review article genetic polymorphism in extracellular regulators...

Review ArticleGenetic Polymorphism in Extracellular Regulators ofWnt Signaling Pathway

Garima Sharma12 Ashish Ranjan Sharma1 Eun-Min Seo1 and Ju-Suk Nam13

1 Institute for Skeletal Aging amp Orthopaedic Surgery Hallym University-Chuncheon Sacred Heart Hospital Chuncheon-siGangwon-do 200-704 Republic of Korea2Amity Institute of Nanotechnology Amity University Uttar Pradesh Noida Uttar Pradesh 201313 India3Adbiotech Co Ltd Chuncheon-si Gangwon-do 200-880 Republic of Korea

Correspondence should be addressed to Ju-Suk Nam jsnam88hallymackr

Received 16 January 2015 Accepted 5 March 2015

Academic Editor Andrei Surguchov

Copyright copy 2015 Garima Sharma et alThis is an open access article distributed under the Creative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The Wnt signaling pathway is mediated by a family of secreted glycoproteins through canonical and noncanonical mechanismThe signaling pathways are regulated by various modulators which are classified into two classes on the basis of their interactionwith either Wnt or its receptors Secreted frizzled-related proteins (sFRPs) are the member of class that binds to Wnt protein andantagonizesWnt signaling pathwayThe other class consists of Dickkopf (DKK) proteins family that binds toWnt receptor complexThe present review discusses the disease related association of various polymorphisms inWnt signaling modulators Furthermorethis review also highlights that some of the sFRPs and DKKs are unable to act as an antagonist for Wnt signaling pathway and thustheir function needs to be explored more extensively

1 Introduction

The Wnt family a group of secreted glycoproteins directscell proliferation and polarity as well as determining the fateof a cell during embryonic development through a seriesof signaling transduction pathways [1] The members ofhuman Wnt family consist of 19 evolutionarily conservedglycoproteins having 22 or 24 cysteine residues [2] Themechanisms followed by Wnt signaling molecules are eitherthrough canonical pathway (cell fate determination) or vianoncanonical pathway (control of cell movement and tissuepolarity) (Figure 1) Signal transduction during canonicalWnt pathway is mediated through the family of frizzled(FZD) receptor and low density lipoprotein related protein5 (LRP5)6 LRP6 coreceptors activating 120573-catenin signalingcascade [3 4] The Wnt signaling pathway continues afterWnt ligand binds and forms a complex with FZD and LRP65together with phosphorylated scaffolding protein dishevelled(DVL)Thereafter phosphorylation of LRP6 leads to bindingof AXIN complex to the receptors thus disabling AXINcomplex to degrade 120573-catenin On the contrary the absence

of Wnt ligand leads to constant degradation of cytoplasmic120573-catenin protein via AXIN complex [5] Scaffold proteinAXIN and the tumor suppressor gene product adenoma-tous polyposis coli (APC) form AXIN complex togetherwith casein kinase 1 (CK1) and glycogen synthase kinase 3(GSK3) CK1 and GSK3 phosphorylate 120573-catenin at aminoterminus followed by 120573-catenin recognition and ubiqui-tination by 120573-transducing repeats-containing proteins (120573-TrCp) an E3 ubiquitin ligase subunit directing proteasomemediated degradation [6] As a result 120573-catenin is unable toreach the nucleus and subsequently Wnt targeted genes arerepressed by DNA-bound T-cell factorlymphoid enhancerfactor (TCFLEF) family of proteins In noncanonical signal-ing pathwayWnt ligand binds to the receptors of FZD familyand receptor tyrosine kinase-like orphan receptor 2receptortyrosine kinase (ROR2RYK) coreceptors to form a complexUpon stimulation by the receptors DVL is activated leadingto sequential activation of the Rho family of GTPases (smallG proteins such as RhoA RhoU RAC and CDC42) andJNKs Another noncanonicalWnt signaling pathway involvesactivation of WntCa++ signaling cascade

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 847529 9 pageshttpdxdoiorg1011552015847529

2 BioMed Research International

LRP 56

Axin

120573 TrCPP

P

JNKROCK

RacRho

APCGSK3120573 120573-cat

120573-

CKI120572

catDsh

Wnt

Fz

(a) Noncanonical pathway

Nucleus

Dsh

TCFLEf1

Target genes

120573-cat

120573-cat

120573-cat

120573-cat

CKI120572 AxinAPCLRP 56 W

nt

GSK3120573Fz

(b) Canonical pathway

Figure 1 Canonical and noncanonical Wnt signaling pathways

Various natural inhibitors of Wnt signaling pathway havebeen identified till date which can antagonize or regulateWnt signaling pathway (Figure 2) The mechanism of Wntantagonists has been highlighted by various developmentalstudies performed in various chick and Xenopus models[7 8] Broadly antagonists of Wnt signaling pathway aredivided into two classes depending on their functionalmechanism that is secreted frizzled-related proteins (sFRPs)and Dickkopfs (DKKs) The members of sFRP class can bindto Wnts and thus regulate the association of Wnt ligandsto their transmembrane receptors inhibiting both canonicaland noncanonical signaling pathways The sFRP class con-stitutes sFRP family proteins WIF-1 and Cerberus Anotherclass of antagonists that is DKK class binds to LRP5LRP6component of the Wnt receptor complex to inhibit canonicalWnt signaling and constitutes DKK family proteins andsclerostin [9] Besides antagonists Wnt signaling pathway isalso activated and regulated by some secreted proteins actingas agonists for example R-spondin (Rspo) [10]

As mentioned earlier Wnt signaling is one of the mostcritical pathways for cellular development even in adulttissues henceforth the polymorphism in genes of Wntsignaling modulators can be a foremost cause for varioustypes of associated diseases The present review highlightsdisease associated polymorphism studies in some of the Wntsignaling modulators Summarizing the role of polymor-phism inWnt signalingmodulators can open a new spectrumto understand the origin of various related diseases and totrace out novel pathways for potential therapeutics

2 Polymorphism in SOSTSclerostin

Sclerostin is a SOST gene encoded secreted glycoproteincontaining cysteine knot which acts as a Wnt antagonist andregulates skeletal mineralization [11 12] Recently expressionof SOST mRNA has also been reported in various cellsincluding liver blood vessels and kidneys [13] though theseorgans are devoid of sclerostin proteinThemajor expressionof sclerostin protein has been found in skeletal tissues suchas articular chondrocytes [14] and cementocytes [15] Evenduring inflammatory diseases like periprosthetic osteolysis ithas been shown to be induced in osteoblasts by cytokines liketumor necrosis factor alpha (TNF120572) [16] In osteocytes andosteoblasts sclerostin functions as aWnt120573-catenin signalingantagonist by binding to LRP56 receptors and thus inhibitingbone formation [17] SOST genes have been associated withosteoporotic fractures and bone mineral density (BMD)[18ndash20] However in a different study performed on 619perimenopausal Scottish women single nucleotide polymor-phism (SNP) in SOST gene region was not found associatedwith high or low BMD at lumbar spine [21] Similarly ina genotypic study of 652 Slovenian populations BMD wasnot associatedwith -1397-1396insGGA SOST polymorphism[22] On the contrary a genome wide linkage analysis ofChinese cohort revealed that the genetic polymorphismin sclerostin domain-containing protein 1 (SOSTDC1) hascorrelation with bone mass density [23] Although differencebetween SOST genotype in correspondence to the allele doseeffect was also observed concluding the necessity for large

BioMed Research International 3

DKK

WntWnt

AxinAPC

Lrp 56

SOST

Kremen

120573-cat

PP

Nucleus

Fz

TCFLEf1

120573-cat

sFRP

120573 TrCP

GSK3120573

(a) No Wnt

Wnt

Lrp 56

DKK

Nucleus

Target genes

PCP

RhoRAC

JNK

Fz

Dsh

CKI120572

Axin

120573-cat

120573-cat120573-cat

120573-cat

120573-catTCFLEf1

sFRP

GSK3120573

APC

(b) Wnt binding

DKKWnt

Nucleus

APC

Lrp 56

Kremen

PCP

RhoRAC

JNK

Fz

120573-cat 120573-cat

TCFLEf1

Axin

P PGSK3120573

120573 TrCP

(c) Wnt with DKK

Figure 2 Role of antagonists in Wnt signaling pathway

sample size Li et al 2008 showed increases in BMD in SOSTknockout mice [24] It has been earlier reported that loss offunction mutations in the SOST gene leads to monogenicbone disorder sclerosteosis (Online Mendelian InheritanceinMan ID 269500) characterized by hyperostosis all over theskeleton (massive bone overgrowth) [25 26] Additionallyanother mutation (52 kb deletion) at 35 kb downstream of theSOST gene causes van Buchem disease with similar diseasephenotype [27 28] Uitterlinden et al 2004 [29] hypoth-esized that polymorphism in SOST gene region influencesthe function of sclerostin causing variations in BMD in asubset of the population Further to verify their hypothesisthey observed eight polymorphisms within the region of theSOST gene which were in relation to BMD observed in 1939elderly Dutch white According to their results a decreasein BMD of spinefemoral neck in Dutch white females wasassociated with a 3 bp insertion in the SOST promoter region(SOST gene region polymorphism 3) and increase in BMDof spinefemoral neck in Dutch white males was associatedwith G variant of SOST-region polymorphism 9 that is vanBuchem deletion region Recently two BMD associated SNPs(rs851054 and rs851056) were also identified in 51015840 region ofSOST gene [18] Styrkarsdottir et al 2009 also identifiedthree SNPs that were in association with BMD and werelocated at 31015840 SOST gene region between 23 kb and 57 kb(rs1513670 rs7220711 and rs1107748) [30] Evidence of associ-ation between BMD and minus9247 polymorphism (rs1230399) at51015840 SOST gene region was also proved by a gene wide tag SNPassociation study performed on Chinese population (1243subjects) with low and high BMD [31]

3 Polymorphism in Secreted FrizzledRelated Protein (sFRP)

Based on sequence homology the five members of sFRPfamily (sFRP1 to sFRP5) are divided into two subgroupssFRP1 sFRP2 and sFRP5 constitute one subgroup whilesFRP3 and sFRP4 are in another subgroup These proteinsare soluble cysteine rich and bind directly to Wnt moleculesantagonizingWnt signaling pathway [38] sFRP3 also knownas FrzB was the first purified chondrogenic factor fromcartilage [39] Conflicting roles of sFRPs have recently beenreported such as sFRP1 that acts as an agonist in vitro atlow concentration [40] while sFRP1 promotes angiogenesisin a chick chorioallantoic membrane model [41] The role ofsFRP3 in the etiology of osteoarthritis has been discussed inmany reports Replication studies among Caucasian womenshowed two SNPs in sFRP3FrzB gene R200W (rs288326)and R324G (rs7775) may elevate knee osteoarthritis [32] Inanother SNP analysis association of these haplotypes withhip osteoarthritis have also been shown in a large populationof postmenopausal Caucasian women [33] In addition theauthors considered the contribution of SNPs and suggestedthem as a biomarker for osteoarthritis Transfection studiesin human embryonic kidney 293 cells (HEK293) performedby Loughlin et al 2004 [42] displayed that substitutionof highly conserved positively charged arginine residuesreduces the antagonizing ability of sFRP3FrzB sFRP3 asexpressed by chondrocytes mediated inhibition of Wntsignaling pathway is known to be vital for maintainingthe integrity of cartilage-bone junction Therefore R324G


SNP in sFRP3 results in structurally occult hip dysplasialeading to osteoarthritis Further they revealed that theG allele of R324G variant is in close association with hipreplacement in elderly females Furthermore Min et al2005 also showed increased incidence of G allele of thisvariant in individuals with hip radiographic osteoarthritisAccording to them individuals as G allele carrier have ahigh risk for hip radiographic osteoarthritis [43] Similarresults were also observed in a study performed in Spanishcohort observing association between FRZB and hip kneeand hand osteoarthritis Group observed increased frequencyof R324G in patients with multiple joint osteoarthritis andin females with hip osteoarthritis [34] Besides osteoarthritisrs7775 SNP in sFRP gene has been shown to exhibit a strongassociation with breast cancer SNP rs7775 was found in exon6 and was observed to encode arginine (CGC) or glycine(GGC) in Saudi women [35]

4 Polymorphism in Dickkopf

Another class of Wnt antagonist is cysteine rich secretedprotein known as Dickkopf (DKK-1 to -4) which binds toLRP56 receptor and Kremen 12 (transmembrane protein)and inhibits Wnt signaling pathway In human the genefor DKK-1 is located in 10q112 position of chromosome(NM 0122422) As a result the canonical pathway of Wntsignaling is inhibited [44 45] Studies in human DKK-1showed a multifaceted effect on proliferation and differen-tiation of various cells like human adult bone marrow cells[46] adipocytes [47] and osteoblasts [48] Moreover theelevation of the DKK-1 level by glucocorticoids in osteoblaststhat may lead to osteoporosis has also been observed [49]In addition Tian et al 2003 observed the association oflytic bone lesions and elevated DKK-1 level in patients withmultiple myeloma [50] Reports suggest that the induction ofDKK-1 is dependent on p53 and thus DKK1 acting as Wntantagonist may lead to p53 tumor suppression [51] Shouet al 2002 also suggested the proapoptotic role of DKK-1 which links oncogenic Wnt and p53 tumor suppressorpathways [52] Various reports showed antitumor effect ofDKK-1 on different cell lines like HeLa cervical cancer cells[53 54] colon cancer cells [55 56] breast cancer cells [57 58]renal cancer cells [59] and so forth

Ralston et al [60] suggested the association of DKK-1gene containing chromosomal region 10q21 with BMD inmen through genome wide linkage scan The influence ofgenetic variation in DKK-1 on hip geometry BMD andbone turnover has been studied earlier by Piters et al 2010[36] They selected three SNPs (rs2241529 (GA) rs1569198(AG) and rs1991392 (AC)) using HapMap within 1353 kbDKK-1 region and studied a group of 783 Caucasian men of20ndash29 years According to them rs1569198 had significantassociation with hip axis length (HAL) and was independentof BMD and height Results observed were further confirmedby haplotype analysis indicating increased risk of hip fracturein the general population However they further concludedthat all the variants do not influence BMD or bone turnovermarker in chosen subjects which was later on supported byother reports [61] For the first time the association of SNP

rs6485350 inDKK-3 gene and rs3763511 inDKK-4with breastcancer risk was studied by Alanazi et al 2013 [35] Studyreported 2-fold reduced breast cancer risk in women withGG genotype as compared to AA genotype in case of DKK-3 gene SNP Furthermore GG genotype and AG genotypeshowed enhanced protection against estrogen receptor posi-tive tumor and estrogen receptor negative tumor progressionrespectively Conversely SNP in DKK-4 gene was stronglyassociated with age independent increased breast cancer riskof estrogen receptor negative tumor In order to determine therelationship between polymorphism in DKK genes and renalcancer Hirata et al 2009 [37] examined 210 renal cancerpositive patients (145 male and 65 female) Through PCR-RFLP and direct sequencing genotype of SNP rs17037102and rs419559 rs447372 in DKK-2 rs3206824 rs11022095rs1472189 rs7396187 and rs2291599 inDKK-3 and rs2073664in DKK-4 were analyzed Results demonstrated significantassociation ofDKK-3 rs1472189 CTwith renal cell carcinomaand SNP rs17037102 G DKK-2 may contribute to increasedsurvival rate in patients after radical nephrectomy

5 Wnt Inhibitory Factor 1

Another evolutionary conserved modulator protein of Wntsignaling is Wnt inhibitory factor 1 (Wif 1) It is similar tosFRPs and inhibitsWnt signaling by binding toWnt proteinsWif 1 contains epidermal growth factor like repeats (EGFrepeats) and Wif domain which binds to Wnt proteins [6263] As reported Wif 1 is responsible for tumor suppressionand epigenetic silencing and may lead to increased riskof cancer by modulating Wnt signaling pathway Studiesshowed increasedWif 1 expression in C2C12 MC3T3-E1 andKS483 cells during BMP-2 induced osteoblasts differentiationsuggesting the role of Wif 1 as modulator of osteoblastsdifferentiation and maturation [64] Various studies havedemonstrated that tumorigenesis gene silencing can be aresult of abnormal methylation in promoter region of tumorsuppressor genes [65 66] Kawakami et al 2009 reportedthe downregulation of Wif 1 by promoter hypermethylationin renal cancer cells [67] In addition hypermethylation ofWif 1 gene promoter region was found to downregulate Wif 1gene in prostate cancer cell lines Further a decreasedmotilityand invasiveness of prostate cancer cells were reported afterrestoration of Wif 1 expression [68] Correlation of thereducedWif 1 expression due toWif 1 promoter hypermethy-lation and increase in bladder tumor has also been reportedby other research groups [69 70] Wif 1 gene has also beenreported to be involved in osteosarcoma Study performed byKansara et al revealed that in primary human osteosarcomapromoter hypermethylation leads to Wif 1 gene silencingwhich results in loss of differentiation and increased cellproliferation [71] Taking into account the importance ofWifgene in regulation of tumorigenesis and any probability ofexistence of polymorphism inWif gene which may result indeleterious effect makes it a probable candidate for requiringurgent studies for verifying its role in regulation of Wntsignaling pathway


Table 1 SNPs in the selected genes and associated clinical phenotypes

Gene Chromosome SNP ID Geographical cohort Phenotype Reference

SOSTDC1 7p211

rs16878759rs12699800rs17619769

China Osteoporosis [23]

SOST 17q213 rs851054rs851056 Australia BMD and BMC at total hip [18]

SOST 17q213rs1513670rs7220711rs1107748

Iceland Denmark and Australia Hip BMD associated [30]

SOST 17q213 rs1230399 China Spine FN trochanter andtotal hip BMD [31]

sFRP3 2q321 rs288326rs7775 Caucasian Spanish Knee osteoarthritis hip

osteoarthritis [32ndash34]

sFRP3 2q321 rs7775 Saudi Breast cancer [35]DKK1 10q21 rs1569198 Caucasian Hip axis length [36]DKK3 11p153 rs6485350 Saudi Breast cancer [35]DKK3 11p153 rs1472189 Japan Renal cancer [37]DKK4 8p111 rs3763511 Saudi Breast cancer [35]

6 R-Spondins

R-spondins are a newly discovered cysteine rich and con-taining a thrombospondin type 1 domainrepeat-1 secretedprotein family consisting of 4 members (Rspo1-4) RecentlyRspo has been reported to act as modulators ofWnt signalingpathway Rspo has been demonstrated to upregulate the Wntsignaling pathway by stabilizing cytosolic 120573-catenin [72 73]This is achieved by the binding of Rspo to LRP6 and thusdisrupting LRP6-DKK complex which further enhances thedeactivation of canonicalWnt signaling [10 74] All themem-bers of Rspo family have common structural organizationand share around 60 sequence homology [75] Recently fewstudies reported that Rspo modulates Wnt signaling pathwaythrough G protein-coupled receptors called leucine-richrepeat-containingGprotein-coupled receptor (LGR) [76 77]Till date three types of LGRs (LGR4-6) have been identifiedAs 7 transmembrane receptors LGRs consist of leucine-richrepeats at extracellular N-terminal domain and are capable ofbinding to all four Rspo proteins [78] Studies suggested thatLRPWntFz complex interacts with LRG-Rspo complex [7980] Although the functional mechanism of Rspo mediatedWnt signaling has been discussed in some reports yet theexact mechanism of action for Rspo still remains to be eluci-dated The association of Rspo family and bone metabolismhas been documented in some studies signified by the highlevel of Rspo protein expression in skeletal tissues at develop-mental stages and lacking of Rspo resulting in defected skele-tal formation [81 82] Lately mutations in Rspo4 have beenreported andwere found associatedwith the absence of fingerand toe nails (autosomal recessive anonychiahyponychia)(OMIM 206800) in humans [83ndash86] Khan et al 2012 iden-tified mutations (c178CgtT (pR60W) c353GgtA (pC118Y)and c3GgtA (pM1I)) within chromosome 20p13 at Rspo4locus after genotyping three anonychiahyponychia Pakistanifamilies usingmicrosatellitemarkers Study expandedRSPO4mutations related with anonychiahyponychia to 17 and all of

them were found located in the first three exons encoding asignal peptide and the highly conserved furin-like cysteine-rich domains Study concluded and suggested that pM1Ivariant is a recurrent mutation among Pakistani patients andcan be considered as a polymorphism having no effect on theobserved disorder [87]

7 Conclusion and Perspectives

The functional complexity of Wnt signaling pathway hasdriven the interest of leading researchers towards in-depthanalysis ofWnt signaling controlling factorsThe extracellularantagonists and agonists provide defined regulation of signaland their further transmission Herein we have tried tosummarize the various reported polymorphisms in knownantagonists (sFRP DKK and Wif-1) and agonists (Rspo) ofWnt signaling pathway leading to the observed diseased statein humans (Table 1) As discussed in above sections bothantagonists and agonists possess polymorphisms and havebeen linked to deleterious effects on humanhealthThereforethe detailed genetic study of these antagonists and agonistsmay serve as a useful tool for understanding the developmentand progression of various diseases Furthermore geneticidentification of Wnt signaling antagonists responsible fordisease susceptibility remains at priority attention for cellbiologists Although extensive work has been carried out inrecent years nevertheless we still need to understand theassociation of polymorphism in genes of antagonists andthe progression of diseases Advancements in this area mayprovide an insight and tend to open new opportunities for theearly identification and treatments for yet incurable diseases

Abbreviations

LRP 56 Low density lipoprotein receptor-relatedprotein 56


Fz Frizzled receptor proteinGSK3 120573 Glycogen synthase kinase 3 betaAPC Adenomatosis polyposis coli proteinCKI120572 Cyclin-dependent kinase inhibitor alpha120573 TrCp Beta-transducin repeat containing E3

ubiquitin protein ligaseWNT Wingless-type MMTV integration site

protein familyTCFLEf1 T-cell factorlymphoid-enhancing factor

type 1DVL Dishevelled proteinRho Ras-like proteinsROCK Rho-associated kinaseROR2 Receptor tyrosine kinase-like orphan

receptor 2JNKs c-Jun N-terminal kinasesDKK DickkopfsFRP Secreted frizzled-related proteinKremen Kringle containing transmembrane

proteinWif Wnt inhibitory factorRspo R-spondinLGR Leucine-rich repeat-containing G

protein-coupled receptorOMIM Online mendelian inheritance in man

Conflict of Interests

The authors declare that they do not have a conflict ofinterests for any of the organizations or authors that mighthave influenced the performance or presentation of the workdescribed in this paper

Acknowledgment

This research was supported by the Basic Science ResearchProgram through the National Research Foundationof Korea (NRF) funded by the Ministry of Education(2014R1A1A2055560)

References

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[2] M Katoh ldquoWNT and FGF gene clusters (review)rdquo InternationalJournal of Oncology vol 21 no 6 pp 1269ndash1273 2002

[3] P Bhanot M Brink C H Samos et al ldquoA new member ofthe frizzled family from Drosophila functions as a winglessreceptorrdquo Nature vol 382 no 6588 pp 225ndash231 1996

[4] K I Pinson J Brennan S Monkley B J Avery and WC Skarnes ldquoAn LDL-receptor-related protein mediates Wntsignalling inmicerdquoNature vol 407 no 6803 pp 535ndash538 2000

[5] A Kikuchi H Yamamoto and A Sato ldquoSelective activationmechanisms ofWnt signaling pathwaysrdquo Trends in Cell Biologyvol 19 no 3 pp 119ndash129 2009

[6] X He M Semenov K Tamai and X Zeng ldquoLDL receptor-related proteins 5 and 6 in Wnt120573-catenin signaling arrowspoint the wayrdquoDevelopment vol 131 no 8 pp 1663ndash1677 2004

[7] C Niehrs O Kazanskaya W Wu and A Glinka ldquoDickkopf1and the Spemann-Mangold head organizerrdquo International Jour-nal of Developmental Biology vol 45 no 1 pp 237ndash240 2001

[8] T P Yamaguchi ldquoHeads or tails Wnts and anterior-posteriorpatterningrdquoCurrent Biology vol 11 no 17 pp R713ndashR724 2001

[9] C Beyer and G Schett ldquoNovel targets in bone and cartilagerdquoBest Practice and Research Clinical Rheumatology vol 24 no4 pp 489ndash496 2010

[10] K-A Kim M Wagle K Tran et al ldquoR-Spondin familymembers regulate theWnt pathway by a commonmechanismrdquoMolecular Biology of the Cell vol 19 no 6 pp 2588ndash2596 2008

[11] X Li Y Zhang H Kang et al ldquoSclerostin binds to LRP56 andantagonizes canonical Wnt signalingrdquoThe Journal of BiologicalChemistry vol 280 no 20 pp 19883ndash19887 2005

[12] D G Monroe M E McGee-Lawrence M J Oursler and J JWestendorf ldquoUpdate onWnt signaling in bone cell biology andbone diseaserdquo Gene vol 492 no 1 pp 1ndash18 2012

[13] M J C Moester S E Papapoulos C W G M Lowik andR L van Bezooijen ldquoSclerostin current knowledge and futureperspectivesrdquo Calcified Tissue International vol 87 no 2 pp99ndash107 2010

[14] B Y Chan E S Fuller A K Russell et al ldquoIncreased chon-drocyte sclerostin may protect against cartilage degradation inosteoarthritisrdquo Osteoarthritis and Cartilage vol 19 no 7 pp874ndash885 2011

[15] A Jager W Gotz S Lossdorfer and B Rath-Deschner ldquoLocal-ization of SOSTsclerostin in cementocytes in vivo and inmineralizing periodontal ligament cells in vitrordquo Journal ofPeriodontal Research vol 45 no 2 pp 246ndash254 2010

[16] S-S Lee A R Sharma B-S Choi et al ldquoThe effect of TNFal-pha secreted frommacrophages activated by titanium particleson osteogenic activity regulated by WNTBMP signaling inosteoprogenitor cellsrdquo Biomaterials vol 33 no 17 pp 4251ndash4263 2012

[17] M Semenov K Tamai and X He ldquoSOST is a ligand forLRP5LRP6 and aWnt signaling inhibitorrdquo Journal of BiologicalChemistry vol 280 no 29 pp 26770ndash26775 2005

[18] A-M Sims N Shephard K Carter et al ldquoGenetic analyses in asample of individuals with high or low BMD shows associationwith multiple Wnt pathway genesrdquo Journal of Bone and MineralResearch vol 23 no 4 pp 499ndash506 2008

[19] J-M Liu M-J Zhang L Zhao et al ldquoAnalysis of recentlyidentified osteoporosis susceptibility genes in Han Chinesewomenrdquo Journal of Clinical Endocrinology and Metabolism vol95 no 9 pp E112ndashE120 2010

[20] U Styrkarsdottir B V Halldorsson D F Gudbjartsson et alldquoEuropean bone mineral density loci are also associated withBMD in East-Asian populationsrdquo PLoS ONE vol 5 no 10Article ID e13217 2010

[21] W Balemans D Foernzler C Parsons et al ldquoLack of asso-ciation between the SOST gene and bone mineral density inperimenopausal women analysis of five polymorphismsrdquo Bonevol 31 no 4 pp 515ndash519 2002

[22] S Mencej-Bedrac J Prezelj T Kocjan R Komadina and JMarc ldquoAnalysis of association of LRP5 LRP6 SOST DKK1and CTNNB1 genes with bone mineral density in a Slovenianpopulationrdquo Calcified Tissue International vol 85 no 6 pp501ndash506 2009

[23] J-W He H Yue W-W Hu Y-Q Hu and Z-L ZhangldquoContribution of the sclerostin domain-containing protein 1(SOSTDC1) gene to normal variation of peak bone mineral


density in Chinese women and menrdquo Journal of Bone andMineral Metabolism vol 29 no 5 pp 571ndash581 2011

[24] X Li M S Ominsky Q-T Niu et al ldquoTargeted deletion of thesclerostin gene in mice results in increased bone formation andbone strengthrdquo Journal of Bone and Mineral Research vol 23no 6 pp 860ndash869 2008

[25] W BalemansM EbelingN Patel et al ldquoIncreased bone densityin sclerosteosis is due to the deficiency of a novel secretedprotein (SOST)rdquo Human Molecular Genetics vol 10 no 5 pp537ndash543 2001

[26] M E Brunkow J C Gardner J van Ness et al ldquoBone dysplasiasclerosteosis results from loss of the SOST gene product a novelcystine knot-containing proteinrdquo American Journal of HumanGenetics vol 68 no 3 pp 577ndash589 2001

[27] W Balemans N Patel M Ebeling et al ldquoIdentification of a 52kb deletion downstream of the SOST gene in patients with vanBuchem diseaserdquo Journal of Medical Genetics vol 39 no 2 pp91ndash97 2002

[28] K Staehling-Hampton S Proll B W Paeper et al ldquoA 52-kbdeletion in the SOST-MEOX1 intergenic region on 17q12-q21 isassociated with van Buchem disease in the Dutch populationrdquoAmerican Journal ofMedical Genetics vol 110 no 2 pp 144ndash1522002

[29] AGUitterlinden P P Arp BW Paeper et al ldquoPolymorphismsin the sclerosteosisvan Buchem disease gene (SOST) regionare associated with bone-mineral density in elderly whitesrdquoAmerican Journal of Human Genetics vol 75 no 6 pp 1032ndash1045 2004

[30] U Styrkarsdottir B V Halldorsson S Gretarsdottir et al ldquoNewsequence variants associated with bonemineral densityrdquoNatureGenetics vol 41 no 1 pp 15ndash17 2009

[31] Q-Y Huang G H Y Li and A W C Kung ldquoThemdash9247 TCpolymorphism in the SOST upstream regulatory region thatpotentially affects CEBP120572 and FOXA1 binding is associatedwith osteoporosisrdquo Bone vol 45 no 2 pp 289ndash294 2009

[32] A M Valdes J Loughlin M Van Oene et al ldquoSex andethnic differences in the association ofASPN CALM1 COL2A1COMP and FRZBwith genetic susceptibility to osteoarthritis ofthe kneerdquo Arthritis and Rheumatism vol 56 no 1 pp 137ndash1462007

[33] N E Lane K Lian M C Nevitt et al ldquoFrizzled-related proteinvariants are risk factors for hip osteoarthritisrdquo Arthritis ampRheumatism vol 54 no 4 pp 1246ndash1254 2006

[34] J Rodriguez-Lopez M Pombo-Suarez M Liz J J Gomez-Reino and A Gonzalez ldquoFurther evidence of the role offrizzled-related protein gene polymorphisms in osteoarthritisrdquoAnnals of the Rheumatic Diseases vol 66 no 8 pp 1052ndash10552007

[35] M S Alanazi N R Parine J P Shaik H A AlabdulkarimS A Ajaj and Z Khan ldquoAssociation of single nucleotidepolymorphisms in Wnt signaling pathway genes with breastcancer in Saudi patientsrdquo PLoS ONE vol 8 no 3 Article IDe59555 2013

[36] E Piters W Balemans T L Nielsen et al ldquoCommon geneticvariation in the DKK1 gene is associated with hip axis lengthbut not with bone mineral density and bone turnover markersin young adult men results from the Odense Androgen StudyrdquoCalcified Tissue International vol 86 no 4 pp 271ndash281 2010

[37] H Hirata Y Hinoda K Nakajima et al ldquoWnt antagonist genepolymorphisms and renal cancerrdquo Cancer vol 115 no 19 pp4488ndash4503 2009

[38] B Zhang and J-X Ma ldquoWnt pathway antagonists and angio-genesisrdquo Protein and Cell vol 1 no 10 pp 898ndash906 2010

[39] B Hoang M Moos Jr S Vukicevic and F P Luyten ldquoPrimarystructure and tissue distribution of FRZB a novel proteinrelated to Drosophila frizzled suggest a role in skeletal mor-phogenesisrdquo Journal of Biological Chemistry vol 271 no 42 pp26131ndash26137 1996

[40] J Hu A Dong V Fernandez-Ruiz et al ldquoBlockade of Wntsignaling inhibits angiogenesis and tumor growth in hepatocel-lular carcinomardquo Cancer Research vol 69 no 17 pp 6951ndash69592009

[41] P Dufourcq T Couffinhal J Ezan et al ldquoFrzA a secreted friz-zled related protein induced angiogenic responserdquo Circulationvol 106 no 24 pp 3097ndash3103 2002

[42] J Loughlin B Dowling K Chapman et al ldquoFunctional variantswithin the secreted frizzled-related protein 3 gene are associatedwith hip osteoarthritis in femalesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no26 pp 9757ndash9762 2004

[43] J L Min I Meulenbelt N Riyazi et al ldquoAssociation of thefrizzled-related protein gene with symptomatic osteoarthritisat multiple sitesrdquo Arthritis and Rheumatism vol 52 no 4 pp1077ndash1080 2005

[44] A Bafico G Liu A Yaniv A Gazit and S A Aaronson ldquoNovelmechanism ofWnt signalling inhibitionmediated byDickkopf-1 interaction with LRP6Arrowrdquo Nature Cell Biology vol 3 no7 pp 683ndash686 2001

[45] B Mao W Wu G Davidson et al ldquoKremen proteins areDickkopf receptors that regulate Wnt120573-catenin signallingrdquoNature vol 417 no 6889 pp 664ndash667 2002

[46] C A Gregory H Singh A S Perry and D J Prockop ldquoTheWnt signaling inhibitor Dickkopf-1 is required for reentry intothe cell cycle of human adult stem cells from bone marrowrdquoThe Journal of Biological Chemistry vol 278 no 30 pp 28067ndash28078 2003

[47] C Christodoulides M Laudes W P Cawthorn et al ldquoTheWnt antagonist Dickkopf-1 and its receptors are coordinatelyregulated during early human adipogenesisrdquo Journal of CellScience vol 119 no 12 pp 2613ndash2620 2006

[48] F Morvan K Boulukos P Clement-Lacroix et al ldquoDeletionof a single allele of the Dkk1 gene leads to an increase inbone formation and bone massrdquo Journal of Bone and MineralResearch vol 21 no 6 pp 934ndash945 2006

[49] K Ohnaka H Taniguchi H Kawate H Nawata andR Takayanagi ldquoGlucocorticoid enhances the expression ofdickkopf-1 in human osteoblasts novel mechanism of gluco-corticoid-induced osteoporosisrdquo Biochemical and BiophysicalResearch Communications vol 318 no 1 pp 259ndash264 2004

[50] E Tian F Zhan RWalker et al ldquoThe role of theWnt-signalingantagonist DKK1 in the development of osteolytic lesions inmultiple myelomardquo The New England Journal of Medicine vol349 no 26 pp 2483ndash2494 2003

[51] J Wang J Shou and X Chen ldquoDickkopf-1 an inhibitor of theWnt signaling pathway is induced by p53rdquoOncogene vol 19 no14 pp 1843ndash1848 2000

[52] J Shou F Ali-Osman A S Multani S Pathak P Fedi andK S Srivenugopal ldquoHuman Dkk-1 a gene encoding a Wntantagonist responds to DNA damage and its overexpressionsensitizes brain tumor cells to apoptosis following alkylationdamage of DNArdquo Oncogene vol 21 no 6 pp 878ndash889 2002

[53] A Y Lee B He L You et al ldquoDickkopf-1 antagonizes Wntsignaling independent of 120573-catenin in human mesotheliomardquo


Biochemical and Biophysical Research Communications vol 323no 4 pp 1246ndash1250 2004

[54] A M Mikheev S A Mikheeva B Liu P Cohen and HZarbl ldquoA functional genomics approach for the identificationof putative tumor suppressor genes dickkopf-1 as suppressor ofHeLa cell transformationrdquo Carcinogenesis vol 25 no 1 pp 47ndash59 2004

[55] O Aguilera M F Fraga E Ballestar et al ldquoEpigenetic inac-tivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene inhuman colorectal cancerrdquo Oncogene vol 25 no 29 pp 4116ndash4121 2006

[56] O Aguilera C Pena J M Garcıa et al ldquoThe Wnt antagonistDICKKOPF-1 gene is induced by 112057225-dihydroxyvitamin D

3

associated to the differentiation of human colon cancer cellsrdquoCarcinogenesis vol 28 no 9 pp 1877ndash1884 2007

[57] W H Xu Z B Liu C Yang W Qin and Z M Shao ldquoExpres-sion of Dickkopf-1 and beta-catenin related to the prognosisof breast cancer patients with triple negative phenotyperdquo PLoSONE vol 7 no 5 Article ID e37624 2012

[58] H Kim E-M Seo A R Sharma et al ldquoRegulation of Wntsignaling activity for growth suppression induced by quercetinin 4T1 murine mammary cancer cellsrdquo International Journal ofOncology vol 43 no 4 pp 1319ndash1325 2013

[59] H Hirata Y Hinoda K Nakajima et al ldquoWnt antagonistDKK1 acts as a tumor suppressor gene that induces apoptosisand inhibits proliferation in human renal cell carcinomardquoInternational Journal of Cancer vol 128 no 8 pp 1793ndash18032011

[60] S H Ralston N Galwey I Mackay et al ldquoLoci for regulation ofbone mineral density in men and women identified by genomewide linkage scan the FAMOS studyrdquoHumanMolecular Genet-ics vol 14 no 7 pp 943ndash951 2005

[61] T Koromila P Georgoulias Z Dailiana et al ldquoCER1 genevariations associated with bone mineral density bone markersand early menopause in postmenopausal womenrdquo HumanGenomics vol 7 no 1 article 21 2013

[62] J-C Hsieh L Kodjabachian M L Rebbert et al ldquoA newsecreted protein that binds to Wnt proteins and inhibits theiractivitesrdquo Nature vol 398 no 6726 pp 431ndash436 1999

[63] S W Cho J-Y Yang H J Sun et al ldquoWnt inhibitory factor(WIF)-1 inhibits osteoblastic differentiation in mouse embry-onic mesenchymal cellsrdquo Bone vol 44 no 6 pp 1069ndash10772009

[64] B L T Vaes K J Dechering E P van Someren et al ldquoMicroar-ray analysis reveals expression regulation of Wnt antagonistsin differentiating osteoblastsrdquo Bone vol 36 no 5 pp 803ndash8112005

[65] K Kawamoto H Hirata N Kikuno Y Tanaka M Nakagawaand R Dahiya ldquoDNA methylation and histone modificationscause silencing of Wnt antagonist gene in human renal cellcarcinoma cell linesrdquo International Journal of Cancer vol 123no 3 pp 535ndash542 2008

[66] MM L Baldewijns I J H vanVlodrop L J Schouten PMMB Soetekouw A P de Bruıne and M van Engeland ldquoGeneticsand epigenetics of renal cell cancerrdquo Biochimica et BiophysicaActa vol 1785 no 2 pp 133ndash155 2008

[67] K Kawakami H Hirata S Yamamura et al ldquoFunctionalsignificance of Wnt inhibitory factor-1 gene in kidney cancerrdquoCancer Research vol 69 no 22 pp 8603ndash8610 2009

[68] D S Yee Y Tang X Li et al ldquoThe Wnt inhibitory factor 1restoration in prostate cancer cells was associated with reduced

tumor growth decreased capacity of cellmigration and invasionand a reversal of epithelial to mesenchymal transitionrdquoMolecu-lar Cancer vol 9 article 162 2010

[69] C Wissman P J Wild S Kaiser et al ldquoWIF1 a component ofthe Wnt pathway is down-regulated in prostate breast lungand bladder cancerrdquo Journal of Pathology vol 201 no 2 pp204ndash212 2003

[70] S Urakami H Shiina H Enokida et al ldquoEpigenetic inacti-vation of Wnt inhibitory factor-1 plays an important role inbladder cancer through aberrant canonical Wntbeta-cateninsignaling pathwayrdquo Clinical Cancer Research vol 12 no 2 pp383ndash391 2006

[71] M Kansara M Tsang L Kodjabachian et al ldquoWnt inhibitoryfactor 1 is epigenetically silenced in human osteosarcoma andtargeted disruption accelerates osteosarcomagenesis in micerdquoThe Journal of Clinical Investigation vol 119 no 4 pp 837ndash8512009

[72] A R Sharma C Chakraborty S-S Lee et al ldquoComputationalbiophysical biochemical and evolutionary signature of humanR-spondin family proteins the member of canonical Wnt120573-catenin signaling pathwayrdquo BioMed Research International vol2014 Article ID 974316 22 pages 2014

[73] A R Sharma B S Choi J M Park et al ldquoRspo1 promotesosteoblast differentiation via Wnt signaling pathwayrdquo IndianJournal of Biochemistry and Biophysics vol 50 no 1 pp 19ndash252013

[74] M E Binnerts K-A Kim J M Bright et al ldquoR-Spondin1regulates Wnt signaling by inhibiting internalization of LRP6rdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 104 no 37 pp 14700ndash14705 2007

[75] K-A Kim J Zhao S Andarmani et al ldquoR-spondin proteins anovel link to 120573-catenin activationrdquo Cell Cycle vol 5 no 1 pp23ndash26 2006

[76] A Glinka C Dolde N Kirsch et al ldquoLGR4 and LGR5 areR-spondin receptors mediating Wnt120573-catenin and WntPCPsignallingrdquo EMBO Reports vol 12 no 10 pp 1055ndash1061 2011

[77] W de Lau N Barker T Y Low et al ldquoLgr5 homologues asso-ciate with Wnt receptors and mediate R-spondin signallingrdquoNature vol 476 no 7360 pp 293ndash297 2011

[78] K S Carmon X Gong Q Lin A Thomas and Q Liu ldquoR-spondins function as ligands of the orphan receptors LGR4 andLGR5 to regulate Wntbeta-catenin signalingrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 108 no 28 pp 11452ndash11457 2011

[79] J Schuijers and H Clevers ldquoAdult mammalian stem cells therole of Wnt Lgr5 and R-spondinsrdquo EMBO Journal vol 31 no12 pp 2685ndash2696 2012

[80] W B M de Lau B Snel and H C Clevers ldquoThe R-spondinprotein familyrdquo Genome Biology vol 13 no 3 article 242 2012

[81] J-S Nam T J Turcotte and J K Yoon ldquoDynamic expression ofR-spondin family genes in mouse developmentrdquo Gene Expres-sion Patterns vol 7 no 3 pp 306ndash312 2007

[82] K D Hankenson M T Sweetwyne H Shitaye and K LPosey ldquoThrombospondins and novel TSR-containing proteinsR-spondins regulate bone formation and remodelingrdquo CurrentOsteoporosis Reports vol 8 no 2 pp 68ndash76 2010

[83] D C Blaydon Y Ishii E A OrsquoToole et al ldquoThe gene encodingR-spondin 4 (RSPO4) a secreted protein implicated in Wntsignaling is mutated in inherited anonychiardquo Nature Geneticsvol 38 no 11 pp 1245ndash1247 2006


[84] C Bergmann J Senderek D Anhuf et al ldquoMutations inthe gene encoding the Wnt-signaling component R-spondin 4(RSPO4) cause autosomal recessive anonychiardquo The AmericanJournal of Human Genetics vol 79 no 6 pp 1105ndash1109 2006

[85] NWasif andW Ahmad ldquoA novel nonsense mutation in RSPO4gene underlies autosomal recessive congenital anonychia in aPakistani familyrdquo Pediatric Dermatology vol 30 no 1 pp 139ndash141 2013

[86] Y Ishii M Wajid H Bazzi et al ldquoMutations in R-spondin 4(RSPO4) underlie inherited anonychiardquo Journal of InvestigativeDermatology vol 128 no 4 pp 867ndash870 2008

[87] T N Khan J Klar S Nawaz et al ldquoNovel missense mutationin the RSPO4 gene in congenital hyponychia and evidence for apolymorphic initiation codon (pM1I)rdquo BMC Medical Geneticsvol 13 article 120 2012

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


LRP 56

Axin

120573 TrCPP

P

JNKROCK

RacRho

APCGSK3120573 120573-cat

120573-

CKI120572

catDsh

Wnt

Fz

(a) Noncanonical pathway

Nucleus

Dsh

TCFLEf1

Target genes

120573-cat

120573-cat

120573-cat

120573-cat

CKI120572 AxinAPCLRP 56 W

nt

GSK3120573Fz

(b) Canonical pathway

Figure 1 Canonical and noncanonical Wnt signaling pathways

Various natural inhibitors of Wnt signaling pathway havebeen identified till date which can antagonize or regulateWnt signaling pathway (Figure 2) The mechanism of Wntantagonists has been highlighted by various developmentalstudies performed in various chick and Xenopus models[7 8] Broadly antagonists of Wnt signaling pathway aredivided into two classes depending on their functionalmechanism that is secreted frizzled-related proteins (sFRPs)and Dickkopfs (DKKs) The members of sFRP class can bindto Wnts and thus regulate the association of Wnt ligandsto their transmembrane receptors inhibiting both canonicaland noncanonical signaling pathways The sFRP class con-stitutes sFRP family proteins WIF-1 and Cerberus Anotherclass of antagonists that is DKK class binds to LRP5LRP6component of the Wnt receptor complex to inhibit canonicalWnt signaling and constitutes DKK family proteins andsclerostin [9] Besides antagonists Wnt signaling pathway isalso activated and regulated by some secreted proteins actingas agonists for example R-spondin (Rspo) [10]

As mentioned earlier Wnt signaling is one of the mostcritical pathways for cellular development even in adulttissues henceforth the polymorphism in genes of Wntsignaling modulators can be a foremost cause for varioustypes of associated diseases The present review highlightsdisease associated polymorphism studies in some of the Wntsignaling modulators Summarizing the role of polymor-phism inWnt signalingmodulators can open a new spectrumto understand the origin of various related diseases and totrace out novel pathways for potential therapeutics

2 Polymorphism in SOSTSclerostin

Sclerostin is a SOST gene encoded secreted glycoproteincontaining cysteine knot which acts as a Wnt antagonist andregulates skeletal mineralization [11 12] Recently expressionof SOST mRNA has also been reported in various cellsincluding liver blood vessels and kidneys [13] though theseorgans are devoid of sclerostin proteinThemajor expressionof sclerostin protein has been found in skeletal tissues suchas articular chondrocytes [14] and cementocytes [15] Evenduring inflammatory diseases like periprosthetic osteolysis ithas been shown to be induced in osteoblasts by cytokines liketumor necrosis factor alpha (TNF120572) [16] In osteocytes andosteoblasts sclerostin functions as aWnt120573-catenin signalingantagonist by binding to LRP56 receptors and thus inhibitingbone formation [17] SOST genes have been associated withosteoporotic fractures and bone mineral density (BMD)[18ndash20] However in a different study performed on 619perimenopausal Scottish women single nucleotide polymor-phism (SNP) in SOST gene region was not found associatedwith high or low BMD at lumbar spine [21] Similarly ina genotypic study of 652 Slovenian populations BMD wasnot associatedwith -1397-1396insGGA SOST polymorphism[22] On the contrary a genome wide linkage analysis ofChinese cohort revealed that the genetic polymorphismin sclerostin domain-containing protein 1 (SOSTDC1) hascorrelation with bone mass density [23] Although differencebetween SOST genotype in correspondence to the allele doseeffect was also observed concluding the necessity for large


DKK

WntWnt

AxinAPC

Lrp 56

SOST

Kremen

120573-cat

PP

Nucleus

Fz

TCFLEf1

120573-cat

sFRP

120573 TrCP

GSK3120573

(a) No Wnt

Wnt

Lrp 56

DKK

Nucleus

Target genes

PCP

RhoRAC

JNK

Fz

Dsh

CKI120572

Axin

120573-cat

120573-cat120573-cat

120573-cat

120573-catTCFLEf1

sFRP

GSK3120573

APC

(b) Wnt binding

DKKWnt

Nucleus

APC

Lrp 56

Kremen

PCP

RhoRAC

JNK

Fz

120573-cat 120573-cat

TCFLEf1

Axin

P PGSK3120573

120573 TrCP

(c) Wnt with DKK
















SOSTDC1 7p211

rs16878759rs12699800rs17619769



SOST 17q213rs1513670rs7220711rs1107748






6 R-Spondins





Abbreviations












Acknowledgment


References





























































3










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


DKK

WntWnt

AxinAPC

Lrp 56

SOST

Kremen

120573-cat

PP

Nucleus

Fz

TCFLEf1

120573-cat

sFRP

120573 TrCP

GSK3120573

(a) No Wnt

Wnt

Lrp 56

DKK

Nucleus

Target genes

PCP

RhoRAC

JNK

Fz

Dsh

CKI120572

Axin

120573-cat

120573-cat120573-cat

120573-cat

120573-catTCFLEf1

sFRP

GSK3120573

APC

(b) Wnt binding

DKKWnt

Nucleus

APC

Lrp 56

Kremen

PCP

RhoRAC

JNK

Fz

120573-cat 120573-cat

TCFLEf1

Axin

P PGSK3120573

120573 TrCP

(c) Wnt with DKK
















SOSTDC1 7p211

rs16878759rs12699800rs17619769



SOST 17q213rs1513670rs7220711rs1107748






6 R-Spondins





Abbreviations












Acknowledgment


References





























































3










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology












SOSTDC1 7p211

rs16878759rs12699800rs17619769



SOST 17q213rs1513670rs7220711rs1107748






6 R-Spondins





Abbreviations












Acknowledgment


References





























































3










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology











Acknowledgment


References





























































3










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






































3










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology













Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

review article genetic polymorphism in extracellular regulators...

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