic granular localisation) associated to t(2;17)(p23;q23) (most frequently), or (rarely) NPM1-ALK in t(2;5)(p23;q35); tumours are EMA+, CD30- and CD20-negative.

Prognosis Poor prognosis: aggressive lymphoma with 25% five year survival.

Cytogenetics t(2;5)(p23;q35) or t(2;17)(p23;q23).

Hybrid/Mutated gene 5' NPM1 or CLTC - 3' ALK.

Abnormal protein N-term amino acids from the partner gene fused to the 563 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); homodimerization of the fusion protein is known or suspected.

Oncogenesis Fused-ALK is constitutively activated.

ALK+ non-small cell lung cancer (NSCLC) Disease 1-6 % of all NSCLC present a rearrangement involving ALK fused to EML4 in an inv(2)(p21p23); studies on East Asian and American/European patients (Soda et al., 2007; Perner et al., 2008).

Prognosis 50% survival at 24 months, so far (first identification in 2007).

Cytogenetics inv(2)(p21;p23).

Hybrid/Mutated gene 5' EML4 - 3' ALK; multiple variants of EML4-ALK noted depending on the breakpoint on the EML gene;

ALK fusion starts at a portion encoded by exon 20.

Abnormal protein N-term amino acids from the partner gene fused to the 563 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); homodimerization of the fusion protein is known or suspected; protein is difficult to detect by classical immunohistochemistry methods (low expression).

Oncogenesis Fused-ALK is constitutively activated. Note: in a European study, EML4-ALK fusion transcript has also been found in up to 9% non-tumour lung tissue from lung tumour patients. Interestingly, the EML4-ALK transcript was not detected in matching tumour samples from the same patients (Martelli et al., 2009).

Familial neuroblastoma and sporadic neuroblastoma Disease Neuroblastoma is a cancer of early childhood that arises from the developing autonomic nervous system, giving rise to peripheral tumours. It is the most common malignancy diagnosed in the first year of life and shows a wide range of clinical phenotypes, with a few patients having tumours that regress spontaneously, whereas most patients have aggressive metastatic disease. It can be transmitted in an autosomal dominant mode as a familial predisposition, or occur as a sporadic disease.

Prognosis Aggressive neuroblastoma cases have survival probabilities of less then 40% despite intensive chemoradiotherapy, and the disease continues to account for 15% of childhood cancer mortality.

Cytogenetics Gene amplifications or mutations of ALK; Associated alterations: tumours from patients with an aggressive phenotype often show amplification of the MYCN oncogene, and/or deletions of chromosome arms 1p and 11q.

Hybrid/Mutated gene Several point mutations located in the coding region of the receptor intracellular portion, mostly in the tyrosine kinase domain.

Abnormal protein 54 ALK mutations reported, affecting 12 different residues (Caren et al., 2008; Chen et al., 2008; George et al., 2008; Janoueix-Lerosey et al., 2008; Mosse et al., 2008); two hotspots: F1174 and R1275. Most frequent germline mutations (familial cases): G1128A, R1192P, R1275Q.



Most frequent somatic mutations (sporadic cases): F1174L/I, F1245C/V.

Oncogenesis Gene amplifications or point mutations both confer constitutive kinase activation.

Breakpoints Note Most of the breakpoints occur in the same intron of ALK, whichever partner is involved in the fusion protein.

To be noted Note ALK in fusion to several gene partners, is found implicated both in hematopoietic and non-hematopoietic solid tumours; this was a new concept in 2003, that several different types of tumour may result from the same chromosomal/genes rearrangement(s).

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Gene Section Review




AXL (AXL receptor tyrosine kinase) Justine Migdall, Douglas K Graham

Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA (JM, DKG)


Online updated version: http://AtlasGeneticsOncology.org/Genes/AXLID733ch19q13.html DOI: 10.4267/2042/44895


Identity Other names: JTK11; UFO

HGNC (Hugo): AXL

Location: 19q13.2

DNA/RNA Description The human AXL gene is located on chromosome 19q13.2 and encodes 20 exons. Exons 1-10 encode the extracellular domain, which includes a signal peptide (exon 1), two immunoglobulin (Ig) domains (exons 2-3 and 4-5), and two fibronectin type III (FNIII) domains (exons 6-7 and 8-9). Exon 11 encodes a short extracellular region subject to

proteolytic cleavage (see protein description), as well as the entire transmembrane domain. Exons 12-20 encode the intracellular domain, which includes the tyrosine kinase domain (exons 13-20) (O'Bryan et al., 1991; Hubbard et al., 2009).

Transcription There are two 4.7 kb mRNA variants of AXL distinguished by the presence or absence of exon 10, a 27 bp region in the C-terminal end of the extracellular domain, via alternative splicing. Both variants exist ubiquitously and at much higher levels in many cancers. Although the longer transcript is more highly expressed in tumor tissue relative to its shorter counterpart, both forms of the protein have the same transforming potential (O'Bryan et al., 1991).

The diagram depicts the structure of the AXL gene (bottom) roughly aligned with its corresponding functional protein domains (top). Boxes represent individual exons with widths roughly relative to the base-pair length; connecting lines between exon boxes represent introns, which are drawn approximately 10-fold smaller to better align with the protein domains. The open-ended boxes of exons 1 and 20 indicate untranslated regions (not shown). Exon 10, which can be removed via alternative splicing, encodes an extracellular region at the C-terminal end of the second FNIII domain.

AXL (AXL receptor tyrosine kinase) Migdall J, Graham DK


The diagram on the top depicts the domain organization of the AXL receptor tyrosine kinase. The intracellular kinase domain includes the seven-residue sequence conserved among TAM family receptor tyrosine kinases: at positions 3 and 5 within this conserved sequence, AXL and MERTK contain isoleucine (I) residues, while TYRO3 contains leucine (L) residues. Proteolytic cleavage of residues between the transmembrane and closest FNIII domains renders a soluble isoform of AXL, which contains its fully functioning extracellular domains. The diagram on the bottom depicts the domain structure of GAS6, the AXL ligand. GAS6 is activated by vitamin K-dependent carboxylation of the gamma-carboxyglutamic acid (Gla) domain.

Protein Description The full-length AXL protein contains 894 amino acids and has a molecular weight of 104 kDa. As the extracellular domain contains six N-linked glycosylation sites, two other post-translationally modified forms weighing 120 and 140 kDa -representing partial and complete glycosylation, respectively- have been identified. The extracellular component of the AXL receptor contains two Ig-like domains (aa 37-124 for domain 1, 141-212 for domain 2) followed by two FNIII domains (aa 224-322 for domain 1, 325-428 for domain 2) (O'Bryan et al., 1991). This particular tandem arrangement defines AXL as part of the TAM family of receptor tyrosine kinases (RTKs), which also includes TYRO3 and MERTK (Graham et al., 1994). All three TAM family proteins bind the ligand GAS6, a vitamin K-dependent protein structurally similar to Protein S (PROS1), which activates MERTK and TYRO3 but not AXL (Prasad et al., 2006). Like all TAM family members, each immunoglobulin domain of the AXL receptor provides a binding site for each of the two laminin G-like (LG) domains of GAS6, the only identified ligand for AXL as of yet (Sasaki et al., 2006).

Carboxy-terminal to the second FNIII domain, fourteen amino acids (aa 438-451 in the longer variant) serve as a proteolytic cleavage site, yielding an 80 kD soluble form of AXL with only the extracellular domains of the full-length protein. As this cleavage site translates from exon 11, proteins from both transcript variants are subject to proteolysis. The intact ligand-binding domains in this soluble form highlight its potential role in signal transduction as an inhibitor of the membrane-bound receptor (O'Bryan et al., 1995). The intracellular tyrosine kinase domain of AXL contains the sequence KW(I/L)A(I/L)ES (aa 714-720), which is conserved among all TAM family RTKs. Within this signature motif, the third and fifth amino acids are isoleucine (I) in both AXL and MERTK, while leucine (L) occupies these positions in TYRO3 (Graham et al., 1994). Activation of the AXL receptor occurs within its intracellular domain and is characterized by the phosphorylation of tyrosine residues at sites that have yet to be defined. MERTK is the only TAM family member with validated tyrosine autophosphorylation sites; AXL also has three tyrosine residues -Y697, Y702, and Y703- conserved in sequence context within its kinase domain, but no evidence exists implicating their role in autophosphorylation (Ling et al., 1996). Numerous



mass spectrometry analyses confirm that these and several other tyrosine residues are, in fact, phosphorylated (Hornbeck et al., 2004), and a recent study demonstrated that phosphorylation occurs at Y702 and Y703 upon GAS6 stimulation (Pao-Chun et al., 2009). However, neither of these sites has been shown to directly regulate or interact with the downstream effectors of AXL activation. Three other tyrosine residues within the AXL intracellular domain -Y779, Y821, and Y866- mediate binding of various substrates, suggesting that they may be more likely candidates for autophosphorylation sites. Y779 partially contributes to binding PI3K, while Y866 plays an integral role in binding PLC. Y821 has been shown to be a critical docking site for multiple substrates, including PI3K, PLC, GRB2, c-SRC, and LCK (Braunger et al., 1997). Despite this evidence, an in vivo study refuted the significance of Y821 in AXL autophosphorylation and activation, as mutants without Y821 display normal GAS6-stimulated tyrosine phosphorylation (Fridell et al., 1996). Along with conventional ligand-induced dimerization and autophosphorylation, AXL activation can also occur through ligand-independent pathways. AXL overexpression causes homophilic binding between its extracellular domains on neighboring cells and leads to increased phosphorylation of its intracellular domain (Bellosta et al., 1995). AXL also engages in cross-talk with the IL-15 receptor, which transactivates AXL and requires it for survival from TNF-alpha-mediated apoptosis (Budagian et al., 2005).

Expression AXL is expressed throughout all tissue and cell types (O'Bryan et al., 1991). Higher expression is observed in endothelial cells, heart and skeletal muscle, liver, kidney, testis, platelets, myelomonocytic cells, hippocampus, and cerebellum (Neubauer et al., 1994; Bellosta et al., 1995; Graham et al., 1995; Angelillo-Scherrer et al., 2001). Relative to normal expression levels, AXL is increased in a number of disease states as reviewed by Linger et al (2008).

Localisation AXL is a transmembrane receptor tyrosine kinase.

Function Activation of the AXL receptor initiates various signaling pathways involved in cell survival, proliferation, apoptosis inhibition, migration, cell adhesion, and cytokine production. This is mediated via interactions with a spectrum of signaling molecules, including PI3K/Akt, ERK1/ERK2, GRB2, RAS, RAF1, MEK-1, and SOCS-1. Beyond its overexpression and oncogenic potential in numerous cancers, AXL has also been implicated in angiogenesis and metastasis (Linger et al., 2008).

Homology AXL and the two other TAM family members, MERTK and TYRO3, share 31-36% and 54-59% sequence identities in the extracellular and intracellular regions, respectively (Graham et al., 1995).

Mutations Note Although AXL overexpression is implicated in oncogenesis, no mutations in the gene have been identified as the underlying cause.

Implicated in Malignancy Disease The transforming properties of AXL were first identified in patients with chronic myelogenous leukemia (O'Bryan et al., 1991). AXL overexpression has also been reported in glioblastoma, melanoma, osteosarcoma, erythroid and megakaryocytic leukemias, and uterine, colon, prostate, thyroid, ovarian, and liver cancers (Linger et al., 2008). AXL overexpression positively correlates with tumor metastasis and invasiveness in a number of tumor types, including renal cell carcinoma (Chung et al., 2003), glioblastoma (Hutterer et al., 2008), and breast (Meric et al., 2002), gastric (Wu et al., 2002), lung (Shieh et al., 2005), and prostate cancers (Sainaghi et al., 2005). AXL expression increases in response to both targeted therapeutics and traditional chemotherapy, conferring drug resistance in gastrointestinal stromal tumors (Mahadevan et al., 2007) and acute myeloid leukemia (Hong et al., 2008). Along with other signaling molecules -including some that function with AXL to mediate drug resistance- AXL plays an important role in breast cancer epithelial-to-mesenchymal transition (EMT), a key program in metastasis induction (Gjerdrum et al., 2009). The effects of AXL inhibition on cancer cells make AXL an attractive target for cancer treatment. In mouse xenografts of human breast cancer, RNAi-mediated AXL inhibition decreases angiogenesis by impairing endothelial cell migration, proliferation, and tube formation (Holland et al., 2005). Antibodies against the extracellular AXL domain decrease tumor growth and invasion in in vitro models of breast and lung cancer (Zhang et al., 2008; Li et al., 2009). More recently, several small molecules have been identified as promising AXL inhibitors: MP470 has cytotoxic effects on gastrointestinal stromal tumors and synergizes with other standard treatments (Mahadevan et al., 2007). In breast cancer, 3-quinolinecarbonitrile compounds decrease motility and invasion (Zhang et al., 2008), and R428 selectively blocks AXL and its ability to promote angiogenesis and metastasis (Holland et al., 2010).



Autoimmune disease Disease Mice devoid of TYRO3, AXL, and MERTK develop autoimmune diseases, including rheumatoid arthritis and lupus, with more pronounced susceptibility to autoimmunity in triple-knockout (relative to single- or double-knockout) TAM mutants (Cohen et al., 2002; Lemke and Lu, 2003). Transgenic mice with ectopic AXL expression develop noninsulin-dependent diabetes mellitus and have increased levels of TNF-alpha (Augustine et al., 1999). In humans, AXL promotes survival of endothelial cells in the synovial joints of patients with rheumatoid arthritis (O'Donnell et al., 1999) and mediates injury-induced chemotaxis and vascular remodeling (Fridell et al., 1998).

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Shieh YS, Lai CY, Kao YR, Shiah SG, Chu YW, Lee HS, Wu CW. Expression of axl in lung adenocarcinoma and correlation with tumor progression. Neoplasia. 2005 Dec;7(12):1058-64

Prasad D, Rothlin CV, Burrola P, Burstyn-Cohen T, Lu Q, Garcia de Frutos P, Lemke G. TAM receptor function in the retinal pigment epithelium. Mol Cell Neurosci. 2006 Sep;33(1):96-108

Sasaki T, Knyazev PG, Clout NJ, Cheburkin Y, Göhring W, Ullrich A, Timpl R, Hohenester E. Structural basis for Gas6-Axl signalling. EMBO J. 2006 Jan 11;25(1):80-7

Mahadevan D, Cooke L, Riley C, Swart R, Simons B, Della Croce K, Wisner L, Iorio M, Shakalya K, Garewal H, Nagle R, Bearss D. A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene. 2007 Jun 7;26(27):3909-19

Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT, Lai GM, Chuang SE. Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett. 2008 Sep 18;268(2):314-24



Hutterer M, Knyazev P, Abate A, Reschke M, Maier H, Stefanova N, Knyazeva T, Barbieri V, Reindl M, Muigg A, Kostron H, Stockhammer G, Ullrich A. Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res. 2008 Jan 1;14(1):130-8

Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008;100:35-83

Zhang YX, Knyazev PG, Cheburkin YV, Sharma K, Knyazev YP, Orfi L, Szabadkai I, Daub H, Kéri G, Ullrich A. AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Res. 2008 Mar 15;68(6):1905-15

Hubbard TJ, Aken BL, Ayling S, Ballester B, Beal K, Bragin E, Brent S, Chen Y, Clapham P, Clarke L, Coates G, Fairley S, Fitzgerald S, Fernandez-Banet J, Gordon L, Graf S, Haider S, Hammond M, Holland R, Howe K, Jenkinson A, Johnson N, Kahari A, Keefe D, Keenan S, Kinsella R, Kokocinski F, Kulesha E, Lawson D, Longden I, Megy K, Meidl P, Overduin B, Parker A, Pritchard B, Rios D, Schuster M, Slater G, Smedley D, Spooner W, Spudich G, Trevanion S, Vilella A, Vogel J, White S, Wilder S, Zadissa A, Birney E, Cunningham F, Curwen V, Durbin R, Fernandez-Suarez XM, Herrero J, Kasprzyk A, Proctor G, Smith J, Searle S, Flicek P. Ensembl 2009. Nucleic Acids Res. 2009 Jan;37(Database issue):D690-7

Li Y, Ye X, Tan C, Hongo JA, Zha J, Liu J, Kallop D, Ludlam MJ, Pei L. Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis. Oncogene. 2009 Oct 1;28(39):3442-55

Pao-Chun L, Chan PM, Chan W, Manser E. Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. J Biol Chem. 2009 Dec 11;284(50):34954-63

Gjerdrum C, Tiron C, Høiby T, Stefansson I, Haugen H, Sandal T, Collett K, Li S, McCormack E, Gjertsen BT, Micklem DR, Akslen LA, Glackin C, Lorens JB. Axl is an essential epithelial-

to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1124-9

Holland SJ, Pan A, Franci C, Hu Y, Chang B, Li W, Duan M, Torneros A, Yu J, Heckrodt TJ, Zhang J, Ding P, Apatira A, Chua J, Brandt R, Pine P, Goff D, Singh R, Payan DG, Hitoshi Y. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010 Feb 15;70(4):1544-54


Migdall J, Graham DK. AXL (AXL receptor tyrosine kinase). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1065-1069.

Gene Section Review




BAK1 (BCL2-antagonist/killer 1) Grant Dewson, Ruth Kluck

The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Melbourne, Australia (GD, RK)


Online updated version : http://AtlasGeneticsOncology.org/Genes/BAK1ID752ch6p21.html DOI: 10.4267/2042/44896


Identity Other names: BAK; BAK-LIKE; BCL2L7; Bcl2-L-7; CDN1; MGC117255; MGC3887

HGNC (Hugo): BAK1

Location: 6p21.31

Local order: Orientation: minus strand.

Located approximately 380 kb centromeric to the human major histocompatibility complex (MHC) class II region.

Note The BAK1 gene produces the Bak protein, a pro-apoptotic protein from the Bcl-2 protein family. Either Bak or Bax is required to permeabilize the mitochondrial outer membrane during the mitochondrial (intrinsic) pathway of apoptotic cell death. Bak is a single-pass membrane protein that localises to the mitochondrial outer membrane in healthy cells, while Bax moves to mitochondria during apoptosis. Both Bak and Bax convert to the activated, pro-apoptotic form by undergoing a large conformational change before oligomerising to form apoptotic pores in the mitochondrial outer membrane. Pore formation allows the release of cytochrome c, Smac and other proteins that promote protease (caspase) activity to kill the cell. Thus, Bak/Bax pore formation is a major point of no return in cell death. The activation of Bak (and Bax) is initiated when the cell up-regulates the pro-apoptotic BH3-only members of the Bcl-2 family. Bak activation is blocked if sufficient prosurvival (anti-apoptotic) Bcl-2 family members (e.g. Bcl-xL, Mcl-1, Bcl-2 and A1) are present to sequester the BH3-only proteins and also perhaps the activated Bak and Bax proteins. As cancer cells often express high levels of these prosurvival

proteins, several agents that target the prosurvival proteins are being developed as novel cancer therapeutics.

DNA/RNA Description The BAK1 gene, with 7748 bases in length, and contains 6 exons. The first exon is non-coding, and most of the largest, final exon is untranslated.

Transcription The BAK1 gene transcribes a 211 aa protein Bak. A possible 101 aa splice variant, called BAK-like, contains BH1, BH2 and TM domains, but no BH3 domain, with a 2.4 kb transcript of BAK-like detected in most human tissues and exhibiting pro-apoptotic activity. Two other human BAK1 mRNA variants are present in GenBak but may not be expressed: the BakM variant would be 190 aa and lack 21 amino acids in the linker region between alpha-helices 1 and 2; another would be 153 aa with the stop codon upstream of a splice junction and therefore predicted to be subject to nonsense-mediated mRNA decay. However in mice, a similar 151 aa N-Bak that contains only the BH3 domain is reportedly expressed in neurons.

Pseudogene There are two pseudogenes: Bak2 (chromosome 20) and Bak3 (chromosome 11).

Protein Note The BAK1 gene encodes for a 23409 Da protein, named Bak. The Bak cDNA was isolated by three groups by virtue of its protein product interacting with the adenovirus E1B 19K protein, or its homo-

BAK1 (BCL2-antagonist/killer 1) Dewson G, Kluck R


The human Bak protein is 211 aa in length. Bcl-2 homology (BH) domains indicate regions of sequence homology with other Bcl-2 family members, with the BH3 domain being present in all members. The structure of non-activated Bak is similar to that of the prosurvival Bcl-2 family members, with alpha helices 1-9 indicated. The oligomerization domain is important for homo-oligomerization and pore formation, while the transmembrane domain anchors Bak in the mitochondrial outer membrane. logy to the BH1 and BH2 domains of Bcl-2. The BH3 domain of Bak is essential for its binding to a hydrophobic surface groove on the prosurvival proteins Bcl-xL and Mcl-1. The Bak BH3 domain is also important for binding to a similar hydrophobic groove in another activated Bak molecule to form Bak oligomers and the formation of pores.

Expression BAK1 mRNA is expressed widely in different tissues as an approximately 2.4 kb transcript. Highest mRNA levels are in the heart and skeletal muscle.

Localisation The Bak protein is inserted in the mitochondrial outer membrane in healthy cells, while its close homologue Bax translocates to mitochondria after an apoptotic stimulus. A small proportion of Bak has also been detected at the endoplasmic reticulum membrane.

Function Bak (or Bax) is required to form pores in the mitochondrial outer membrane during apoptotic cell death. The killing activity of Bak is regulated by other members of the Bcl-2 family. For example, certain BH3-only proteins (Bim and Bid) are reported to directly bind Bak to convert it into the activated conformation, while the prosurvival proteins (e.g. Bcl-xL and Mcl-1) can sequester activated Bak and so prevent Bak homo-oligomerization and pore formation. The role of Bak at the ER membrane is unclear.

Homology Human Bak shares 99.5% amino acid identity with Pan troglodytes, 91.9% identity with Canis lupus familiaris, 86.2% with Bos taurus, 77.2% with Rattus norvegicus. BAK1 is not found in the Danio rerio genome. Human Bak has 53% amino-acid sequence identity with the BH1 and BH2 domains of Bcl-2. Over the full sequence, Bak is 25, 33 and 19% identical to Bcl-2, Bcl-xL and Bax, respectively.

Mutations Note Several Bak single point mutations have been associated with autoimmune diseases, aortic

aneurysms, and cervical, colorectal and gastric cancers, although the causal relationship is not clear. In addition, around 200 SNPs, with unknown clinical association have been reported in Entrez SNP database.

Somatic Somatic mutations were increased in uterine cervical carcinoma (6 from 42) compared with non-neoplastic tissue (0 from 32). While an early study reported somatic mutations in 17% of samples of colorectal and gastric cancers in Korean patients, a later study reported no somatic mutations in 192 colorectal and gastric cancers.

Implicated in Lymphoma and leukemia Note Lymphomas and leukemias have high levels of Bcl-2 prosurvival proteins that prevent Bak (and Bax) from inducing apoptosis. New anti-cancer therapies that target prosurvival proteins can activate Bak (or Bax) to re-instate apoptotic cell death. In one example, a new drug, GX15-070, was found to induce apoptosis in mantle cell lymphoma cell lines by binding to Mcl-1 and assist in Bak activation (Pérez-Galán et al., 2007). This drug is in clinical trials for refractory chronic lymphocytic leukemia (Storey, 2008), and is presumably acting by indirectly activating Bak (or Bax).

Gastric and colorectal cancer Note The first report of Bak mutations being associated with gastrointestinal cancers was of missense BAK1 mutations in 3 of 24 gastric cancers and 2 of 20 colorectal cancers, with mutations observed only in advanced-stage cancers (Kondo et al., 2000). In another study, BAK1 mutations were also rare (3/107) in patients with gastric adenocarcinomas, and were each associated with late stage disease (Kim et al., 2003). However, no somatic mutations were found in 192 patients with colorectal and gastric cancers, and the rare single-nucleotide substitutions (4/129) were also found in the corresponding normal tissue samples (Sakamoto et al., 2004).



Uterine cervical carcinoma Note Possible role for Bak mutation in uterine cervical carcinoma was reported (Wani et al., 2003). In a study of 42 patients, 6 missense (M60V, D30N, D57N, V74M, I80T and V191A) and one silent mutations in the coding region of BAK1 were found, with no mutations detected in 32 non-neoplastic cervix tissue samples. Mutations were associated with late-stage disease and with resistance to chemotherapy, but were not statistically significant due to sample size.

Melanoma Note In patients with superficial-spreading melanoma high Bak levels corresponded to improved survival (10-year survival of 62%), while low Bak correlated with low survival (10-year survival of 10%) (Fecker et al., 2006). Bax levels correlated in a similar way.

Autoimmune diseases Note Severe autoimmune disease occurs in adult mice following deletion of both Bak and its close relative Bax (Takeuchi et al., 2005). The mice accumulate excess memory B- and T-cells in lymphoid and mesenchymal organs, leading to hepato-splenomegaly, lymphadenopathy, and thymic selection impairment. In humans, similar deletion of two copies of BAK1 (and BAX) does not occur, however less marked changes in Bak protein levels, as well as BAK1 mutations, have been associated with autoimmune disease in rare cases (see below).

Sjogren's syndrome Note The Bak protein and its gene mutation may participate in the pathology and susceptibility of Sjogren's syndrome, as Bak was over-expressed in patient autoimmune lesions (Anaya et al., 2005). In a later study three polymorphisms in BAK1 were associated with Sjogren's syndrome (Delgado-Vega et al., 2009).

Coeliac disease Note A significant increase in Bak mRNA and protein levels was found in the intestinal lesions of patients with untreated coeliac disease (Chernavsky et al., 2002). The increase in Bak and in apoptosis of enterocytes may be due to increased IFN-gamma signalling.

Graves' disease Note Differential expression of Bak (and Bcl-2 and Bax) was associated with apoptosis in thyrocytes and lymphoid follicles, implicating Bak in the pathology of Grave's disease (Hiromatsu et al., 2004).

Multiple sclerosis Note Bak mRNA levels were increased in the autoimmune lesions of patients with multiple sclerosis (Banisor and Kalman, 2004).

Ataxia telangiectasia Note BAK1 mutations were observed in 8 of 50 patients with ataxia telangiectasia, and were each a silent mutation in exon 2 in codon 14 (TGC>TGT), while none of the healthy controls had such an alteration (Isaian et al., 2009).

Transient platelet loss Note Bak can be activated to kill platelets as a side effect of new anti-cancer treatments (Mason et al., 2007; Oltersdorf et al., 2005). The small molecule ABT-737 is a BH3-mimetic that binds specifically to prosurvival proteins (Bcl-2, Bcl-xL, Bcl-w) that are commonly over-expressed in cancers. As platelets contain Bcl-xL as the predominant prosurvival protein guarding Bak, ABT-737 causes Bak activation and transient loss of platelets.

Age-related hearing loss Note In mice, Bak-mediated apoptosis exacerbated age-related hearing loss (Someya et al., 2009; Someya et al., 2007). Moreover, hearing loss was decreased if Bak was deleted, if mice were kept on a calorie restriction diet, or given oral supplementation with antioxidants. In keeping with oxidative stress was proposed to induce Bak expression in primary cells from cochlear cells.

Aortic aneurysms Note A possible role for Bak mutation in aortic aneurysms was evident in a study of 31 patients with abdominal aortic aneurysms (Gottlieb et al., 2009). Two single nucleotide polymorphisms (R42H and V52A) in the BAK1 gene were present in both diseased (31 cases) and healthy aortic tissue (5 cases), but not in matching blood samples. The authors propose that multiple variants of a gene such as BAK1 might pre-exist within disease-susceptible tissues, and can be selected for during disease progression.

To be noted Note The Bak protein plays a role in many diseases due to its central role in apoptotic cell death. However, most Bak dysregulation is not due to mutations in Bak, but rather to altered expression or mutation of Bak regulators (e.g. Bcl-xL and Mcl-1). If Bak (and its homologue Bax) fail



to activate and form a pore in mitochondria, the cell may survive when it was meant to die, and so contribute to cancer. In the opposite scenario, if Bak (or Bax) is activated inappropriately and mitochondria are permeabilized, excessive cell death can occur, for example, in neurodegenerative disease, autoimmune disease, and platelet loss following anti-cancer treatments. Agents that can trigger Bak-mediated apoptosis in a non-targeted way include most anti-cancer agents, while agents that may trigger Bak (and Bax) indirectly by targeting Bcl-2, Bcl-xL, Bcl-w, Mcl-1 and A1, include antisense, antibody and small molecule approaches (Storey, 2008).

References Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B, Chinnadurai G, Lutz RJ. A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J. 1995 Nov 15;14(22):5589-96

Chittenden T, Harrington EA, O'Connor R, Flemington C, Lutz RJ, Evan GI, Guild BC. Induction of apoptosis by the Bcl-2 homologue Bak. Nature. 1995 Apr 20;374(6524):733-6

Kiefer MC, Brauer MJ, Powers VC, Wu JJ, Umansky SR, Tomei LD, Barr PJ. Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak. Nature. 1995 Apr 20;374(6524):736-9

Herberg JA, Phillips S, Beck S, Jones T, Sheer D, Wu JJ, Prochazka V, Barr PJ, Kiefer MC, Trowsdale J. Genomic structure and domain organisation of the human Bak gene. Gene. 1998 Apr 28;211(1):87-94

Kondo S, Shinomura Y, Miyazaki Y, Kiyohara T, Tsutsui S, Kitamura S, Nagasawa Y, Nakahara M, Kanayama S, Matsuzawa Y. Mutations of the bak gene in human gastric and colorectal cancers. Cancer Res. 2000 Aug 15;60(16):4328-30

Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K, Chen Y, Wei M, Eng VM, Adelman DM, Simon MC, Ma A, Golden JA, Evan G, Korsmeyer SJ, MacGregor GR, Thompson CB. The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell. 2000 Dec;6(6):1389-99

Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev. 2000 Aug 15;14(16):2060-71

Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001 Apr 27;292(5517):727-30

Cherñavsky AC, Rubio AE, Vanzulli S, Rubinstein N, de Rosa S, Fainboim L. Evidences of the involvement of Bak, a member of the Bcl-2 family of proteins, in active coeliac disease. Autoimmunity. 2002 Feb;35(1):29-37

Kim SP, Hwang MS, Cho YR, Kwon SY, Kang YN, Kim IH, Sohn SS, Mun KC, Kwon TK, Lee SR, Suh SI. Mutations of the BAK gene are infrequent in advanced gastric adenocarcinomas in Koreans. Cancer Lett. 2003 May 30;195(1):87-91

Wani KM, Huilgol NG, Hongyo T, Shah K, Chatterjee N, Nair CK, Nomura T. Genetic alterations in the coding region of the

bak gene in uterine cervical carcinoma. Br J Cancer. 2003 May 19;88(10):1584-6

Banisor I, Kalman B. Bcl-2 and its homologues in the brain of patients with multiple sclerosis. Mult Scler. 2004 Apr;10(2):176-81

Hiromatsu Y, Kaku H, Mukai T, Miyake I, Fukutani T, Koga M, Shoji S, Toda S, Koike N. Immunohistochemical analysis of bcl-2, Bax and Bak expression in thyroid glands from patients with Graves' disease. Endocr J. 2004 Aug;51(4):399-405

Kim JK, Kim KS, Ahn JY, Kim NK, Chung HM, Yun HJ, Cha KY. Enhanced apoptosis by a novel gene, Bak-like, that lacks the BH3 domain. Biochem Biophys Res Commun. 2004 Mar 26;316(1):18-23

Sakamoto I, Yamada T, Ohwada S, Koyama T, Nakano T, Okabe T, Hamada K, Kawate S, Takeyoshi I, Iino Y, Morishita Y. Mutational analysis of the BAK gene in 192 advanced gastric and colorectal cancers. Int J Mol Med. 2004 Jan;13(1):53-5

Anaya JM, Mantilla RD, Correa PA. Immunogenetics of primary Sjögren's syndrome in Colombians. Semin Arthritis Rheum. 2005 Apr;34(5):735-43

Aouacheria A, Brunet F, Gouy M. Phylogenomics of life-or-death switches in multicellular animals: Bcl-2, BH3-Only, and BNip families of apoptotic regulators. Mol Biol Evol. 2005 Dec;22(12):2395-416

Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005 Jun 2;435(7042):677-81

Takeuchi O, Fisher J, Suh H, Harada H, Malynn BA, Korsmeyer SJ. Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease. Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11272-7

Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 2005 Jun 1;19(11):1294-305

Fecker LF, Geilen CC, Tchernev G, Trefzer U, Assaf C, Kurbanov BM, Schwarz C, Daniel PT, Eberle J. Loss of proapoptotic Bcl-2-related multidomain proteins in primary melanomas is associated with poor prognosis. J Invest Dermatol. 2006 Jun;126(6):1366-71

Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B, Brandt GS, Iwakoshi NN, Schinzel A, Glimcher LH, Korsmeyer SJ. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science. 2006 Apr 28;312(5773):572-6

Karbowski M, Norris KL, Cleland MM, Jeong SY, Youle RJ. Role of Bax and Bak in mitochondrial morphogenesis. Nature. 2006 Oct 12;443(7112):658-62

Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, Kelly PN, Ekert PG, Metcalf D, Roberts AW, Huang DC, Kile BT. Programmed anuclear cell death delimits platelet life span. Cell. 2007 Mar 23;128(6):1173-86

Pérez-Galán P, Roué G, Villamor N, Campo E, Colomer D. The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood. 2007 May 15;109(10):4441-9



Someya S, Yamasoba T, Weindruch R, Prolla TA, Tanokura M. Caloric restriction suppresses apoptotic cell death in the mammalian cochlea and leads to prevention of presbycusis. Neurobiol Aging. 2007 Oct;28(10):1613-22

Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE, Ierino H, Lee EF, Fairlie WD, Bouillet P, Strasser A, Kluck RM, Adams JM, Huang DC. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science. 2007 Feb 9;315(5813):856-9

Xu JX, Hoshida Y, Hongyo T, Sasaki T, Miyazato H, Tomita Y, Aozasa K. Analysis of p53 and Bak gene mutations in lymphoproliferative disorders developing in rheumatoid arthritis. J Cancer Res Clin Oncol. 2007 Feb;133(2):125-33

Dewson G, Kratina T, Sim HW, Puthalakath H, Adams JM, Colman PM, Kluck RM. To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3:groove interactions. Mol Cell. 2008 May 9;30(3):369-80

Storey S. Targeting apoptosis: selected anticancer strategies. Nat Rev Drug Discov. 2008 Dec;7(12):971-2

Dewson G, Kluck RM. Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. J Cell Sci. 2009 Aug 15;122(Pt 16):2801-8

Dewson G, Kratina T, Czabotar P, Day CL, Adams JM, Kluck RM. Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices. Mol Cell. 2009 Nov 25;36(4):696-703

Gottlieb B, Chalifour LE, Mitmaker B, Sheiner N, Obrand D, Abraham C, Meilleur M, Sugahara T, Bkaily G, Schweitzer M. BAK1 gene variation and abdominal aortic aneurysms. Hum Mutat. 2009 Jul;30(7):1043-7

Someya S, Xu J, Kondo K, Ding D, Salvi RJ, Yamasoba T, Rabinovitch PS, Weindruch R, Leeuwenburgh C, Tanokura M, Prolla TA. Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis. Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19432-7

Delgado-Vega AM, Castiblanco J, Gómez LM, Diaz-Gallo LM, Rojas-Villarraga A, Anaya JM. Bcl-2 antagonist killer 1 (BAK1) polymorphisms influence the risk of developing autoimmune rheumatic diseases in women. Ann Rheum Dis. 2010 Feb;69(2):462-5

Isaian A, Bogdanova NV, Houshmand M, Movahadi M, Aghamohammadi A, Rezaei N, Atarod L, Sadeghi-Shabestari M, Tonekaboni SH, Chavoshzadeh Z, Hassani SM, Mirfakhrai R, Cheraghi T, Kalantari N, Ataei M, Dork-Bousset T, Sanati MH. BAK, BAX, and NBK/BIK proapoptotic gene alterations in Iranian patients with ataxia telangiectasia. J Clin Immunol. 2010 Jan;30(1):132-7


Dewson G, Kluck R. BAK1 (BCL2-antagonist/killer 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1070-1074.

Leukaemia Section Short Communication




t(3;12)(q27;p13) Jean-Loup Huret

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0312q27p13ID1337.html DOI: 10.4267/2042/44897


Clinics and pathology Disease Non Hodgkin lymphomas (NHL)

Epidemiology One case to date, a 78-year-old female patient with a multifocal lymphoma, CD20+ diffuse large B-cell lymphoma (DLBCL) type, presenting as a primary central nervous system lymphoma (PCNSL) (Montesinos-Rongen et al., 2003). PCNSL are extra nodal NHL localized to -and remaining in- the central nervous system.

Genes involved and proteins BCL6 Location 3q27

Protein 706 amino acids; composed of a NH2-term BTB/POZ domain (amino acids 1-130 (32-99 according to Swiss-Prot) which mediates homodimerization and protein-protein interactions with other corepressors (including HDAC1 and NCOR2/SMRT ) to constitute a large repressing complex, another transcription repression domain (191-386), PEST sequences (300-417) with a KKYK motif (375-379), and six zinc finger at the C-term (518-541, 546-568, 574-596, 602-624, 630-652, 658-681), responsible for sequence specific DNA binding. Transcription repressor; recognizes the consensus sequence: TTCCT(A/C)GAA (Albagli-Curiel, 2003).

GAPDH Location 12p13.3

Protein 335 amino acids; possess a nucleotide binding site for NAD+, and sites for glyceraldehyde 3-phosphate binding; catalyzes the phosphorylation and oxidation of glyceraldehyde-3-phosphate to 1,3-biphosphoglycerate (interconversion), using NAD+ as electron acceptor. Role in endocytosis and in nuclear membrane assembly. Associates with microtubules and RAB2, which stimulates the recruitment of dynein, to regulate microtubule motility and cargo transport. Also binds mRNA and t-RNA; may participate in tRNA export and mRNA stability. Role in the cell cycle, in DNA repair, and in apoptosis associated with oxidative stress (reviews in Sirover, 1999; Hara and Snyder, 2006; Hara et al., 2006; Colell et al., 2009).

Result of the chromosomal anomaly Hybrid gene Description Breakpoint in the intron 2 of GAPDH; leads to the juxtaposition of the GAPDH promotor region with the 2 first exons and the entire BCL6, inducing deregulated expression of BCL6.

References Sirover MA. New insights into an old protein: the functional diversity of mammalian glyceraldehyde-3-phosphate dehydrogenase. Biochim Biophys Acta. 1999 Jul 13;1432(2):159-84

Albagli-Curiel O. Ambivalent role of BCL6 in cell survival and transformation. Oncogene. 2003 Jan 30;22(4):507-16

Montesinos-Rongen M, Akasaka T, Zühlke-Jenisch R, Schaller C, Van Roost D, Wiestler OD, Siebert R, Deckert M. Molecular characterization of BCL6 breakpoints in primary diffuse large B-cell lymphomas of the central nervous system identifies

t(3;12)(q27;p13) Huret JL


GAPD as novel translocation partner. Brain Pathol. 2003 Oct;13(4):534-8

Hara MR, Cascio MB, Sawa A. GAPDH as a sensor of NO stress. Biochim Biophys Acta. 2006 May;1762(5):502-9

Hara MR, Snyder SH. Nitric oxide-GAPDH-Siah: a novel cell death cascade. Cell Mol Neurobiol. 2006 Jul-Aug;26(4-6):527-38

Colell A, Green DR, Ricci JE. Novel roles for GAPDH in cell death and carcinogenesis. Cell Death Differ. 2009 Dec;16(12):1573-81


Huret JL. t(3;12)(q27;p13). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1075-1076.





t(3;3)(q25;q27) Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0303q25q27ID2127.html DOI: 10.4267/2042/44898


Clinics and pathology Disease Non Hodgkin lymphoma.

Epidemiology One case of follicular lymphoma transformed to diffuse aggressive lymphoma, from a study with no individual data (Akasaka et al., 2003).

Genes involved and proteins MBNL1 Location: 3q25

Protein Various splicing forms; one isoform comprises 388 amino acids, with 4 zinc fingers at amino acids 13-41, 47-73, 179-207 and 215-241, according to Swiss-Prot. RNA-binding protein which regulates alternative splicing of pre-mRNAs. MBNL1 has a high-affinity binding for UGCU motifs, but cytidines are also often present in position 1 or 4, and general MBNL1 binding site can be defined as YGCY (Goers et al., 2010). Plays an important role in the development of myotonic dystrophy 1 pathology. MBNL1 and MBNL2 play a facilitatory role in insulin receptor exon 11 splicing (Dansithong et al., 2005). MBNL1 also regulates sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 1 (SERCA1), the cardiac troponin T (cTNT) , and the fast troponin T (TNNT3) splicings.

BCL6 Location: 3q27

Protein 706 amino acids; composed of a NH2-term BTB/POZ domain (amino acids 1-130 (32-99 according to Swiss-Prot) which mediates homodimerization and protein-protein interactions with other corepressors (including HDAC1 and NCOR2/SMRT to constitute a large repressing complex, another transcription repression domain (191-386), PEST sequences (300-417) with a KKYK motif (375-379), and six zinc finger at the C-term (518-541, 546-568, 574-596, 602-624, 630-652, 658-681), responsible for sequence specific DNA binding. Transcription repressor; recognizes the consensus sequence: TTCCT(A/C)GAA (Albagli-Curiel, 2003).

References Akasaka T, Lossos IS, Levy R. BCL6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma. Blood. 2003 Aug 15;102(4):1443-8

Albagli-Curiel O. Ambivalent role of BCL6 in cell survival and transformation. Oncogene. 2003 Jan 30;22(4):507-16

Dansithong W, Paul S, Comai L, Reddy S. MBNL1 is the primary determinant of focus formation and aberrant insulin receptor splicing in DM1. J Biol Chem. 2005 Feb 18;280(7):5773-80

Goers ES, Purcell J, Voelker RB, Gates DP, Berglund JA. MBNL1 binds GC motifs embedded in pyrimidines to regulate alternative splicing. Nucleic Acids Res. 2010 Apr;38(7):2467-84


Huret JL. t(3;3)(q25;q27). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1077.





dic(7;9)(p11-12;p12-13) PAX5/LOC392027 Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Anomalies/dic0709p11p12ID1554.html DOI: 10.4267/2042/44899


Identity Note See also the paper on dic(9;20)(p11-13;q11).

Clinics and pathology Disease Acute lymphoblastic leukaemia (ALL).

Phenotype/cell stem origin B-cell precursor ALL.

Epidemiology 13 cases to date; sex ratio was 7M/6F, median age was 17 years (range 2-51 years) (An et al., 2008).

Prognosis No data.

Cytogenetics Additional anomalies The dic(7;9) was the sole anomaly in 8 cases, accompanied a t(9;22) with BCR-ABL1 involvement in 3 cases, and was accompanied with other anomaly in 2 other cases, including a del(6q).

Genes involved and proteins LOC392027 Location 7p12

Protein Ribosome-binding protein 1 pseudogene.

PAX5 Location 9p13.2

Protein Lineage-specific transcription factor; recognizes the concensus recognition sequence GNCCANTGAAGCGTGAC, where N is any nucleotide. Involved in B-cell differentiation. Entry of common lymphoid progenitors into the B cell lineage depends on E2A, EBF1, and PAX5; activates B-cell specific genes and repress genes involved in other lineage commitments. Activates the surface cell receptor CD19 and repress FLT3. Pax5 physically interacts with the RAG1/RAG2 complex, and removes the inhibitory signal of the lysine-9-methylated histone H3, and induces V-to-DJ rearrangements. Genes repressed by PAX5 expression in early B cells are restored in their function in mature B cells and plasma cells, and PAX5 repressed (Fuxa et al., 2004; Johnson et al., 2004; Zhang et al., 2006; Cobaleda et al., 2007).

Result of the chromosomal anomaly Hybrid gene Description Break in PAX5 intron 4. Out of frame fusion of 5' PAX5 - 3' LOC392027.

dic(7;9)(p11-12;p12-13) PAX5/LOC392027 Huret JL


Fusion protein Description The predicted fusion protein contains the DNA binding paired domain of PAX5.

Oncogenesis Loss of function of PAX5 is likely to be the oncogenic event.

References Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E, Busslinger M. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev. 2004 Feb 15;18(4):411-22

Johnson K, Pflugh DL, Yu D, Hesslein DG, Lin KI, Bothwell AL, Thomas-Tikhonenko A, Schatz DG, Calame K. B cell-specific loss of histone 3 lysine 9 methylation in the V(H) locus depends on Pax5. Nat Immunol. 2004 Aug;5(8):853-61

Zhang Z, Espinoza CR, Yu Z, Stephan R, He T, Williams GS, Burrows PD, Hagman J, Feeney AJ, Cooper MD. Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes. Nat Immunol. 2006 Jun;7(6):616-24

Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5: the guardian of B cell identity and function. Nat Immunol. 2007 May;8(5):463-70

An Q, Wright SL, Konn ZJ, Matheson E, Minto L, Moorman AV, Parker H, Griffiths M, Ross FM, Davies T, Hall AG, Harrison CJ, Irving JA, Strefford JC. Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17050-4


Huret JL. dic(7;9)(p11-12;p12-13) PAX5/LOC392027. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1078-1079.





dic(9;12)(p13;p12) PAX5/SLCO1B3 Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Anomalies/dic0912p13p12ID1555.html DOI: 10.4267/2042/44900


Identity Note While dic(9;12)(p13;p12) is usually associated with PAX5/ETV6 involvement, one case has been described with SLCO1B3 involvement instead of ETV6. See also the paper on dic(9;20)(p11-13;q11).

Clinics and pathology Disease Acute lymphoblastic leukaemia (ALL).

Phenotype/cell stem origin B-cell precursor ALL.

Epidemiology One case to date, a 1-year-old girl (An et al., 2008).

Prognosis No data.

Cytogenetics Additional anomalies The dic(9;12) was the sole anomaly.

Genes involved and proteins PAX5 Location 9p13.2

Protein Lineage-specific transcription factor; recognizes the concensus recognition sequence

GNCCANTGAAGCGTGAC, where N is any nucleotide. Involved in B-cell differentiation. Entry of common lymphoid progenitors into the B cell lineage depends on E2A, EBF1, and PAX5; activates B-cell specific genes and repress genes involved in other lineage commitments. Activates the surface cell receptor CD19 and repress FLT3. Pax5 physically interacts with the RAG1/RAG2 complex, and removes the inhibitory signal of the lysine-9-methylated histone H3, and induces V-to-DJ rearrangements. Genes repressed by PAX5 expression in early B cells are restored in their function in mature B cells and plasma cells, and PAX5 repressed (Fuxa et al., 2004; Johnson et al., 2004; Zhang et al., 2006; Cobaleda et al., 2007).

SLCO1B3 Location 12p12.2

Protein Multi-pass membrane protein. Organic anion transporting polypeptide. Mediates the transport for various molecules such as bile acids, steroids, thyroid hormones, and exogenous drugs. Normally expressed in the basolateral membrane of hepatocytes around the central vein (Hagenbuch and Meier, 2003; Briz et al., 2006).

Result of the chromosomal anomaly Hybrid gene Description Break in PAX5 intron 4. Out of frame fusion of 5' PAX5 - 3' SLCO1B3

dic(9;12)(p13;p12) PAX5/SLCO1B3 Huret JL


Fusion protein

Description The predicted fusion protein contains the DNA binding paired domain of PAX5.

Oncogenesis Loss of function of PAX5 is likely to be the oncogenic event.

References Hagenbuch B, Meier PJ. The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta. 2003 Jan 10;1609(1):1-18

Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E, Busslinger M. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev. 2004 Feb 15;18(4):411-22

Johnson K, Pflugh DL, Yu D, Hesslein DG, Lin KI, Bothwell AL, Thomas-Tikhonenko A, Schatz DG, Calame K. B cell-specific loss of histone 3 lysine 9 methylation in the V(H) locus depends on Pax5. Nat Immunol. 2004 Aug;5(8):853-61

Briz O, Romero MR, Martinez-Becerra P, Macias RI, Perez MJ, Jimenez F, San Martin FG, Marin JJ. OATP8/1B3-mediated

cotransport of bile acids and glutathione: an export pathway for organic anions from hepatocytes? J Biol Chem. 2006 Oct 13;281(41):30326-35

Zhang Z, Espinoza CR, Yu Z, Stephan R, He T, Williams GS, Burrows PD, Hagman J, Feeney AJ, Cooper MD. Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes. Nat Immunol. 2006 Jun;7(6):616-24

Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5: the guardian of B cell identity and function. Nat Immunol. 2007 May;8(5):463-70

An Q, Wright SL, Konn ZJ, Matheson E, Minto L, Moorman AV, Parker H, Griffiths M, Ross FM, Davies T, Hall AG, Harrison CJ, Irving JA, Strefford JC. Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17050-4


Huret JL. dic(9;12)(p13;p12) PAX5/SLCO1B3. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1080-1081.

Leukaemia Section Mini Review




t(2;14)(p13-16;q32) Adriana Zamecnikova

Kuwait Cancer Control Center, Laboratory of Cancer Genetics, Department of Hematology, Shuwaikh, 70653, Kuwait (AZ)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0214p13q32ID1231.html DOI: 10.4267/2042/44901

This article is an update of : Huret JL. t(2;14)(p13;q32). Atlas Genet Cytogenet Oncol Haematol 2002;4(6):289. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

(A) Partial karyotype showing the t(2;14)(p13;q32) Top - Courtesy Adriana Zamecnikova; Middle and below - Courtesy Melanie Zenger and Claudia Haferlach. (B) Fluorescence in situ hybridization with LSI IgH/MYC and LSI ALK probe showing the juxtaposition of ALK (fusion signal) from 2p23 to the region proximal to IgH locus (green signal) on chromosome 14 and translocation of IgH segments to der(2) chromosome resulting in a green signal on rearranged chromosome 2 - Courtesy Adriana Zamecnikova.

t(2;14)(p13-16;q32) Zamecnikova A


Clinics and pathology Disease Identified predominantly in B-cell malignancies, including CLL/SLL, found in 20 cases of chronic lymphocytic leukemia (CLL), 1 B-prolymphocytic leukemia, 1 diffuse, mixed small/large cell non Hodgkin lymphoma (NHL); 8 cases of acute lymphocytic leukemia (ALL): one T-ALL and 7 B-ALL (two in association with t(1;19), one in Ph+ ALL, one with 3-way translocation); two AML (Ph+ M1 and inv(16)) cases and in one Ph+ CML case. CLL cases are characterized by marrow involvement, absolute lymphocytosis, lymphadenopathy, atypical morphologic features; prolymphocytes may be increased. Serum lactate dehydrogenase and beta-microglobulin levels are elevated, ZAP70 is expressed. IgVH genes are unmutaded; most cases are positive for CD5, CD19 and CD23; weak intensity of immunoglobuline and CD20, weak or negative CD79b, CD22, absence of FMC-7.

Epidemiology Sex ratio: CLL cases 10 males and 6 females patients, 4 unknown; adults: aged 40-68 years, and 3 children aged 6, 10 and 15 years; ALL cases (3 males, 5 females) were 1 adult 37 years old and 7 children aged 1-17 years; 2 AML cases (1 male, 1 female) were 34 and 45 years old; the CML case was a 21 years old male patient.

Prognosis 8 CLL cases were dead after 27-145 months survival; from available data on 3 ALL cases: they were all dead (one after 15 months, 2 after bone marrow transplantation).

Cytogenetics Cytogenetics morphological Sole anomaly in 8 documented cases; found in complex karyotypes; associated with t(14;19)(q32;q13) in 2 CLL cases, del(6)q in 4 cases, i(9)(q10) in 2 cases, +12 in 3 cases. In two pediatric ALL cases, it was associated with t(1;19) and in 3 cases it was associated with Ph+ leukemia.

Genes involved and proteins BCL11A Location 2p16.1

DNA/RNA Originally assigned to region 1, band 3, 2p13; it has subsequently been reassigned to 2p16.1.

Protein BCL11A/EVI9 is a zinc-finger protein, containing 6 Krüppel C2H2 zinc fingers as well as a proline-rich

domain between zinc fingers 1 and 2 and an acidic domain between 3 and 4. 835 amino acids; 91197 Da, alternative splicing: 6 isoforms, sharing a common N-terminus. Originally named EV19 human homolog BCL11A; high level of conservation across a wide range of species; highly homologous to another gene (BCL11B) on chromosome 14q32.1; like BCL11A, BCL11B is remarkable in having a large 5' CpG island. Predominantly expressed in brain and hematopoietic cells, expression is tightly regulated during B-cell development; low-level or undetectable BCL11A RNA expression in most adult tissues. BCL11A is a DNA sequence-specific transcriptional repressor, an essential factor in lymphopoiesis, required for B-cell formation in fetal liver.

IgH Location 14q32

Result of the chromosomal anomaly Fusion protein Oncogenesis Juxtaposition of IgH enhancer elements leading to inappropriate overexpression of the partner gene product. BCL11A may be activated through chromosomal translocation or amplification, leading to myeloid leukemias in mice and lymphoid malignancies in humans; the conserved N-terminus of BCL11A. deregulated expression of BCL11A may play a major role in the pathogenesis; gains and amplifications of the region of chromosome 2p13-16 have been reported in B-cell malignancies, REL, a NF-kappaB gene family member, mapping within the amplified region is coamplified with BCL11A in B-NHL cases and HD lymphoma cell lines; with gains and amplifications, BCL11A interacts directly with BCL6, that serves a crucial role in lymphocyte development, also involved in IG translocations. The structure of the t(2;14) translocation is a "head-to-head" arrangement, with the breakpoints falling centromeric to the first exon adjacent to a large CpG island at the 5' end; BCL11A is deregulated as a consequence of the translocation, suggesting that BCL11A may be involved in lymphoid malignancies through either chromosomal translocation or amplification.

References Ueshima Y, Bird ML, Vardiman JW, Rowley JD. A 14;19 translocation in B-cell chronic lymphocytic leukemia: a new recurring chromosome aberration. Int J Cancer. 1985 Sep 15;36(3):287-90

Nishida K, Taniwaki M, Misawa S, Abe T. Nonrandom rearrangement of chromosome 14 at band q32.33 in human lymphoid malignancies with mature B-cell phenotype. Cancer Res. 1989 Mar 1;49(5):1275-81

t(2;14)(p13-16;q32) Zamecnikova A


Uckun FM, Gajl-Peczalska KJ, Provisor AJ, Heerema NA. Immunophenotype-karyotype associations in human acute lymphoblastic leukemia. Blood. 1989 Jan;73(1):271-80

Yoffe G, Howard-Peebles PN, Smith RG, Tucker PW, Buchanan GR. Childhood chronic lymphocytic leukemia with (2;14) translocation. J Pediatr. 1990 Jan;116(1):114-7

Watson MS, Land VJ, Carroll AJ, Pullen J, Borowitz MJ, Link MP, Amylon M, Behm FG. t(2;14)(p13;q32): a recurring abnormality in lymphocytic leukemia. A Pediatric Oncology Group study. Cancer Genet Cytogenet. 1992 Feb;58(2):121-4

Geisler CH, Philip P, Christensen BE, Hou-Jensen K, Pedersen NT, Jensen OM, Thorling K, Andersen E, Birgens HS, Drivsholm A, Ellegaard J, Larsen JK, Plesner T, Brown P, Andersen PK, Hansen MM. In B-cell chronic lymphocytic leukaemia chromosome 17 abnormalities and not trisomy 12 are the single most important cytogenetic abnormalities for the prognosis: a cytogenetic and immunophenotypic study of 480 unselected newly diagnosed patients. Leuk Res. 1997 Nov-Dec;21(11-12):1011-23

Sonoki T, Matsuzaki H, Satterwhite E, Nakazawa N, Hata H, Tucker PW, Taniwaki M, Kuribayashi N, Harada N, Matsuno F, Mitsuya H. A plasma cell leukemia patient showing bialleic 14q translocations: t(2;14) and t(11;14). Acta Haematol. 1999;101(4):197-201

Satterwhite E, Sonoki T, Willis TG, Harder L, Nowak R, Arriola EL, Liu H, Price HP, Gesk S, Steinemann D, Schlegelberger B, Oscier DG, Siebert R, Tucker PW, Dyer MJ. The BCL11 gene family: involvement of BCL11A in lymphoid malignancies. Blood. 2001 Dec 1;98(12):3413-20

Yin CC, Lin KI, Ketterling RP, Knudson RA, Medeiros LJ, Barron LL, Huh YO, Luthra R, Keating MJ, Abruzzo LV. Chronic lymphocytic leukemia With t(2;14)(p16;q32) involves the BCL11A and IgH genes and is associated with atypical morphologic features and unmutated IgVH genes. Am J Clin Pathol. 2009 May;131(5):663-70


Zamecnikova A. t(2;14)(p13-16;q32). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1082-1084.

Solid Tumour Section Short Communication




t(6;22)(p21;q12) in hidradenoma of the skin Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Tumors/t0622p21q12HidradID6281.html DOI: 10.4267/2042/44902


Clinics and pathology Disease Hidradenoma or eccrine/apocrine acrospiroma, is a benign adnexal tumour developing most often in adults.

Epidemiology Three cases to date, 3 female patients aged 24, 63, and 85 years (Möller et al., 2008).

Pathology There was one atypical, one poroid, and one solid hidradenoma.

Prognosis Prognosis is good in this benign disease.

Cytogenetics Cytogenetics Morphological The t(6;22)(p21;q12) was the sole anomaly in the only case with karyotypic studies; the 2 other cases were detected by the presence of the fusion transcript.

Genes involved and proteins POU5F1 Location 6p21

Protein Homeobox protein (homeodomain in amino acids 230-289 in the 360 aa isoform) with a POU domain (in aa 138-212). Binds the sequence 5'-ATTTGCAT-3'. Transcription factor.

EWSR1 Location 22q12

Protein From N-term to C-term: a transactivation domain (TAD) containing multiple degenerate hexapeptide repeats, 3 arginine/glycine rich domains (RGG regions), a RNA recognition motif, and a RanBP2 type Zinc finger. Role in transcriptional regulation for specific genes and in mRNA splicing.

Result of the chromosomal anomaly Hybrid Gene Description 5' EWSR1 - 3' POU5F1. EWSR1 exon 6 is fused in frame to POU5F1 exon 2.

Fusion Protein Description Fusion of the N terminal transactivation domain of EWSR1 to the POU and the homeobox (DNA binding domain) of POU5F1.

References Möller E, Stenman G, Mandahl N, Hamberg H, et al. POU5F1, encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands. J Pathol. 2008 May;215(1):78-86


Huret JL. t(6;22)(p21;q12) in hidradenoma of the skin. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1085.





t(6;22)(p21;q12) in mucoepidermoid carcinoma of the salivary glands Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Tumors/t0622p21q12MucoepidID6282.html DOI: 10.4267/2042/44903


Clinics and pathology Disease Mucoepidermoid carcinoma is the most common type of malignant salivary gland tumor, mostly located to the parotid gland; it is associated with a t(11;19)(q21;p13) translocation with expression of chimeric genes 5' CRTC1 - 3' MAML2 in about half of the cases, mainly associated with a highly or moderately differentiated histology and an excellent outcome.

Epidemiology One case to date, an 85-year-old male patient; the patient died of an unrelated disease one year after diagnosis (Behboudi et al., 2006; Moller et al., 2008).

Pathology The mucoepidermoid carcinoma was poorly differentiated.


Protein Homeobox protein (homeodomain in amino acids 230-289 in the 360 aa isoform) with a POU domain (in aa 138-212). Binds the sequence 5'-ATTTGCAT-3'. Transcription factor.

EWSR1 Location 22q12 Protein From N-term to C-term: a transactivation domain

(TAD) containing multiple degenerate hexapeptide repeats, 3 arginine/glycine rich domains (RGG regions), a RNA recognition motif, and a RanBP2 type Zinc finger. Role in transcriptional regulation for specific genes and in mRNA splicing.

Result of the chromosomal anomaly Hybrid Gene Description 5' EWSR1 - 3' POU5F1. EWSR1 exon 6 is fused in frame to POU5F1 exon 2.

Fusion Protein Description Fusion of the N terminal transactivation domain of EWSR1 to the POU and the homeobox (DNA binding domain) of POU5F1.

References Behboudi A, Enlund F, Winnes M, Andrén Y, Nordkvist A, Leivo I, Flaberg E, Szekely L, Mäkitie A, Grenman R, Mark J, Stenman G. Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene. Genes Chromosomes Cancer. 2006 May;45(5):470-81

Möller E, Stenman G, Mandahl N, Hamberg H, Mölne L, van den Oord JJ, Brosjö O, Mertens F, Panagopoulos I. POU5F1, encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands. J Pathol. 2008 May;215(1):78-86


Huret JL. t(6;22)(p21;q12) in mucoepidermoid carcinoma of the salivary glands. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1086.





t(6;22)(p21;q12) in undifferentiated sarcoma Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Tumors/t0622p21q12UndifID5411.html DOI: 10.4267/2042/44904


Clinics and pathology Disease A case of undifferentiated sarcoma of the pubic bone, with multiple pulmonary metastases at diagnosis, was described in a 39-year-old female patient. The patient died 6 months after diagnosis (Yamaguchi et al., 2005).

Cytogenetics Cytogenetics Morphological The t(6;22)(p21;q12) was accompanied with a marker chromosome.


Protein 360 amino acids in the longest isoform; contains a bipartte DNA-binding domain, composed of a POU- specific domain (amino acids 138-212), and a homeobox (aa 230-289). Transcription factor with a major role during embryogenesis. Binds specifically ATTTGCAT.

EWSR1 Location 22q12

Protein From N-term to C-term: a transactivation domain (TAD) containing multiple degenerate hexapeptide repeats, 3 arginine/glycine rich domains (RGG regions), a RNA recognition motif, and a RanBP2 type Zinc finger. Role in transcriptional regulation for specific genes and in mRNA splicing.

Result of the chromosomal anomaly Hybrid Gene Description 5' EWSR1 - 3' POU5F1. Fusion of exons 1-6 of EWSR1 to part of exon 1, and exons 2-5 of POU5F1.

Fusion Protein Description The N terminal transactivation domain of EWSR1 was fused to the DNA binding domains of POU5F1.

References Yamaguchi S, Yamazaki Y, Ishikawa Y, Kawaguchi N, Mukai H, Nakamura T. EWSR1 is fused to POU5F1 in a bone tumor with translocation t(6;22)(p21;q12). Genes Chromosomes Cancer. 2005 Jun;43(2):217-22


Huret JL. t(6;22)(p21;q12) in undifferentiated sarcoma. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1087.

Deep Insight Section




Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Ioannis A Voutsadakis

Department of Medical Oncology, University Hospital of Larissa, Larissa 41110, Greece (IAV)


Online updated version : http://AtlasGeneticsOncology.org/Deep/UbiquitininCancerID20083.html DOI: 10.4267/2042/44905


Ubiquitin: Gene and protein Ubiquitin is a 8 kDa protein of 76 amino-acids that has taken its name from its ubiquitous presence in cells. Its covalent link to a target protein is a signal for different fates for this target protein. Ubiquitination (or ubiquitylation) refers to this covalent link and represents a signal analogous to phosphorylation. Ubiquitin gene exists in multiple copies in eukaryotic cells. Ubiquitin protein contains seven lysine residues at positions 6, 11, 27, 29, 33, 48 and 63 through which it can be attached to the substrate or to one another. Ubiquitin is characterized by a β-grasp superfold termed ubiquiton in which a central α-helix is surrounded by four β-sheets (Welchman et al., 2005). This superfold defines also ubiquitin-like proteins such as SUMO (Small Ubiquitin-like modifier) and NEDD8 (Neuronal Precursor cell-expressed developmentally down-regulated protein 8). Other human ubiquitin-like proteins containing ubiquitons include ISG15 (Interferon stimulated gene 15), FAT10 (Human leukocyte antigen F-associated Transcript 10), FUB1 (Fan Ubiquitin-like protein 1) and URM1 (Ubiquitin Related Modifier 1). All ubiquitin-like proteins, although varying in amino-acid sequence, share with ubiquitin the common structure and the common biochemical mechanism of tagging through an isopeptide bond (Pickart, 2004; Pickart and Eddins, 2004).

Ubiquitination The covalent attachment of ubiquitin to a target protein is a very well controlled process that is executed with the aid of three types of enzymes. A first type of enzyme called E1 or Ubiquitin activating enzyme,

using energy from the conversion of ATP to ADP, binds ubiquitin and transfers it onto a second type of enzyme called E2 or Ubiquitin conjugating enzyme. E2-loaded ubiquitin is then attached, with the help of a third type of enzymes called E3 or Ubiquitin ligase, to the ε-amino group of a lysine residue on a target protein. Two E1 enzymes exist in the human genome called Ubiquitin-activating enzyme 1 (UBE1) and Ubiquitin-like modifier Activating enzyme 6 (UBA6) (Groettrup et al., 2008). UBA6 is also performing the activation function for fatylation, the addition of FAT10 to target proteins (Chiu et al., 2007). E2 enzymes are more abundant (about 30 to 40 exist in the human genome) and have a conserved 150 aminoacids central structure that includes four β sheets and four α-helices and surrounds the active cysteine residue. This cysteine accepts ubiquitin through the formation of thiol-ester bond with the final glysine residue of ubiquitin. A signature HPN (Histidine-proline-asparagine) sequence is found 7 to 8 amino-acids amino-terminal to this cysteine (Michelle et al., 2009). The formation of thiol-ester group requires ubiquitin to be activated, that is linked to the E1 enzyme, while free ubiquitin has very low affinity for E2 enzymes. E2-bound ubiquitin transfer to the target protein is facilitated by a ubiquitin ligase or E3 enzyme. There are about 600 E3 ligases in human genome. This step confers substrate specificity to the process of ubiquitination given that every E3 ligase can interact only with specific substrate proteins. Nevertheless this specificity is partial, as several substrates can interact with an E3 ligase while a specific protein undergoing ubiquitination can interact with several E3 ligases. In addition each E3 ligase can interact with several E2 enzymes and the reverse is also true given that

Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Voutsadakis IA


Figure 1: Enzymatic cascade of ubiquitination.

each E2 can interact with several E3s (Van Wijk et al., 2009). Two types of E3 ligases exist having a mechanistically different catalytic mode of action through which they perform ubiquitin ligation. RING (Really Interesting New Gene) type E3s act by bringing E2-bound ubiquitin in close proximity with the substrate protein in order for ubiquitin to be directly transferred to the substrate. In addition, RING E3s probably mediate a conformational change of bound E2 that facilitates ubiquitin transfer (Passmore and Barford, 2004). In contrast HECT (Homologous to Human Papilloma Virus E6 Carboxyterminal domain) type E3s possesses an active cysteine residue that forms a thiol-ester bond with ubiquitin before it is transferred to the substrate. A third type of E3 ligases called U-box domain E3 ligases is considered by many as a sub-type of RING type E3s because U-box domain has a RING domain-like conformation and the mechanism of action is also by bridging E2-bound ubiquitin with the substrate, similarly to RING type E3s.

Type RING HECT

% human E3s about 95% about 5%

Covalent link with Ubiquitin No Yes

Ubiquitination type specificity No Yes

Table: Comparison of two major classes of E3 ligases

RING type E3s are by far more abundant than HECT E3s and comprise about 95% of human E3s (Li et al., 2008). RING domain has several cysteines and a histidine in its core structure which binds two zinc atoms. RING domains create the rigid platform that constitutes the surface for the Ubiquitin conjugating enzyme bound with ubiquitin binding. Some E3s are comprised of a single polypeptide that possesses both the RING E2-binding domain and the substrate binding domain, while other E3s are constituted by several

distinct proteins, one of which is the RING domain E2-binding protein and another binds the substrate protein to be ubiquitinated (Deshaies and Joazeiro, 2009). The prototype of this latter group is the cullin-RING ubiquitin ligases (CRLs) comprised of a RING protein linked through a family of proteins called cullins to a substrate binding sub-unit (Bosu and Kipreos, 2008). In addition to transferring a first ubiquitin molecule to a substrate (chain initiation), RING E3 ligases perform chain elongation, the attachment of further ubiquitin molecules. These are distinct reactions and chain initiation is taking place in a much slower pace than the elongation step which, in many occasions, is completed 5 to 30 times quicker than the initiation (Petroski and Deshaies, 2005). In the U-box type E3 ligases the conserved cysteines and histidine of RING type ligases are replaced by charged and polar residues. The other major type of E3s, HECT type has 28 members in human genome (Rotin and Kumar, 2009). All HECT ligases possess in the carboxy-terminal part of their molecule a HECT domain first identified and named by E3 ligase E6-AP (Human Papilloma Virus E6-Associated Protein), while their amino-terminal part is comprised of various other domains. HECT domain has two sub-domains, one of which binds the E2 Ubiquitin conjugating enzyme and the other binds the substrate protein. Ubiquitination is a reversible process and there are specific de-ubiquitinating enzymes that reverse it. These enzymes recognize the isopeptide bond between the carboxyterminal glycine of a ubiquitin molecule and the ε-aminogroup of a lysine of another ubiquitin molecule or of a target protein. There are five families of de-ubiquitinating enzymes: the UBP (Ubiquitin-specific processing protease) family, the UCH (Ubiquitin Carboxy-terminal Hydrolase) family, the OTU (Ovarian Tumor related proteases) family, the ataxin/Josephin group having ataxin 3 as the only member and the JAMM (Jab1/MPN domain metalloenzyme)/MPN+ motif proteases (Amerik and Hochstrasser, 2004). The role of de-ubiquitinating enzymes is to maintain the ubiquitin pool in the cell and to perform proof-reading for proteins that had been



inappropriately ubiquitinated. De-ubiquitinating enzyme Rpn11 of the JAMM/MPN+ family is part of the proteasome (see also next) and recycles ubiquitin from proteins that had been recognized and processed for degradation. The importance of de-ubiquitination is underlined by the fact that their dysfunction is associated with diverse diseases (Singhal et al., 2008).

Different types of ubiquitination and role Although ubiquitination was initially identified as a signal that leads to proteasome degradation of the target protein, it has become since clear that attachment of ubiquitin can lead to different outcomes depending on the type of this attachment. All lysine residues of the ubiquitin molecules can be used for isopeptide bond formation and result to different outcomes. In addition another dimension of diversification is conferred by whether one ubiquitin molecule or a chain of ubiquitins is attached. A chain of at least four ubiquitin molecules linked through lysine 48 is the signal for recognition of a target protein by the proteasome complex in order to be degraded. The entire structure that leads to degradation of a target protein by the proteasome is called a degron and is comprised of two parts, the first being the covalently attached ubiquitin tag and the second being an unstructured region of the target protein that is a pre-requisite for the delivery of the recognized and captured protein to the interior of the core proteasome particle where the enzymatic degradation activities reside (Schrader et al., 2009). Other lysines such as lysine 6 and 11 of the ubiquitin molecule can also serve as anchors of proteasome-recognized ubiquitin chains. Ubiquitin chains linked through lysine 63 regulate processes such as DNA repair, endocytosis and protein kinases activation (Hoeller et al., 2006). Proteasome degradation after lysine 63 poly-ubiquitination has been described in some instances to occur (Babu et al., 2005) but most often lysine 63 poly-ubiquitination leads to proteolysis through autophagy (Li and Ye, 2008). Lysine 63-linked chains differ significantly in their conformation from their lysine 48-linked counterparts. Lysine 63-linked chains undertake an open conformation with little contact between ubiquitins except for the covalent link (Varadan et al., 2004), although in solution lysine 63 chains can adopt a continuum of conformations in a dynamic manner (Datta et al., 2009). In contrast, lysine 48-linked chains have a more compact conformation with neighboring ubiquitins developing additional non-covalent links with each other. These differences between ubiquitin chains form the basis for divergent functions (Tenno et al., 2004) due to recognition specificity by different ubiquitin receptor proteins (Raasi et al., 2005). The Ubiquitin-Proteasome System (UPS) plays an important role in DNA transcription. Co-activators bound to activated transcription factors recruit histone acetyltransferases such as CBP (CREB Binding Protein)/p300 and p/CAF (p300/CBP-associated

Factor) and histone arginine methyltransferases such as CARM1 (Coactivator-associated Arginine Methyltransferase-1) and PRMT-1 (Protein Arginine Methyltransferase-1) (Jenster et al., 1997). These enzymes promote histone acetylation and methylation that opens nucleosomes in order for transcription complex to obtain access to transcription factor binding sequences in target promoters. The signal for histone methylation is provided by sequential histone mono-ubiquitination and de-ubiquitination (Zhang, 2003; Dover et al., 2002; Sun and Allis, 2002), a process in which the 19S regulatory part of the proteasome is also involved (Laribee et al., 2007; Ezhkova and Tansey, 2004). This process is important in transcription elongation and defines a point of regulation of transcription by the UPS. RING domain-containing E3 ligase hPIRH2 (human p53-induced ring-containing H2) binds transcription factors such as nuclear receptors and promotes suppression of histone deacetylase 1 (HDAC1) stabilizing histones in the acetylated state (Logan et al., 2006). Histone modifications are an intermediary state that promotes nucleosomal histone octamer dissociation from the promoter transcription initiation site and leave DNA naked for transcription machinery binding (Boeger et al., 2005; Boeger et al., 2004). In addition ubiquitination of co-repressors CtBP1/2 and NCoR/SMRT leads to their proteasome degradation releasing transcriptional repression in order for the transcription complex to bind DNA (Perissi et al., 2008). Many transcription factors such as nuclear receptors undergo ubiquitination after DNA binding (Gaughan et al., 2005; Ramamoorthy and Nawaz, 2008). In parallel a molecular complex called mediator is recruited and helps recruit, in its turn, RNA polymerase II to begin transcription (Vijayvargia et al., 2007). After a few rounds of transcription ubiquitin ligases have attached four ubiquitin molecules to transcription factor molecules which can now be recognized by the proteasome for degradation. Components of the general transcription machinery that possess E3 ligase activity collaborate in this ubiquitination (Conaway et al., 2002). Some transcription factors such as the AR (Androgen Receptor) are stabilized in a transient monoubiquitinated state by a protein called TSG101 (Tumor Susceptibility Gene 101), which later is displaced from the AR for poly-ubiquitination to take place (Burgdorf et al., 2004). Proteasomal degradation is a pre-requisite for the transcription process to continue because it frees the way for new transcription factor molecules to occupy the promoter as long as the signal that activates the transcription factor exists. In this way there is a strict time regulation of transcription. Ubiquitination plays also significant role in DNA repair. Nucleotide Excision Repair (NER), one of the modes of DNA repair is activated when DNA damage, for example after UV light, is detected. NER requires



ubiquitin-associated (UBA) domain of protein hHR23 in order to interact with ATP activity-possessing components of 19S proteasome (Reed and Gillette, 2007). This interaction does not result in proteasome degradation but promotes XPC (Xeroderma Pigmentosum Complementation group C) protein stabilization by preventing this protein from being poly-ubiquitinated and recognized by the proteasome for degradation (Raasi and Pickart, 2002). XPC mono-ubiquitination is at least temporarily promoted (as poly-ubiquitination is inhibited) and may serve as the signal for further factors involved in NER recruitment. A role of ubiquitination exists in DNA damage tolerance pathway. In this instance, after DNA damage the protein PCNA (Proliferating Cell Nuclear Antigen) is mono-ubiquitinated and recruits trans-lesion synthesis polymerases that bypass DNA lesion allowing replication despite lesion existence. In contrast, PCNA lysine 63 poly-ubiquitination promotes recovering of stalled replication fork at sites of DNA damage in an error-free manner (Chiu et al., 2006). Other DNA repair pathways such as base excision repair (BER), mismatch repair (MMR) and Double Strand Break (DSB) repair involve both proteolytic and non-proteolytic ubiquitin regulation (Vlachostergios et al., 2009). Mono-ubiquitination is a signal involved in receptor endocytosis and lysosomal sorting. Many receptor tyrosine kinases (RTKs) such as EGFR (Epidermal Growth Factor Receptor) and PDGFR (Platelet-Derived Growth Factor Receptor) undergo ligand-induced mono-ubiquitination. In this process ligand-induced phosphorylation of the receptor gives the signal for receptor ubiquitination. E3 ligase cbl facilitates receptor ubiquitination and is the major E3 ligase for this purpose (Hugland et al., 2003). Ubiquitinated receptors interact with ubiquitin-binding proteins of the endocytic pathway and are escorted through clathrin-coated pits to clathrin-coated vesicles, endosomes and finally lysosomes. In this travel, surface receptors are transferred to different ubiquitin-binding proteins. Mono-ubiquitination in multiple receptor sites (multiple mono-ubiquitination) has also been found to play a role in receptor endocytosis. Cbl E3 ligase mediates also multiple mono-ubiquitination. Multiple mono-ubiquitination is believed to stabilize interaction of receptors with ubiquitin receptors in order to enhance their transfer to lysosomes. Some ubiquitin receptors may also recognize only multi-ubiquitinated RTKs through multiple domain interactions. The type of ubiquitination performed which, as discussed, will specify the fate of the target protein

depends on the E2 and E3 enzymes that are involved. It appears that HECT type E3s due to their distinctive mode of action retain the decision of the ubiquitination type while RING type E3s are more promiscuous in the type of ubiquitination performed and depend on their E2 partner in each case to define ubiquitination type (Ikeda and Dikic, 2008). For example, HECT domain ligase E6-AP forms lysine 48 ubiquitin chains, while RING domain ligase BRCA1 can mono-ubiquitinate substrates when interacting with E2 enzymes UBCH6, UBE2E2, UBCM2 and UBE2W, forms lysine 63-linked chains when interacting with E2 MMS2-UBC13 and lysine 48-linked ubiquitin chains when interacting with E2 UBE2K (Christensen et al., 2007).

The proteasome The whole proteasome structure is called 26S proteasome representing a complex of 2.5 MDa. It is localized in both the nucleus and the cytoplasm, near the endoplasmic reticulum and even in the centrosome (Fabunmi et al., 2000). 26S proteasome is comprised of two parts: The 19S regulatory particle (RP) and the 20S Core Particle (CP), comprised in their turn of several protein sub-units each. After attachment of at least four ubiquitin molecules the target protein is recognized by specific sub-units of 19S regulatory particle (RP) of the proteasome. 19S RP is a multi-protein structure that caps the two sides of the core particle (CP) of the proteasome. 19S (also known with the alternative name PA700) is made of two sub-complexes called the lid and the base and a total of 17 peptide molecules. Six of them possess ATPase activity while the 11 others are non-ATPases. The lid sub-complex is comprised of eight sub-units, six of which contain a PCI [Proteasome, COP9 signalosome and eIF3 (eukaryotic Initiation Factor 3)] domain mediating interactions between them. One of the other two sub-units, S13 in mammals and Rpn11 in yeast, is the metallopeptidase that performs de-ubiquitination of the substrates in order for ubiquitin molecules to be recycled. Both S13 and the eighth lid sub-unit contain a so called MPN (Mpr1p and Pad1p N-terminal regions) domain (Hanna and Finley, 2007). Nevertheless Rpn8 lacks key residues in the MPN domain and has no metallopeptidase activity. The 19S base sub-complex is made up of the six ATPases and three other peptides. ATPases belong to the AAA (ATPases Associated with various cellular Activities) family and are able to hydrolyze all four nucleotide triphosphates and to alter the conformation of protein, preventing aggregation.



Figure 2: Schematic representation of the proteasome multi-protein complex.

Thus, they function to prevent aggregation of proteasome substrate proteins before these proteins enter the Core Particle to be degraded. AAA ATPases have also functions independent of their membership in the proteasome structure notably in transcription and membranes fusion (Hanson and Whiteheart, 2005; Meyer, 2005). The three other peptides of the 19S base possess ubiquitin recognition domains that allow them to recognize poly-ubiquitin chains. The core particle of the proteasome is a cylinder-shaped multi-unit structure with a hollow central chamber (Rechsteiner, 2005). Inside this chamber enzymatic degradation of target proteins takes place executed by three enzymatic activity-possessing subunits of the CP. CP consists of four seven-member rings that are stacked one on the other. The two peripheral rings are similar and are called α rings and the two central rings are also similar and are called β rings. Each of the seven sub-units of the α and β rings is distinct resulting in the CP to be comprised of two copies each of 14 distinct sub-units. Three of the seven sub-units of the β rings, β1, β2 and β5 possess the enzymatic activities of the proteasome, trypsin-like (post-basic residues cleavage) activity, chymotrypsin-like (post-hydrophobic residues cleavage) activity and post-glutamyl (caspase-like or post-acidic residues cleavage) activity respectively. Resulting fragments after proteasome degradation range in general between 4 and 14 amino-acids in length (Wolf and Hilt, 2004).

Carcinogenesis processes: the role of the UPS Normal cells need to obtain six essential capabilities to become malignant (Hanahan and Weinberg, 2000): Self sufficiency in growth signals, insensitivity to anti-growth signals, inhibition of apoptosis, limitless replicative potential, angiogenesis potential and ability to invade and metastasize. UPS is involved in the

regulation of all these processes as will be discussed briefly below. Cell cycle machinery is in the heart of cell growth and the final destination of growth and anti-growth signals. Cell cycle is regulated in multiple levels by the UPS. Proteins called cyclins are associated with Cyclin-dependent kinases (CDKs) to activate their actions of phosphorylation of substrates for the cell to progress through the different phases of the cell cycle. In late G1 phase, cyclin D in collaboration with CDKs 4 and 6 phosphorylates and inactivates protein Rb. As a result transcription factor E2F is freed to transcribe genes necessary for the progression into the S phase. Transcription of Cyclin D is induced by the β-catenin/TCF4 transcription factor complex. β-catenin is regulated by the UPS through degradation after phosphorylation and ubiquitination with the aid of E3 ligase βTrCP (β-Transducin repeat Containing Protein). The stability of Cyclin D is also regulated directly by the UPS. Proteasome degradation keeps it in low levels through the cell cycle except for its up-regulation in late G1 (Kitagawa et al., 2009). Cyclins E1, E2 and A in collaboration with CDKs 1 and 2 get cell through S phase into G2 and Cyclin B functions in collaboration with CDK1 at G2 phase and is degraded by the proteasome at late mitosis (Vodermaier, 2004). CDKs are further regulated by CDK inhibitors such as p21 and p27, the stability of which are also determined by proteasome degradation (Carrano et al., 1999; Bornstein et al., 2003). The E3 ligase facilitating degradation of these CDK inhibitors is a RING finger type E3 with four sub-units. Of these sub-units F-box protein Skp2 (S-phase kinase protein 2) is the substrate recognition sub-unit. The same SCF type E3 is involved in the degradation of other cell cycle inhibitors such as the Rb family protein p130. In contrast, a SCF ligase with three identical sub-units but a different substrate recognition sub-unit called Fbxw7



(alternatively named hCDC4 or Archipelago) is involved in the proteasome degradation of proliferator promoting transcription factor c-myc as well as of cyclin E (Onoyama and Nakayama, 2008). Given their respective substrates E3 ligase sub-units Skp2 and Fbxw7 are acting as an oncogene the former and a tumor suppressor the latter (Shapira et al., 2005; Onoyama et al., 2007). Another point of particular importance of cell cycle regulation by the UPS is at the anaphase phase of mitosis. At that point the chromosomes are aligned at the center of the cell and develop connections through the centromere with both poles of the mitotic spindle. When all chromosomes have completed their attachment to both poles the signal is given for each sister chromatid to begin moving to a pole, detached from the other sister chromatid. Up to that point sister chromatids are kept attached at the centromere with the action of proteins cohesins. When all chromosomes are attached, APC/C (Anaphase Promoting Complex/Cyclosome), an E3 ligase, ubiquitinates the protein securin which is degraded by the proteasome (Castro et al., 2003). Securin is an inhibitor of the enzyme separase, which, after securin destruction, is activated and cleaves cohesins allowing sister chromatids to be pulled to the two poles at the end of anaphase. In parallel APC/C promotes the destruction of Cyclin B allowing dephosphorylation and inactivation of CDK1, another prerequisite for progression from anaphase to telophase and completion of mitosis (Matyskiela et al., 2009). Apoptosis is another process important in carcinogenesis that is regulated by the UPS. Many

proteins of the cellular core apoptosis machinery are substrates of the proteasome. Bcl-2 family includes both pro-apoptotic and anti-apoptotic members and both categories contain members that are proteasome substrates. UPS regulates the balance between the pro-apoptotic and anti-apoptotic family members which in turn will determine ultimate cell fate after various stimuli (Yang and Yu, 2003). IAPs (Inhibitors of Apoptosis) are a family of RING finger E3 ligases that inhibit apoptosis through ubiquitination and degradation of effectors of apoptosis, caspases. Apoptotic stimuli promote auto-ubiquitination of IAPs which leads to caspase stabilization in order to perform their apoptotic function (Vaux and Silke, 2005; Ni et al., 2005). p53 is a transcription factor of importance for the induction of apoptosis after DNA damage and thus, it has been named "the guardian of the genome". p53 is regulated by the UPS through ubiquitination by several E3 ligases. Mdm2 (mouse double minute 2, also known as hdm2 in humans) is the first identified E3 ligase that ubiquitinates p53 for proteasomal degradation. In different stress conditions, p53 degradation is inhibited either through its phosphorylation that prevents interaction with mdm2 or through inhibition of mdm2 activity through interaction with inhibitor p14 ARF (Alternative Reading Frame, a name that this protein takes from the fact that it is transcribed from the same DNA sequence but with a different reading frame with the CDK inhibitor p16INK4a at chromosome 9p). p53 degradation is also prevented by de-ubiquitination by the enzyme HAUSP (Herpes virus-Associated Ubiquitin Specific Protease).

Figure 3: Schematic representation of events leading to sister chromatids separation in anaphase.



Other E3 ligases have been found to ubiquitinate p53. In papilloma virus-infected cells, the HECT domain E3 ligase E6-AP (E6-Associated Protein) binds with viral protein E6 and promotes p53 degradation, an event that, together with degradation of tumor suppressor Rb, greatly contributes to viral oncogenesis. PIRH2 (p53-induced RING H2) is a RING type E3 ligase that promotes p53 ubiquitination independently of mdm2 and inhibits p53 transcription (Leng et al., 2003). Like mdm2, PIRH2 is a p53 target gene, this fact serving in both occasions as a negative feed-back loop. Another ubiquitin ligase ubiquitinating p53 is ARF-BP1/Mule (ARF-Binding Protein 1/Mcl1 ubiquitin ligase E3). This is a HECT domain ubiquitin ligase that, as its name implies, can be bound and inactivated by p14/ARF, in a manner analogous to mdm2 (Chen et al., 2005). ARF-BP1/Mule inactivation leads to promotion of apoptosis in both p53-dependent and -independent ways implying that the ligase has other apoptosis promoting substrates besides p53. In addition it ubiquitinates and promotes degradation of an anti-apoptotic protein, the bcl2 family member Mcl1 (Zhong et al., 2005). ARF-BP1/Mule possesses a BH3 (Bcl2 homology 3) domain through which it interacts with Mcl1. As a result of having both p53 and Mcl1 as a substrate, ARF-BP1/Mule can promote or impede apoptosis under different conditions (Shmueli and Oren, 2005). Finally, COP1 (Constitutively Photomorphogenic 1), a RING domain E3 ligase, is also promoting p53 degradation (Dornan et al., 2004).

The existence of multiple pathways regulating p53 stability and degradation by the UPS allow both a strict control of its function and a versatility of its activation and inhibition. Nevertheless the UPS constitutes a vital component of all pathways. In order for a cell to obtain limitless replicative potential, it needs to neutralize the mechanism that shortens telomeres with each successive division and limits the total number of cell cycles that it can successfully undergo. A protein called TRF1 (Telomeric Repeat binding Factor 1, alternatively called PIN2- Protein Interacting with NIMA 2) binds telomeres and prevents access of telomerase, thus physiologically preventing telomere length maintenance through the action of telomerase. In this way, in normal cells, telomere length is decreased with each successive cell cycle. Casein kinase 2 phosphorylates TRF1 and promotes its binding to telomeres (Kim et al., 2008). In contrast in neoplastic cells, TRF1 is ADP-ribosylated by a poly(ADP-ribose) polymerase (PARP), tankyrase and dissociates from telomeres (Smith and de Lange, 2000). Dissociated TRF1 is then ubiquitinated with the mediation of F-box family E3 ligase Fbx4 and degraded by the proteasome (Chang et al., 2003; Lee et al., 2006). This degradation allows telomerase to access the telomere and perform telomere length maintenance contributing to limitless replicative potential avoiding chromosome erosion that would lead to apoptosis.

Figure 4: Regulation of p53 by ubiquitination. Ubiquitin ligases involved in p53 ubiquitination are depicted.



Figure 5: The role of UPS in telomere maintenance in cancer. In normal cells (left), telomerase access to telomeres is prevented by protein TRF1 and telomeres are shortened with each cell division. In neoplastic cells (right), after ADP-ribosylation, TRF1 is displaced from the telomere and is ubiquitinated and degraded by the proteasome. As a result, telomerase can access telomeres and prevent their shortening.Angiogenesis is a crucial process in carcinogenesis and is regulated by the UPS in multiple levels. For example, the α sub-units of transcription factor HIF-1 (Hypoxia Inducible Factor-1) is kept suppressed under normoxic conditions by proteasome degradation (Corn, 2007). This degradation requires the action of oxygen sensing prolyl-hydroxylases (PHDs) that hydroxylate HIFα in two proline residues (Pro402 and Pro564) of a so-called oxygen-dependent degradation domain (ODD). Proline hydroxylation gives the signal for HIFα ubiquitination with the help of E3 ligase complex consisting of VHL (Von Hippel Lindau) protein, elongin B, elongin C, Cul2 and Rbx1. Ubiquitination is followed by HIFα proteasome degradation (Koh et al., 2008). In contrast, in hypoxia, prolyl-hydroxylases are inactive and HIFα remains hypo-hydroxylated and is stabilized in order to perform, in collaboration with constitutively present factor HIF-1β, a transcription program which induces dozens of genes among which genes important for angiogenesis, such as VEGF, are included. VHL protein constituent of HIFα's E3 ligase is mutated in Von Hippel Lindau syndrome which encompasses increased frequency of renal cell carcinomas (RCCs), retinal and central nervous system tumors as well as in sporadic RCCs, leading to constitutively active HIFα in this malignancy. PHDs are themselves proteasome substrates and their ubiquitination is mediated by E3 ligases Siah1 and 2 (Seven in absentia Homolog 1 and 2) (Nakayama and Ronai, 2004). Several other control points of angiogenesis by the UPS exist and include, as another example, direct HIF transcription regulation by proteasome-dependent and -independent functions of ubiquitin and regulation of the intra-cellular signal emanating from VEGFR (the receptor of VEGF).

Invasive and metastatic potential is another characteristic of the neoplastic cell and is also regulated by the UPS. Activation of several receptor tyrosine kinases such as EGFR, PDGFR and GDNFR (Glial cell line-Derived Neurotrophic Factor Receptor, also known as ret) favour invasion. These receptor proteins are proteasome substrates (Gur et al., 2004; Pierchala et al., 2006; Kim et al., 2008; Baron and Schwartz, 2000) and the same is true for intracellular proteins that take part in signal transduction such as Akt and ERK (Adachi et al., 2003; Mikalsen et al., 2005) as well as transcription factors that are final effectors of the pathways.



Figure 6: Regulation of transcription factor HIF-1 by the UPS. In normoxia (left), HIF1 is hydroxyprolinated and ubiquitinated with the aid of E3 ligase VHL to be degraded by the proteasome. In hypoxia (right), hydroxylation of HIF-1 is inhibited and the transcription factor is stabilized in order to perform its transcription program. Lysophosphatidic acid (LPA) receptors are also an example of invasion and motility promoting receptors. They are seven domain membrane spanning G-protein-coupled receptors. GBM (Glioblastoma multiforme), a central nervous system malignancy characterized by a propensity of tissue invasion, expresses high levels of LPA receptors which are stimulated by LPA derived from lysophosphatidylcholine through the action of autotaxin, an enzyme with lysophospholipase D activity also produced and secreted by GBM cells (Kishi et al., 2006; Hoelzinger et al., 2005). Autotaxin gene is under the control of transcription factor β-catenin which, as already mentioned, is proteasome-regulated (Kenny et al., 2005).

UPS role in cancer: The example of colorectal carcinogenesis Colorectal cancer develops along two major pathways. In the first pathway which takes place in about 85% of sporadic colorectal cancer patients as well as in patients with the hereditary syndrome Familial Adenomatous Polyposis (FAP), there is a sequence of molecular events leading stepwise from hyperplasia to adenoma to carcinoma. These cases have the characteristic of chromosomal instability. The remaining 15% of sporadic cases share molecular pathogenesis with another hereditary syndrome, hereditary non-polyposis colorectal cancer (HNPCC). In these cases there are

mutations of genes involved in mismatch repair (MMR) of DNA such as MSH2, MLH1 and PMS2 leading to microsatellite instability (Voutsadakis, 2007). The FAP type sequence begins with mutations in the gene encoding for APC (Adenomatous Polyposis Coli) protein. This is a protein taking part in a complex together with scaffolding proteins axin and conductin and kinases GSK3β (Glycogen Synthase Kinase 3β) and CKII (Casein Kinase II) that facilitates phosphorylation of transcription factor β-catenin, leading afterwards to ubiquitination with the help of E3 ligase TrCP and proteasomal degradation of β-catenin (Ilyas, 2005). If APC acquires debilitating mutations in both alleles as it happens in about 85% of sporadic colorectal carcinomas, or has already a germline mutation in one allele and acquires a mutation in the other allele as it happens in FAP syndrome, β-catenin cannot be ubiquitinated and degraded by the proteasome and thus, it remains constitutively active to perform a proliferation program leading to formation of lesions called aberrant crypt foci (ACF) in the colon. These are the first lesions in this sequence of colorectal carcinogenesis. Subsequently, activating mutations in the oncogene k-ras promote progression of ACF to adenoma. These mutations activate proliferation programs normally emanating from receptor tyrosine kinases without the need for receptor activation. Both



pathways down-stream of activated k-ras, the Raf/MAPKs pathway and the PI3K/akt pathway have members that are regulated by ubiquitination and proteasome degradation, while additional intersection of k-ras-activated pathways and the UPS exist at the level of transcription factors activated by MAPKs such as AP-1 (Activated Protein 1) given that transcription is a process that requires ubiquitin in both a proteasome-dependent and -independent manner (Voutsadakis, 2008). Next step of colorectal carcinogenesis, the transition from adenoma to carcinoma requires accumulation of additional lesions such as p53 and Smad4 (also known as DPC4- Deleted in Pancreatic Carcinoma 4) mutations. These are also pathways that are UPS regulated. As already discussed in a previous section, stability of p53 is regulated by multiple E3 ligases. Smad4 is part of the TGFβ (Transforming Growth Factor β) signalling cascade and is also a proteasome substrate for proteolytic regulation. The other sequence of colorectal carcinogenesis involving lesions in MMR genes is also UPS-regulated in multiple levels (Hernandez-Pigeon et al., 2004; Hernandez-Pigeon et al., 2005). As mentioned in a previous paragraph, DNA repair processes in general are UPS regulated. It becomes clear from the above discussion that several important lesions and pathways involved in both the FAP type sequence and the MMR sequence of colorectal carcinogenesis are UPS regulated. Given this multitude of regulations in oncogenesis by UPS, there are multiple opportunities for therapeutic interventions. Paradoxically this same multitude may diminish the probability that a single intervention affecting UPS regulation would be beneficial in a wide range of cancers with diverse molecular lesions. In contrast there is the need for identification of sub-sets of cancer types with specific molecular lesions that will be particularly sensitive to a specific therapeutic intervention affecting the UPS. Therapeutic success with proteasome inhibitor bortezomib in multiple myeloma creates a hope that inhibition of UPS can be a valid target in other types of malignancies and specific sub-sets of tumor locations. Further clinical trials based on the rational of solid pre-clinical data are needed to identify them.

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Voutsadakis IA. Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1088-1099.



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