desmosomes: regulators of cellular signaling and adhesion...

Desmosomes: Regulators of Cellular Signalingand Adhesion in Epidermal Health and Disease

Jodi L. Johnson1,2, Nicole A. Najor1, and Kathleen J. Green1,2

1Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 606112Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Correspondence: [email protected]

Desmosomes are intercellular junctions that mediate cell–cell adhesion and anchor theintermediate filament network to the plasma membrane, providing mechanical resilienceto tissues such as the epidermis and heart. In addition to their critical roles in adhesion,desmosomal proteins are emerging as mediators of cell signaling important for proper celland tissue functions. In this review we highlight what is known about desmosomal proteinsregulating adhesion and signaling in healthy skin—in morphogenesis, differentiation andhomeostasis, wound healing, and protection against environmental damage. We alsodiscuss how human diseases that target desmosome molecules directly or interfere indirectlywith these mechanical and signaling functions to contribute to pathogenesis.

Desmosomes are intercellular junctions thatstrengthen mechanically challenged tissues

by linking intermediate filaments of adjoin-ing cells. They are crucial for both embryonicdevelopment and adult tissue integrity. Insultsagainst or mutations in desmosomal proteinslead to potentially lethal skin and heart diseases(Bazzi and Christiano 2007; Amagai and Stanley2012; Petrof et al. 2012; Kowalczyk and Green2013).

Members of three protein families make upthe core components of the desmosome (Figs. 1and 2): cadherins including desmogleins anddesmocollins (Dsgs, Dscs), armadillo proteinsincluding plakoglobin and plakophilins (Pg andPkps), and a plakin, desmoplakin (Dp) (Greenand Simpson 2007; Delva et al. 2009). Oth-

er tissue-specific desmosome proteins includePerp (p53 apoptosis effector related to PMP-22) (Ihrie and Attardi 2005) and the outer epi-dermal cornified envelope components corneo-desmosin, periplakin, envoplakin, involucrin,and kazrin (Groot et al. 2004; Sonnenberg andLiem 2007; Leclerc et al. 2009). The desmo-somal cadherins join cells together throughtheir extracellular domains and associate withPg and the Pkps through their intracellular do-mains. The cadherin–armadillo complex bindsin turn to Dp, which tethers the intermedi-ate filament network to the junctional plaque(Green and Simpson 2007; Kowalczyk andGreen 2013). The ability to confer mechanicalstrength through interaction with flexible,mechanically resilient intermediate filaments

Editors: Anthony E. Oro and Fiona M. Watt

Additional Perspectives on The Skin and Its Diseases available at www.perspectivesinmedicine.org

Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a015297

Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

1

ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org

on March 4, 2021 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from

http://perspectivesinmedicine.cshlp.org/

distinguishes desmosomes from a similar cad-herin-based organelle, the adherens junction,which interacts with the more rigid actin cyto-skeleton (Chu et al. 2004; Mucke et al. 2004;Gardel et al. 2008).

Desmosomal components change as kerati-nocytes differentiate and stratify (Fig. 2). Forinstance, Dsg2 is concentrated in the basal pro-liferating layers, whereas Dsg1 is first expressedas cells transit out of the basal layer and becomesprogressively concentrated in suprabasal layers

during stratification. Different desmosomal cad-herins have inherent differences in adhesivestrength(Hartliebetal.2013).Therefore, switch-ing components in each layer may allow cellplasticity in the lower, proliferative layers andincreased strength and barrier function in theupper layers. In addition to their adhesive func-tions, desmosomal components regulate intra-cellular signaling (Green and Gaudry 2000;Green and Simpson 2007; Kowalczyk and Green2013), and forced expression of a cadherin in

Dense midline

Plasma membrane

Outer denseplaque

Inner denseplaque

Dp

IF

Pg

Dsc

Dsg

Pkp

Figure 1. Desmosome structure and organization. Electron micrograph of a desmosome from bovine tongueepithelium overlaid with a representation of the membrane and plaque components. Desmosomes are com-posed of cadherins (Desmoglein, Dsg; Desmocollin, Dsc), armadillo proteins (Plakoglobin, Pg; Plakophilin,Pkp), and a plakin (Desmoplakin, Dp), which act as a cytolinker to tether the desmosome to the intermediatefilaments (IF).

J.L. Johnson et al.

2 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



the “wrong” layer can lead to alterations in pro-liferation/survival and differentiation (Henkleret al. 2001; Hanakawa et al. 2002; Merritt et al.2002; Hardman et al. 2005; Brennan et al. 2007,2010). The naturally diverse expression of des-mosomal components in each epidermal layerallows desmosomes to serve not only as nutsand bolts to hold cells together but also as atool kit to modulate form and function of thehighly specialized tissue.

In the sections that follow, we review tran-scriptional programs that dictate where andwhen desmosomal cadherins are expressedand the functional implications of the result-ing expression patterns in health and disease.We conclude by introducing how desmosom-al protein expression might be manipulatedpharmacologically, taking advantage of naturalturnover processes that control junction ho-meostasis.

TRANSCRIPTIONAL REGULATIONOF DESMOSOMAL COMPONENTS

The mechanisms responsible for establishingthe spatial patterning of desmosomal compo-nents in stratified epithelia are not yet well un-derstood. Desmosomal cadherin genes grouptogether on chromosome 18, whereas Pkp1-3,Pg, and Dp genes map to chromosomes 1, 12,11, 17, and 6, respectively (Arnemann et al.1991; Wang et al. 1994; Simrak et al. 1995; Cow-ley et al. 1997a,b; Bonne et al. 1998; Whittockand Bower 2003). The chromosomal groupingof the desmosomal cadherins may allow for se-quential expression in which, for example, Dsc1follows Dsg1 expression in epidermal differen-tiation, although a mechanism has not yet beenelucidated (Getsios et al. 2009).

Signaling pathways involved in epidermaldifferentiation regulate keratin and desmosom-

KLF-4KLF-5p63

ZEB MAL/MRTF*SRF*

SLUG*Brn-3b*

CDX-1*CDX-2*TCF-4LEF-1

PGcREL/NF-κB

C/EBP-αC/EBP-γ

C/EBP-βC/EBP-δ

p63p53

TCF-4LEF-1

PG

p63GRHL1KLF-4KLF-5

SMAD1SMAD4SMAD5LEF-1

FOXN-1NICD

HoxC12HoxC13

Dsg4

Dp

Pkp

1

Pkp

3

Pkp

2

Dsc

2

Dsc

3

Dsg

3

Dsg

2

Pg

Dsc

1

Dsg

1

Dsg4

Plakinfamily

Armadillofamily

Cadherinfamily

Str

atum

corn

eum

Str

atum

gran

ulos

umS

trat

umsp

inos

umS

trat

umba

sale

Figure 2. Desmosome differential protein expression pattern in epidermis and the transcription factors linked totheir regulation. Several of the desmosomal components display a unique spatial pattern of expression within theepidermis (depicted as triangles and rectangles). We have summarized the transcriptional regulation of thedesmosomal components from multiple cell types in Table 1. Desmosomal regulators that have been verified inthe epidermis (no asterisk) are distinguished from those verified in other tissues (asterisk). Transcription factorsregulating Pkp1, Dsg3, and Dsg2 are putative or unknown.

Desmosomes in Epidermal Health and Disease

Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297 3

ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



al protein expression in keratinocytes, such asNotch, transforming growth factor b (TGF-b),IkB kinase (IKK), Ras/mitogen activated pro-tein kinase (MAPK), phosphoinositide-3-kinase(PI3K), Wnt, protein kinase C or A (PKC, PKA),and Rho GTPases (Dong and Chen 2009; Leitneret al. 2011; Lopez-Pajares et al. 2013). However,links between these signaling pathways and thespecific downstream transcription factors thatregulate desmosomal protein expression haveonly been elucidated in a few instances. It haslong been known that PKC signaling regulatesexpression of desmosomal cadherins in kerati-nocytes (Denning et al. 1998). Suppression ofPKC-a or PKC-d isoforms increases Dsg3 ex-pression, whereas suppression of PKC-d andPKC-1 isoforms either decreases or increasesDsg1 levels, respectively (Szegedi et al. 2009).However, the specific transcription factors whichact downstream of PKC isoforms to induce orinhibit desmosomal protein expression have notyet been directly shown, even though Dsg1,Dsg3, Dsc2, and Pg promoters all have putativebinding sites for PKC-regulated transcriptionfactors (Table 1). Recently, the Ephrin family ofreceptors and ligands has emerged as regulat-ing expression of differentiation-associated pro-teins, including Dsg1 (Lin et al. 2010; Walshand Blumenberg 2011) but, similarly to PKC,the specific transcription factors controlled bythis pathway have not yet been determined.

More direct links between desmosomalcomponent expression and transcriptional reg-ulators downstream of Notch, Rho, and Wntpathways have recently been shown. Notch andthe transcription factor p63 regulate each other(Roemer 2012) and p63 has been shown bychro-matin immunoprecipitation (ChIP) to bind andactivate Dsg1, Dsc3, and Dp promoters (Feroneet al. 2013; Johnson et al. 2014). Rho-mediatedchanges in the actin cytoskeleton lead to changesin Srf-dependent transcription (Miralles et al.2003) and Srf controls the expression of Pkp2and Dsg1, which in turn drives a program ofterminal differentiation (Leitner et al. 2011; Du-bash et al. 2013), The Wnt-regulated TCF/Leftranscription complex has been implicated inregulation of Dsg4, Dsc2, Dsc3, and Pg expres-sion but direct binding of these transcription

factors to desmosomal component promotershas only been shown in a few instances (Table1) (Bazzi et al. 2009; Bailey et al. 2012; Tokon-zaba et al. 2013). Pg itself complexes with TCF/Lef-1 to regulate the balance of Dsc2 and Dsc3expression (Tokonzaba et al. 2013).

Desmosomal cadherin distribution withinthe stratified epidermis may in part be regulat-ed by the differential activity of transcriptionfactor isoforms. For instance, the more basallyconcentrated Dsc3 is activated by the b formof CCAAT/enhancer-binding protein, whereasDsc1 is activated by the a isoform. This isoformspecificity suggests one potential mechanism forswitching between basal and suprabasal desmo-somal cadherins during differentiation. Expres-sion of desmosomal components and keratinscan be regulated by the same transcription fac-tors. For example, Ap2, HoxC13, Lef-1 andFoxn1, which up-regulate or repress keratin ex-pression, have also been implicated as putativeor shown regulators of Dsgs, Dscs, armadilloproteins, and the associated desmosomal com-ponents periplakin and envoplakin (Byrne et al.1994; Silos et al. 1996; Marsden et al. 1997;Adams et al. 1998; Aho et al. 1999; Maatta et al.2000; Potter et al. 2001; Bazzi et al. 2009).Understanding how transcriptional programscoordinate the expression of cytoarchitecturalbuilding blocks during differentiation will helpus better understand epidermal development,hair follicle cycling, wound healing, and re-sponses to environmental exposure.

Desmosomal components can be transcrip-tionally repressed by factors such as Slug andZeb, which promote epithelial-to-mesenchymal(EMT) transition and wound re-epithelializa-tion (Savagner et al. 2005; Vandewalle et al.2005; Aigner et al. 2007). Epigenetic mecha-nisms, including promoter methylation and his-tone deacetylation (HDAC), also repress the ex-pression of desmosomal proteins, which maycontribute to carcinogenesis (Potter et al. 2001;Cui et al. 2011; Kaz et al. 2012; Yang et al. 2012).The consequent loss of desmosome-mediatedadhesion can be restored in part by HDAC in-hibitors (Shim et al. 2004; Simpson et al. 2010).Furthering our understanding of the transcrip-tional programs that regulate desmosomal pro-

J.L. Johnson et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Table 1. Transcriptional regulators of desmosomal components, representative upstream signaling pathwaysregulating those transcription factors, and biological processes impacted

Component

Transcription

factor

Upstream

regulator

Biological process reported

or potentially implicated

from other references Method References

Dsg1 AP-1 PKC, MAPK Proliferation, differentiation Putative Adams et al. 1998Dsg1 AP-2 Notch Differentiation,

development,tumorigenesis

Putative Adams et al. 1998

Dsg1 0ct-2 MAPK Differentiation,development


Dsg1 0ct-4 Wnt Development,differentiation, maintainsstem cells, tumorigenesis


Dsg1 SP1 PKC, PKA,MAPK,PI3K

Differentiation,development


Dsg1 NF-kB IKK Apoptosis, hair follicledevelopment


Dsg1 C/EBP PKA,MAPK,PI3K

Wound healing,differentiation,tumorigenesis


Dsg1 E2A Cell commitment, growth,differentiation inlymphocytes, muscle cellsand neurons, EMT


Dsg1 p63 Notch Differentiation,stratification,tumorigenesis

ChIP Ferone et al. 2013;Johnson et al.2014

Dsg1 Grainy head-like1

Differentiation, celladhesion, hairdevelopment, eyeliddevelopment, woundrepair

ChIP/Rep Wilanowski et al.2008

Dsg1 Klf-4 NF-kB, Rho Eyelid development Rep/EMSA Swamynathan et al.2011;Kenchegowdaet al. 2012

Dsg1 Klf-5 NF-kB, Rho Eyelid development Rep/EMSA Kenchegowda et al.2012

Dsg3 AP-1 PKC, MAPK Proliferation, differentiation Putative Adams et al. 1998Dsg3 AP-2 Notch Differentiation,

development,tumorigenesis


Dsg3 C/EBP PKA,MAPK,PI3K



Dsg3 0ct-B2 Differentiation,development


Dsg3 Sp1 PKC, PKA,MAPK,PI3K


Putative Silos et al. 1996

Continued



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Table 1. Continued

Component

Transcription

factor

Upstream

regulator




Dsg3 GlucocorticoidRE

Differentiation,stratification, skin barrierformation

Putative Silos et al. 1996

Dsg4 SMAD1 Hair follicle developmentand integrity

ChIP/Rep Owens et al. 2008





Dsg4 HoxC13 Repression of geneexpression in hair follicle

Rep/EMSA Bazzi et al. 2009

Dsg4 Lef-1 Wnt Repression of geneexpression in hair follicle


Dsg4 FoxN1 Repression of geneexpression in hair follicle


Dsg4 HoxC12 Activation of gene expressionin hair follicle


Dsg4 Notch (NICD) Activation of gene expressionin hair follicle,differentiation,tumorigenesis


Dsc1 C/EBP-a PKA,MAPK,PI3K


Rep/EMSA Smith et al. 2004

Dsc1 C/EBP-d PKA,MAPK,PI3K



Dsc2 SP1 PKC, PKA,MAPK,PI3K


Putative Marsden et al. 1997

Dsc2 AP-1 PKC, MAPK Differentiation,development


Dsc2 AP-2 Notch Differentiation,development,tumorigenesis


Dsc2 Pit-1 Differentiation,development


Dsc2 NF-kB IKK Apoptosis, hair follicledevelopment


Dsc2 Retanoic acidRE


Dsc2 TCF-3/TCF-4/Lef-1

Wnt Epidermal development—induction of Dsc2

ChIP/Rep Tokonzaba et al.2013

Dsc2 Pg/Lef-1 Wnt Lef-1 presence or absence isswitch for Pg-regulatedtranscriptional activationof Dsc3 or Dsc2


Continued

J.L. Johnson et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Table 1. Continued

Component

Transcription

factor

Upstream

regulator




Dsc2 c-Rel/NF-kB IKK Hair follicle developmentand integrity


Dsc2 Cdx-1 Colon development,tumorigenesis

Rep/EMSA Funakoshi et al.2008

Dsc2 Cdx-2 Colon development,tumorigenesis

ChIP/Rep Funakoshi et al.2008

Dsc3 C/EBP-b PKA,MAPK,PI3K



Dsc3 C/EBP-d PKA,MAPK,PI3K



Dsc3 p63 Notch Differentiation,stratification,tumorigenesis

ChIP/Rep Ferone et al. 2013

Dsc3 p53 DNA damage response, cell-cycle arrest, apoptosis,differentiation, celladhesion

ChIP Oshiro et al. 2003

Dsc3 TCF-3/TCF-4/Lef-1

Wnt Epidermal development—repression of Dsc3


Dsc3 Pg Lef-1 presence or absence isswitch for Pg-regulatedtranscriptional activationof Dsc3 or Dsc2


Dsc3 Methylation Colorectal cancer Cui et al. 2011

Pg NFY and/or C/EBP

PKA,MAPK,PI3K


Putative Potter et al. 2001

Pg SP-1 PKC, PKA,MAPK,PI3K



Pg AP-2 Notch Differentiation,development,tumorigenesis


Pg Pea3 Wnt Development, tumorigenesis Putative Potter et al. 2001Pg MyoD Wnt Skeletal muscle

differentiationPutative Potter et al. 2001

Pg Nkx2.5 Heart/suprabasal epidermallayers, increased inpsoriasis/SCC, decreasedin atopic dermatitis/BCC


Pg E2 Cell commitment, growth,differentiation inlymphocytes, muscle cellsand neurons, EMT

Putative Bailey et al. 2012

Pg Slug TGF-b, Wnt Breast cancer ChIP/Rep Bailey et al. 2012

Continued



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



tein expression will be an important prerequisitefor pharmacologically intervening in disordersinvolving these molecules.

ROLES FOR DESMOSOME MOLECULESIN MORPHOGENESIS AND HOMEOSTASISOF STRATIFIED TISSUES

Desmosomal protein expression patterningcontributes not just to tissue integrity, but alsoto signaling that controls morphogenesis andhomeostasis. Interfering with desmosomal cad-herin expression patterns can upset the balance

between proliferation and differentiation dur-ing embryogenesis and in the adult (Allen etal. 1996; Chidgey et al. 2001; Elias et al. 2001;Merritt et al. 2002; Kljuic et al. 2003; Hardmanet al. 2005). Forced expression of basally concen-trated Dsg3 in the suprabasal layers of mouseepidermis increases the Dsg3:Dsg1 ratio and dis-tribution to resemble that of oral epithelium(Elias et al. 2001). These mice show alterationsin the stratum corneum and die shortly afterbirth because of excessive transepidermal waterloss. Dsg2, the most broadly expressed Dsg, isrequired for embryonic stem cell proliferation

Table 1. Continued

Component

Transcription

factor

Upstream

regulator




Pg Brn-3b Breast cancer, developmentand differentiation

Rep/EMSA Samady et al. 2006

Pg Methylation Thyroid carcinoma cell linestested

Potter et al. 2001

Pkp1 Methylation Progression of esophagealcarcinogenesis

Kaz et al. 2012

Pkp2 Mal/Mrtf Rho Migration ChIP Leitner et al. 2011Pkp2 Srf Rho, MAPK Migration, proliferation ChIP Leitner et al. 2011

Pkp3 Zeb MAPK,TGF-b

Colon cancer progression,EMT, development

ChIP/Rep Aigner et al. 2007

Dp Klf-4 NF-kB, Rho Eyelid development Rep/EMSA Swamynathan et al.2011;Kenchegowdaet al. 2012

Dp Klf-5 NF-kB, Rho Eyelid development Rep/EMSA Kenchegowda et al.2012

Dp p63 Notch Differentiation,stratification,tumorigenesis

ChIP/Rep Ferone et al. 2013

Dp Methylation Progression of lung cancer Yang et al. 2012

The method by which the transcription factor was determined to interact with the desmosomal component promoter is

listed as either putative (the cloned promoter contained a binding site for the transcription factor, but direct association

between them has not been shown), confirmed by electrophoretic mobility shift assay (EMSA) or reporter assay (such as

luciferase, referred to as Rep), or confirmed by chromatin immunoprecipitation (ChIP). Dsg2 was excluded from the table as

there is currently no published information for its transcriptional regulation.

AP-1/2, activator protein 1/2; Oct, octamer binding; SP1, specificity protein 1; NF-kB, nuclear factor k-light-chain-

enhancer of activated B cells; TCF/Lef, high mobility group transcription factors; C/EBP, CCAAT-enhancer-binding

protein; E2A, E box binding protein, Klf, Kruppel-like factor; RE, responsive element; SMAD, bone morphogenetic protein

(BMP) pathway; Hox, homeobox transcription factor; Fox, forkhead box; Pit, pituitary-specific positive transcription factor;

Cdx, homeobox transcription factor; NFY, CCAAT binding nuclear factor; pea, Ets family member; MyoD, myogenic

regulatory factor; Nkx, homeodomain transcription factor; Brn, Pit-Oct-Unc family member isolated from brain; Mal/MRTF, myocardin related transcription factor; SRF, serum response factor; Zeb, zinc finger E-box-binding homeobox.

J.L. Johnson et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



(Eshkind et al. 2002). Further, its misexpressionin upper epidermal layers results in hyperplasiaby engaging growth factor signaling cascadesthat promote proliferation and survival includ-ing PI3K/AKT, MEK-MAPK, STAT3, and NF-kB (Brennan et al. 2007; Brennan and Mahoney2009). In contrast, Dsg3 knockdown reduces cellproliferation in vitro (Mannan et al. 2011) andDsg3 knockout mice do not show enhanced epi-dermal carcinogenesis compared with controls(Baron et al. 2012). Dsg1, which first emergesas cells stratify, is important for promoting dif-ferentiation through suppression of epidermalgrowth factor receptor (EGFR) and Erk-1/2 sig-naling (Getsios et al. 2009). The adhesive ecto-domain of Dsg1 is dispensable for this function,which instead requires interaction with a newlyidentified binding partner Erbin (ERBB2IP)(Harmon et al. 2013). Erbin blocks Erk signalingby disrupting Ras–Raf complexes mediated bya scaffolding protein called SHOC2. Misexpres-sion or interferencewith other desmosomal cad-herins has similarly been reported to affect epi-dermal or hair follicle differentiation (Chidgeyet al. 2001; Kljuic et al. 2003). These data supportthe idea that basal and suprabasal desmosomalcadherins play a “yin–yang” role to control theproper balance of proliferation and differentia-tion in tissue.

Desmosome molecules may control tissuehomeostasis in part through armadillo protein-dependent signaling. Dscs1-3, Pg, Pkp2, and Dpsuppress b-catenin, which is pro-proliferative,through altering b-catenin subcellular localiza-tion, competing for b-catenin DNA bindingsites to alter its transcriptional function, andregulating b-catenin expression and stability(Chen et al. 2002; Hardman et al. 2005; Thoma-son et al. 2010; Kolegraff et al. 2011; Aktary andPasdar 2012; Yang et al. 2012). Pg has also beenshown to reduce the proliferative capacity inboth normal epidermis and cancer cells, andcan act directly on transcriptional targets or in-directly by competing forb-catenin binding fac-tors (Parker et al. 1998; Charpentier et al. 2000;Aktary and Pasdar 2012).

Cadherin-associated proteins also regulategrowth factor effector signaling. For instance,Dp either supports (Gallicano et al. 1998) or

inhibits proliferation depending on cell type,the latter through suppression of Erk and Akt(Wan et al. 2007). In turn, growth factor signal-ing can convert desmosomal components fromadhesive to pro-proliferative functions as in thecase of insulin signaling via Akt2 causing Pkp1to promote proliferation and migration (Wolfet al. 2013). Collectively, these observationssuggest that the core building blocks of desmo-somes are tailored to support specific functionswithin complex tissues and are important forcontrolling epidermal homeostasis.

DESMOSOMES AND THE EPIDERMALBARRIER

To help maintain the skin’s barrier againstthe environment, desmosomes become modi-fied into structures called corneodesmosomesin the outermost epidermal layers. Differen-tiation-specific components are incorporatedinto corneodesmosomes including Dsg1, Dsc1,envoplakin, periplakin, and corneodesmosin(CDSN). CDSN is thought to support supra-basal adhesion through a glycine-rich domainwithin its amino terminus. The cornified enve-lope forms along the plasma membrane betweendesmosomes through transglutaminase-medi-ated cross-linking of involucrin to itself and toDp, periplakin, and envoplakin (Ruhrberg et al.1997; Steinert and Marekov 1999). A differenti-ation-specific periplakin binding protein calledkazrin assists in promoting differentiation andformation of the cornified envelope, acting toscaffold multiple cytoskeletal elements (Grootet al. 2004) and to regulate cell shape throughRho GTPases (Sevilla et al. 2008; Nachat et al.2009). Thus, just as the early stages of epidermaldifferentiation require proper expression anddistribution of desmosomal cadherins, so dolater differentiation states require specializeddesmosome functions to ensure proper barrierformation.

Desmosomes are subject to regulation byenvironmental interactions, yet at the same timeparticipate in epidermal responses to stressorslike humidity and heat. Dry conditions increasethe number of corneodesmosomes and Dsg1content, associated with decreased desquama-



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



tion and scaly skin in mice (Rawlings et al. 1995;Sato et al. 1998). Desmosomes may protectagainst temperature extremes, as survival ofMDCK cells with tight junctions and desmo-somes is nearly one log higher than cells lackingtight junctions and desmosomes after exposureto 45˚C (Ning and Hahn 1994). Whether thisprotective effect applies to the epidermis is notknown and no mechanism explaining how des-mosomes protect cells against temperature ex-tremes has yet been elucidated. However, it isinteresting to note that heat, which inducesheat shock protein 70 (HSP70) chaperones inthe epidermis (Matsuda et al. 2013), also drivesdesmosomal Pkps to stress granules where theyinteract with RNA binding proteins (Hofmannet al. 2006). It is tempting to speculate that thismovement of Pkps may help regulate increasedexpression or recruitment of HSPs or otherwiseprotect cells against heat-induced death. WhenHSP40 is depleted in cultured human keratino-cytes, expression levels of keratins 5, 14, and 10increase and keratin ubiquitination decreases(Yamazaki et al. 2012) suggesting that heat mayrepress intermediate filaments, which wouldimpact the epidermal structure. HSP Apg-2binds to ZO-1, a tight junction protein that isimportant for epidermal barrier formation. TheApg-2-ZO-1 interaction seems to promote as-sembly of tight junctions as depletion of Apg-2slows their new formation (Aijaz et al. 2007).Therefore, mechanisms behind how heat mayimpact epidermal morphogenesis and barrierfunction are beginning to unfold.

Desmosomes are affected by exposure tocarcinogens including tobacco smoke, air pollu-tion, and UV light (White and Gohari 1984;Tachikawa et al. 1986). UV-induced sunburncells (defined by pyknotic nuclei and eosino-philic cytoplasm) stain negatively for Dsgs andDps (Bayerl et al. 1995) and reduced desmosomemolecule transcripts are frequently observed inUV-exposed keratinocytes (Li et al. 2001; Mu-rakami et al. 2001; Sesto et al. 2002; Rundhauget al. 2005). UVC (below 290 nm wavelength)results in caspase-dependent cleavage of Dsg1and redistribution of Dsg1 from cell bordersinto the cytoplasm (Dusek et al. 2006). In linewith these findings, Dsg1 and Dsc1 are reduced

by UVB (290- to 320-nm wavelengths) exposurein keratinocytes beginning to differentiate. Im-portantly, ectopic Dsg1 expression counteractsUVB-induced loss of differentiation markers(Johnson et al. 2014) indicating that desmoso-mal components contribute directly to epider-mal responses to carcinogenic exposure.

Desmosome molecules are also involvedin apoptosis associated with UV exposure andother environmental stresses (Dusek et al. 2006,2007; Nava et al. 2007; Baron et al. 2012). Where-as loss of Dsg1 protects keratinocytes againstUVC-mediated apoptosis, Dsg3 knockout miceshow no changes in apoptosis following chronicUVB exposure (Dusek et al. 2006; Baron et al.2012). Pg has been reported to be both pro- andantiapoptotic (Aktary and Pasdar 2012). For in-stance, loss of the GTPase Rnd3 protects kerati-nocytes from cisplatin-induced apoptosis; sen-sitivity to cisplatin is restored when Pg, but notDp, is knocked down in a Rnd3-deficient back-ground (Ryan et al. 2012). The mechanismslinking Pg to cell survival are not clear, althoughthe authors speculate it may be through regula-tion of cell survival effectors such as Bcl-2. An-other study indicates that keratinocytes derivedfrom Pg null mice are protected from apoptosis,with null cells showing delayed mitochondrialcytochrome c release and activation of caspase-3as well as increased Bcl-xL expression (Duseket al. 2007). The role of desmosome moleculesin cell survival or death may thus be stimulusand/or context dependent. Together these re-sults suggest that whereas desmosomes are fre-quently targeted by environmental factors, des-mosome molecules also aid epidermal recoveryfollowing stress.

ALTERATIONS IN DESMOSOMALCOMPONENTS AND CELL SIGNALINGIN EPITHELIAL CANCERS

The loss of desmosomes has been associatedwith advanced epithelial tumor grade, increasedmetastasis and poor prognosis (Dusek and At-tardi 2011; Aktary and Pasdar 2012). However,down-regulation of desmosomes is frequentlyan earlier event in carcinogenesis than down-regulation of adherens junctions (Dusek and

J.L. Johnson et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Attardi 2011) suggesting that desmosomal com-ponents suppress both early and late stages ofcarcinogenesis. Expression of desmosomal cad-herins in the proper epidermal layer is an impor-tant factor in suppressing carcinogenesis. Sup-porting this idea, misexpression of Dsg2 in theupper epithelial layers in transgenic mice leadsto an increase in precancerous papillomas andsusceptibility to chemically induced carcino-genesis (Brennan et al. 2007; Brennan and Ma-honey 2009). Multiple signaling pathways areincreased by misexpression of Dsg2 includingEGFR and NF-kB, PI3K/AKT, MEK/MAPK,and STAT3, suggesting that regulation of signal-ing by desmosomal components is importantfor prevention of tumorigenesis. Whereas mis-expression of normally basal Dsg2 promotesEGFR and other growth-related pathways, lossof suprabasal Dsg1 results in a failure to down-regulate EGFR/MAPK signaling required fornormal differentiation. Through its associationwith the scaffolding protein Erbin, Dsg1-depen-dent inhibition of Ras-Raf signaling could beimportant for cancer prevention because aber-rant Ras signaling is oncogenic. In line with this,Dsg1’s loss during head and neck cancer pro-gression has been reported as a better indicatorof poor prognosis than loss of E-cadherin(Wong et al. 2008). In addition, some basal cellcarcinomas (BCCs) show reduced Dsg1 cell sur-face expression and cytoplasmic Erbin localiza-tion (Tada et al. 2000; Lebeau et al. 2005). Re-duced Dsg3 and up-regulated Dsg2 have alsobeen reported in human head and neck squa-mous cell carcinoma (Teh et al. 2011). Loss ofDsg2 later in cancer progression, for instancethrough endocytic turnover which has beenshown to occur in response to EGFR signaling,may promote loss of adhesion and invasion/metastasis (Klessner et al. 2009).

Desmosomal plaque components Dp, Pg,and Pkps are also emerging as critical tumorand migration suppressors in a variety of celltypes including prostate (Franzen et al. 2012),lung (Yang et al. 2012), colon (Khapare et al.2012), pancreas (Chun and Hanahan 2010),and skin (Yin et al. 2005). Pg and Dp have bothbeen implicated in regulating cell signaling tosuppress cell migration—Pg through regulating

victronectin-dependent or fibronectin-depen-dent src signaling (Todorovic et al. 2010; Franzenet al. 2012) and Dp by inhibiting the Wnt/b-catenin signaling pathway (Yang et al. 2012).

Finally, Perp, a p53/p63 regulated pro-tein that promotes desmosome assembly andstrength, promotes UVB-induced apoptosis andsuppresses UV-induced tumorigenesis in mice(Beaudry et al. 2010). Because Perp and Dsc3are transcriptionally regulated by p53 (Oshiroet al. 2003; Reczeket al. 2003), p53 mutation dur-ing carcinogenesis could lead to defective des-mosomes, reduced intercellular adhesion, andaltered desmosome component-mediated cellsignaling. Collectively, these data suggest thatdesmosomes suppress cancer-promoting sig-naling pathways that drive proliferation andmetastasis in multiple epithelia.

DESMOSOMES IN EPIDERMALAUTOIMMUNE DISORDERS AND UNDERATTACK BY TOXINS

The autoimmune skin disorders pemphigusand paraneoplastic pemphigus are associatedwith the presence of circulating autoantibodiesattacking desmosomal components includingDsg1, Dsg3, Dsc3, and possibly Pkp3, bullouspemphigoid antigen 1, envoplakin, periplakin,and Perp (Koulu et al. 1984; Amagai et al. 1991;Nguyen et al. 2009; Mao et al. 2010; Yong andTey 2012; Kalantari-Dehaghi et al. 2013) andreviewed recently by several groups (Amagaiand Stanley 2012; Grando 2012; Cirillo andAl-Jandan 2013). Although a potential role forantibodies directed against cytoplasmic com-ponents in disease pathogenesis has been sug-gested, the majority of data point to Dsg3 andDsg1 as the primary targets in pemphigus vul-garis and foliaceus (see Fig. 4). Steric hindrancecaused byantibody binding has been suggested tointerfere with desmosomal cadherin ectodomaininteraction to cause skin blistering in pemphi-gus; however, autoantibody binding also pro-motes Dsg internalization and activates signal-ing pathways, most notably p38/MAPK. Dsg3loss and/or autoantibody-dependent increasesin p38/MAPK signaling decrease the activityof the small GTPase RhoA, thus destabilizing



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



the actin cytoskeleton (Spindler and Waschke2011). Accordingly, direct RhoA inhibition leadsto pemphigus skin blistering (Waschke et al.2006). In addition to its negative effects on des-mosome function, Dsg3 internalization alsopromotes loss of E-cadherin through Src, possi-bly thereby having a more general effect on cell–cell adhesion (Tsang et al. 2010, 2012b). Howev-er, others report that siRNA-mediated silencingof Dsg1 and/or Dsg3 does not significantlyaffectthe observed IgG-dependent increase in Src andEGFR signaling, suggesting that other targetsmay be involved in activating these tyrosine ki-nases (Grando 2012).

Dsg1 is a target for Staphylococcus ex-foliative toxin in staphylococcal scalded skinsyndrome (SSSS) (Amagai and Stanley 2012;Kowalczyk and Green 2013). Pg and Dsg2 ex-pression reduces the blistering associated withattack by these toxins (Brennan et al. 2010;Simpson et al. 2010). Use of therapeutic agentsthat increase expression of desmosomal cadher-ins and Pg such as EGFR inhibitors, histone de-acetylase inhibitors, or tyrosine phosphatase in-hibitors like sodium pervanadate (Lorch et al.2004; Garrod et al. 2008; Simpson et al. 2010;Aktary and Pasdar 2012) may lessen the severityof blistering in pemphigus and Staphylococcalinfections.

The cellular responses to pemphigus anti-bodies and Dsg-specific toxins have facilitateda better understanding of fundamental signal-ing/assembly circuits that are likely to makeimportant contributions to cell homeostasis.However, much is yet to be done to determinethe relative contribution of signaling-dependentand -independent mechanisms to disease path-ogenesis in vivo (Mao et al. 2011, 2013; Saitoet al. 2012).

ROLE OF DESMOSOMES INPATHOGENESIS OF INHERITED SKINAND HEART DISEASE

Mutation of desmosomal components in hu-mans leads to skin and heart diseases includingskin fragility-ectodermal dysplasia syndrome,lethal congenital epidermolysis bullosa, striatepalmoplantar keratoderma (SPPK) and other

keratodermas, hypotrichosis, wooly hair, ar-rhythmogenic cardiomyopathy (ARVC), anddilated cardiomyopathy (Kowalczyk and Green2013). Several of these diseases are lethal inhumans and embryos from a number of ani-mal models of desmosome diseases die beforebirth or shortly thereafter because of skin andheart defects (Thomason et al. 2010; Kowalczykand Green 2013). Only Pkp3 and Dsc1 have sofar not been associated with mutations leadingto human disease. However, Dsc1 and Dsg1 incorneodesmosomes are targeted for degrada-tion by hyperactive proteases and kallikrein pep-tidases when the protease inhibitor LEKT1(lympho-epithelial Kazal-type related inhibi-tor) is mutated in Netherton syndrome. Skinallergy, inflammation, scaling, and hypotricho-sis are the result (Descargues et al. 2006; Hovna-nian 2013).

Phenotypes resulting from mutations indesmosomal proteins may arise not only fromdefective adhesion, but also from alterations incell signaling cascades. In normal skin, the cyto-plasmic tail of Dsg1 binds Erbin-Shoc2 com-plexes to keep Shoc2 away from Ras (Fig. 3).However, in tissue biopsies taken from SPPKpatients with Dsg1 haploinsufficiency, increasedRas-SHOC2 and decreased Erbin-SHOC2 co-localization occurs, offering a possible explana-tion for the observed impairment of differ-entiation and epidermal hyperplasia (Fig. 4)(Harmon et al. 2013). Dsg1-mediated regula-tion of Erk/MAPK signaling may also play arole in ectodermal dysplasias because a tran-scriptional regulator of Dsg1, p63, is frequentlymutated or misregulated in ectodermal dyspla-sias (Ferone et al. 2013).

Mutations in Dsg2, Dsc2, Pkp2, Pg, and Dphave all been implicated in ARVC, which pre-sents with or without accompanying cutaneoussymptoms (Fig. 4). It is not yet clear whetherARVC results from the response to mechanicalstress imposed on weakened cell–cell junctions,or whether more direct desmosome-dependentsignaling contributes to cardiac myocyte apo-ptosis, fibrofatty deposition, and lethal arrhyth-mias. The existing data would support the ideathat both can occur. Pg loss is a diagnostic fea-ture of ARVC (Asimaki et al. 2009) and its trans-

J.L. Johnson et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



location to the nucleus interferes with b-cate-nin signaling and promotes adipogenic/fibrot-ic transcriptional pathways in a Dp knockoutmousemodel (Garcia-Gras etal.2006). It is spec-ulated that Pg nuclear functions may also ac-count for defects in hair follicles, which leadsto the wooly hair seen in some patients (MacRaeet al. 2006). A Pg truncation mutation leads to

skin abnormalities but still allows normal heartdevelopment (Cabral et al. 2010). Further, onlykeratoderma and not heart defects are observedin a conditional Pg knockout mouse modelwhere Pg nuclear localization cannot occur(Li et al. 2012). In spite of the fact that alterationsin Wnt/b-catenin signaling are not observedin this model, alterations in cell proliferation,

Cytoplasm

PKC-α

ERIF

Dp

PkpPg

GDP

GDP

SosGrb2

EGFR

P P

P P

P PRas

Ras

Ras

Mek

Erk

Shoc2

Differentiation

Nucleus

Raf

P

P

EGF

GTP

GTP

GTP

Dsc

Dsg

1

Erbin

Shoc2

Ca2+

SERCA2

Desmoplakinassembly

Dynamicremodeling/decrease in

hyperadhesion

Figure 3. Signaling roles of the desmosome. The desmosome has been linked to signaling pathways that regulatebiological mechanisms such as wound healing, proliferation, differentiation, and apoptosis. Here we summarizesignaling mechanisms that promote epidermal differentiation and proper desmosome assembly or remodeling.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



apoptosis, differentiation, and the epidermalimmune system occur. It is possible that othersignaling pathways previously associated withloss of Pg (e.g., EGFR) (Pan et al. 2007) orSrc/Rho signaling (Todorovic et al. 2010; Fran-zen et al. 2012) contribute to these changes.It is notable that another armadillo protein,Pkp2, is the most commonly mutated target inARVC (Kowalczyk and Green 2013). Alterationsin RhoA and PKC-a signaling occur follow-ing Pkp2 knockdown in keratinocytes (Godselet al. 2010), raising the possibility that similar

signaling deficits may contribute to ARVC path-ogenesis.

REGULATION OF DESMOSOME DYNAMICS,REMODELING, AND TURNOVER

Although cell adhesion is imperative for main-taining tissue integrity, adhesive contacts cannotremain static during processes like epider-mal development, differentiation, wound heal-ing, and apoptosis. Desmosomes are degradedor internalized in response to EGFR signal-

Pemphigus

Autoimmune againstDsg1,3

Dsg

1,3

Arrhythmogenic right ventricularcardiomyopathy (ARVC)

Mutations inDSG2, DSC2, PKP2, JUP, DSP

Disruption ofarea composita

formation

Fibrofatty tissuereplacement

Loss of electricalconductivity/ventricular

arrhythmia

EGFR and PKCsignaling

Internalization

p38/MAPK

Reduced Rhosignaling

Epidermal fragilityblistering

Con

trol

SP

PK

p.S

132X

Sudden cardiac deathHyperkeratosis affecting

palms and soles

pErkDifferentiation (K10, Lor)

Decrease in Erbinsequestering Shoc2

Decrease in total Dsg1 protein

Truncated dsg1 mRNA

Mutated dsg1 gene

Mutations inDSG1

Striate palmoplantar keratoderma(SPPK)

Truncated dsg1 proteindegraded

Dsg1DAPI

Dermis Dermis

Dsc

Figure 4. Diseases associated with the desmosome. Many diseases causing epidermal and cardiac tissue impair-ment are linked to improper desmosome functioning. Highlighted here are three different diseases (Pemphigus,ARVC, and SPPK) that are caused by autoimmunity and genetic mutations. It is important to note that SPPK isalso caused by mutations in the genes of Plakoglobin and Desmoplakin (JUPand DSP). We have summarized themolecular pathway of SPPK caused by mutations in DSG1, and show tissue staining from SPPK patientsharboring mutant Dsg1 (p.S132X) (Harmon et al. 2013).

J.L. Johnson et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



ing, ADAM sheddases, matrix metalloproteases(MMPs), caspases, and kallikrein peptidases(Bektas et al. 2010; Green et al. 2010; Kowalczykand Green 2013). The ubiquitin proteosomemay reduce cell adhesion by keeping Dp fromcell contacts. Proteosome inhibition stabilizesDp at keratinocyte borders and strengthenscell–cell contacts (Loffek et al. 2012). However,it remains to be seen whether the proteosomeregulates desmosomal adhesion under physio-logical conditions.

Desmosomes in adult tissues show a uniqueproperty termed “hyperadhesion,” character-ized by enhanced stability and adhesive strengtheven in the context of extracellular calcium de-pletion. Desmosomes become hyperadhesiveduring mouse embryonic development beforeembryo implantation; however, migration ofthe trophectoderm requires loss of hyperadhe-sion (Kimura et al. 2012) as does the remodelingthat occurs during wound healing (Thomasonet al. 2010). PKC-a is the predominant regulatorof the switch between hyperadhesion and cal-cium dependence (Wallis et al. 2000). Desmo-somes remain hyperadhesive in PKC-a nullanimals and re-epithelialization after woundingis delayed. In chronic human wounds PKC-aremains cytoplasmic and desmosomes do notbecome hyperadhesive (Thomason et al. 2012).

In addition to its role in converting maturedesmosomes to a more dynamic form compat-ible with epithelial remodeling, PKC-a regu-lates the dynamics of desmosome assembly(Fig. 3). PKC inhibition decreases desmosomeassembly at the leading edge in scratch woundassays (Roberts et al. 2011), and Dp transloca-tion from the cytoplasm to the plasma mem-brane depends on PKC (Sheu et al. 1989; Bass-Zubek et al. 2008). Dp’s responsiveness to PKCis due in part to its association with the arma-dillo protein Pkp2, which serves as a scaffold forPKC-a. Data support a model whereby loss ofPkp2 results in failure of PKC to phosphorylateDp and failure of Dp to incorporate into des-mosomes owing to tight association with inter-mediate filaments (Bass-Zubek et al. 2008). Amutation in the Dp carboxyl terminus at S2849prevents its phosphorylation and delays assem-bly into junctions. However, once incorporated,

this phosphodeficient Dp mediates strongdesmosome adhesion (Hobbs et al. 2011).

PKC-a is a calcium-dependent kinase and isthus sensitive to changes in intracellular calci-um homeostasis. Supporting the importance ofthis relationship for desmosome assembly, theendoplasmic reticulum calcium pump Serca2,which is mutated in a skin disorder known asDarier’s disease, regulates intercellular adhesivestrength through PKC-a (Hobbs et al. 2011).Serca2 deficient cells show reduced PKC-aand Dp movement to the membrane, but con-stitutively active PKC-a rescues this defect.

Desmosome-cytoskeleton interactions areimportant for regulating desmosome assemblystate and turnover and, in turn, desmosomalcomponents control cytoskeletal distributionand function. Desmosomes are well known fortheir role in anchoring keratin intermediate fil-aments to sites of cell adhesion, but they are alsosubject to regulation by keratins, which keepPKC-a-mediated Dp phosphorylation in checkto stabilize desmosomes at the plasma mem-brane (Kroger et al. 2013). The actin cytoskele-ton and associated contractile signaling also en-gages in a reciprocal functional relationship withdesmosomes. Actin regulates desmosome dy-namics during desmosomal plaque assemblyand wound healing (Godsel et al. 2010; Robertset al. 2011). In turn, desmosome molecules reg-ulate contractile signaling through Pkp2, whichrecruits active RhoA at cell–cell interfaces todrive actin reorganization and actin-depen-dent desmosome assembly (Godsel et al. 2010).Dsg3 also dictates cytoskeletal organization andcell migration through regulation of the RhoGTPases Rac-1 and Cdc42 (Tsang et al. 2010,2012a). Finally, desmosomes help remodel themicrotubule cytoskeleton during epidermalstratification. Dp, together with the centrosomalprotein ninein, facilitates redistribution of radi-ally oriented microtubules to the cell cortex.Cortical microtubules in the suprabasal epider-mis recruit myosin II to aid formation of thetight junction barrier (Lechler and Fuchs 2007;Sumigray and Lechler 2012). Microtubule-asso-ciated proteins such as Lis1, Ndel1, and CLIP70regulate desmosome stability and their loss leadsto decreased expression of desmosomal compo-



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



nents (Sumigray et al. 2011; Sumigray and Lech-ler 2011). Thus, desmosomes engage the cyto-skeleton in a more general way than previous-ly recognized, contributing to cytoarchitecturalremodeling during differentiation.

PHARMACOLOGICAL APPROACHES TOREGULATING DESMOSOMAL EXPRESSIONAND STABILITY

Rescuing adhesive defects and improving out-comes for desmosomal diseases would be ad-vantageous to human health. To that end, sever-al pharmacologic strategies have been exploredto regulate desmosome stability in epidermalcells. Treatment of organotypic epidermal mod-els with retinoic acid results in normalization ofdesmosome appearance after a low dose of UVBexposure (Chouinard and Rouabhia 1999) butretinoic acid is more frequently reported todown-regulate expression of desmosomal com-ponents in human skin (Humphries et al. 1998;Wanner et al. 1999; Kim et al. 2011). A serinepalmitoyltransferase inhibitor (ISP-I) increasesthe number of corneodesmosomes leading to athicker stratum corneum and less transepider-mal water loss (Mizukoshi et al. 2011).

Glucocorticoids are used together with im-munosuppressive therapies to treat pemphigus(Frydman and Fairley 2011). Dsg3 and Dsc2contain retinoic acid and glucocorticoid re-sponsive elements in their promoters (Siloset al. 1996; Marsden et al. 1997), so use of theseagents may alter desmosomal component tran-scription. In support of this, mice lacking theglucocorticoid receptor show reduced numbersof desmosomes (Bayo et al. 2008). A novel treat-ment option for pemphigus may also be emerg-ing, as cross-linking of Dsg3 using a topicallyapplied peptide on mice reduces skin blistering.The peptide stabilizes Dsg3 by blocking auto-antibody-mediated interference of Dsg3 trans-interaction, reduces p38/MAPK activation, andallows stabilization of keratins (Spindler et al.2013). It is unknown whether a similar pep-tide-mediated cross-linking of Dsg1 would re-duce blistering in pemphigus foliaceus. Otherdrugs that increase desmosomal protein expres-sion and strengthen desmosomes may lead to

reduced symptoms arising from desmosomaldiseases, reduced epidermal damage after envi-ronmental exposure, and prevention of carcino-genesis. These include EGFR inhibitors, histonedeacetylase inhibitors, cholinergic agonists, ortyrosine phosphatase inhibitors like sodiumpervanadate (Nguyen et al. 2003; Lorch et al.2004; Garrod et al. 2008; Simpson et al. 2010;Aktary and Pasdar 2012; Johnson et al. 2014).

EMERGING AREAS IN DESMOSOMEBIOLOGY: OUTLOOK FOR THE FUTURE

Over the past decade we have come to appreci-ate desmosomes as both critical regulators ofintercellular adhesive strength and modulatorsof intracellular signaling cascades (Green andGaudry 2000; Thomason et al. 2010; Kowalczykand Green 2013). At the same time, cell junc-tions have emerged as transducers of mechan-ical signals that affect stem cell maintenance,tissue morphogenesis, and differentiation.Whereas the mechanical importance of the des-mosome-intermediate filament network is wellaccepted, the field of mechanotransduction hasmainly focused on the role of actin-associatedcontacts. The adherens junction protein a-cat-enin undergoes conformational change in re-sponse to mechanical cues to affect recruitmentof proteins such as vinculin and EPLIN. Thesechanges affect junctional remodeling in re-sponse to shear in endothelial cells and estab-lishment of barrier in simple epithelial cells(Twiss and de Rooij 2013). Desmosomal cadher-ins and plaque proteins may play similar roles inresponse to mechanical stresses experienced byskin and heart. Development of sensors thattrack mechanosensitive conformation changesin desmosome molecules will begin to shed lighton the potential activity of desmosomes in me-chanotransduction.

The critical role desmosomes play in estab-lishing the epidermal barrier raises the possibil-ity that their loss of function may activate path-ways contributing to inflammation and allergy.Indeed, a new syndrome caused by homozygousmutations in Dsg1 was recently described withsymptoms including severe dermatitis, multi-ple allergies and metabolic wasting (SAM syn-

J.L. Johnson et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



drome). Dsg1 deficiency associated with in-creases in allergy-related cytokines strongly sug-gesting that allergy can result from desmosomaldisruption (Samuelov et al. 2013). Further, micedeficient in envoplakin, periplakin, and the cellenvelope protein involucrin show a reduction inthe protease inhibitor serpin1b, delayed degra-dation of desmoglein 1 and corneodesmosin,and alterations in the T-cell population resem-bling atopic dermatitis (Sevilla et al. 2007). Avariant of the protease inhibitor LEKT1 increas-es expression of the proallergic cytokine thymicstromal lymphopoietin (TSLP), a predisposingfactor to atopic dermatitis (Descargues et al.2006; Hovnanian 2013). Finally, there existsan inflammatory subtype of generalized peelingskin syndrome (PSS) in which patients showchronic exfoliation of the stratum corneum at-tributable to mutations in corneodesmosin(Oji et al. 2010). Corneodesmosin mutationsalso confer susceptibility to psoriasis indicatingthat intact desmosome-mediated epidermalbarrier function is important for protectionagainst the disease (Chang et al. 2003, 2006).The extent to which desmosomal disruptionand changes in downstream signaling pathwaysdrive atopy, inflammation, or psoriasis is un-known, but these emerging associations providecompelling basis for future work to directly linkloss of desmosome function to these systemicand collectively common disorders.

ACKNOWLEDGMENTS

We have attempted to be comprehensive in ourreferences throughout this review but regret thatbecause of space constraints we have been un-able to reference all of the researchers workingin the desmosome field. We thank JenniferKoetsier and Drs. Robert Lavker, Lisa Godsel,and Robert Harmon for helpful comments onthe manuscript. K.J.G. is supported by NationalInstitutes of Health Grants RO1 AR041836, R37AR043380, and R01 CA122151, by a grant fromthe Leducq Foundation, and by the JosephL. Mayberry Senior Endowment. J.L.J. is sup-ported by a Dermatology Foundation ResearchCareer Development Award and a Pilot and Fea-sibility grant through the Northwestern Univer-

sity Skin Disease Research Center (Parent GrantNIAMS 5P30 AR057216-04). N.A.N. has beensupported by an NIH/NCI Ruth L. KirschsteinTraining grant through Northwestern Univer-sity’s Robert H. Lurie Comprehensive CancerCenter (T32 CA080621) “Training Program inOncogenesis and Developmental Biology.”

REFERENCES

Adams MJ, Reichel MB, King IA, Marsden MD, GreenwoodMD, Thirlwell H, Arnemann J, Buxton RS, Ali RR. 1998.Characterization of the regulatory regions in the humandesmoglein genes encoding the pemphigus foliaceousand pemphigus vulgaris antigens. Biochem J 329: 165–174.

Aho S, Rothenberger K, Tan EM, Ryoo YW, Cho BH,McLean WH, Uitto J. 1999. Human periplakin: Genomicorganization in a clonally unstable region of chromo-some 16p with an abundance of repetitive sequence ele-ments. Genomics 56: 160–168.

Aigner K, Descovich L, Mikula M, Sultan A, Dampier B,Bonne S, van Roy F, Mikulits W, Schreiber M, BrabletzT, et al. 2007. The transcription factor ZEB1 (dEF1) re-presses Plakophilin 3 during human cancer progression.FEBS Lett 581: 1617–1624.

Aijaz S, Sanchez-Heras E, Balda MS, Matter K. 2007. Regu-lation of tight junction assembly and epithelial morpho-genesis by the heat shock protein Apg-2. BMC Cell Biol8: 49.

Aktary Z, Pasdar M. 2012. Plakoglobin: Role in tumorigen-esis and metastasis. Int J Cell Biol 2012: 189521.

Allen E, Yu QC, Fuchs E. 1996. Mice expressing a mutantdesmosomal cadherin exhibit abnormalities in desmo-somes, proliferation, and epidermal differentiation.J Cell Biol 133: 1367–1382.

Amagai M, Stanley JR. 2012. Desmoglein as a target in skindisease and beyond. J Invest Dermatol 132: 776–784.

Amagai M, Klaus-Kovtun V, Stanley JR. 1991. Autoantibod-ies against a novel epithelial cadherin in pemphigus vul-garis, a disease of cell adhesion. Cell 67: 869–877.

Arnemann J, Spurr NK, Wheeler GN, Parker AE, Buxton RS.1991. Chromosomal assignment of the human genescoding for the major proteins of the desmosome junc-tion, desmoglein DGI (DSG), desmocollins DGII/III(DSC), desmoplakins DPI/II (DSP), and plakoglobinDPIII (JUP). Genomics 10: 640–645.

Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S,Basso C, Thiene G, Tsatsopoulou A, Protonotarios N,McKenna WJ, et al. 2009. A new diagnostic test for ar-rhythmogenic right ventricular cardiomyopathy. N Engl JMed 360: 1075–1084.

Bailey CK, Mittal MK, Misra S, Chaudhuri G. 2012. Highmotility of triple-negative breast cancer cells is due torepression of plakoglobin gene by metastasis modulatorprotein SLUG. J Biol Chem 287: 19472–19486.

Baron S, Hoang A, Vogel H, Attardi LD. 2012. Unimpairedskin carcinogenesis in desmoglein 3 knockout mice. PLoSONE 7: e50024.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Bass-Zubek AE, Hobbs RP, Amargo EV, Garcia NJ, HsiehSN, Chen X, Wahl JK III, Denning MF, Green KJ. 2008.Plakophilin 2: A critical scaffold for PKC-a that regulatesintercellular junction assembly. J Cell Biol 181: 605–613.

Bayerl C, Taake S, Moll I, Jung EG. 1995. Characterization ofsunburn cells after exposure to ultraviolet light. Photo-dermatol Photoimmunol Photomed 11: 149–154.

Bayo P, Sanchis A, Bravo A, Cascallana JL, Buder K, Tuck-ermann J, Schutz G, Perez P. 2008. Glucocorticoid recep-tor is required for skin barrier competence. Endocrinology149: 1377–1388.

Bazzi H, Christiano AM. 2007. Broken hearts, woolly hair,and tattered skin: When desmosomal adhesion goesawry. Curr Opin Cell Biol 19: 515–520.

Bazzi H, Demehri S, Potter CS, Barber AG, Awgulewitsch A,Kopan R, Christiano AM. 2009. Desmoglein 4 is regulat-ed by transcription factors implicated in hair shaft dif-ferentiation. Differentiation 78: 292–300.

Beaudry VG, Jiang D, Dusek RL, Park EJ, Knezevich S, RiddK, Vogel H, Bastian BC, Attardi LD. 2010. Loss of thep53/p63 regulated desmosomal protein Perp promotestumorigenesis. PLoS Genet 6: e1001168.

Bektas M, Jolly P, Rubenstein DS. 2010. Apoptotic pathwaysin pemphigus. Dermatol Res Pract 2010: 456841.

Bonne S, van Hengel J, van Roy F. 1998. Chromosomalmapping of human armadillo genes belonging to thepp120(ctn)/plakophilin subfamily. Genomics 51: 452–454.

Brennan D, Mahoney MG. 2009. Increased expression ofDsg2 in malignant skin carcinomas: A tissue-microarraybased study. Cell Adh Migr 3: 148–154.

Brennan D, Hu Y, Joubeh S, Choi YW, Whitaker-Menezes D,O’Brien T, Uitto J, Rodeck U, Mahoney MG. 2007. Supra-basal Dsg2 expression in transgenic mouse skin confers ahyperproliferative and apoptosis-resistant phenotype tokeratinocytes. J Cell Sci 120: 758–771.

Brennan D, Hu Y, Medhat W, Dowling A, Mahoney MG.2010. Superficial dsg2 expression limits epidermal blisterformation mediated by pemphigus foliaceus antibodiesand exfoliative toxins. Dermatol Res Pract 2010: 410278.

Byrne C, Tainsky M, Fuchs E. 1994. Programming geneexpression in developing epidermis. Development 120:2369–2383.

Cabral RM, Liu L, Hogan C, Dopping-Hepenstal PJ, WinikBC, Asial RA, Dobson R, Mein CA, Baselaga PA, MellerioJE, et al. 2010. Homozygous mutations in the 50 region ofthe JUP gene result in cutaneous disease but normal heartdevelopment in children. J Invest Dermatol 130: 1543–1550.

Chang YT, Tsai SF, Lee DD, Shiao YM, Huang CY, Liu HN,Wang WJ, Wong CK. 2003. A study of candidate genes forpsoriasis near HLA-C in Chinese patients with psoriasis.Br J Dermatol 148: 418–423.

Chang YT, Chou CT, Shiao YM, Lin MW, Yu CW, Chen CC,Huang CH, Lee DD, Liu HN, Wang WJ, et al. 2006. Pso-riasis vulgaris in Chinese individuals is associated withPSORS1C3 and CDSN genes. Br J Dermatol 155: 663–669.

Charpentier E, Lavker RM, Acquista E, Cowin P. 2000. Pla-koglobin suppresses epithelial proliferation and hairgrowth in vivo. J Cell Biol 149: 503–520.

Chen X, Bonne S, Hatzfeld M, van Roy F, Green KJ. 2002.Protein binding and functional characterization of pla-kophilin 2. Evidence for its diverse roles in desmosomesand beta-catenin signaling. J Biol Chem 277: 10512–10522.

Chidgey M, Brakebusch C, Gustafsson E, Cruchley A, HailC, Kirk S, Merritt A, North A, Tselepis C, Hewitt J, et al.2001. Mice lacking desmocollin 1 show epidermal fragil-ity accompanied by barrier defects and abnormal differ-entiation. J Cell Biol 155: 821–832.

Chouinard N, Rouabhia M. 1999. Effects of all-trans retino-ic acid on UVB-irradiated human skin substitute. J CellPhysiol 181: 14–23.

Chu YS, Thomas WA, Eder O, Pincet F, Perez E, Thiery JP,Dufour S. 2004. Force measurements in E-cadherin-me-diated cell doublets reveal rapid adhesion strengthened byactin cytoskeleton remodeling through Rac and Cdc42.J Cell Biol 167: 1183–1194.

Chun MG, Hanahan D. 2010. Genetic deletion of the des-mosomal component desmoplakin promotes tumor mi-croinvasion in a mouse model of pancreatic neuroendo-crine carcinogenesis. PLoS Genet 6: e1001120.

Cirillo N, Al-Jandan BA. 2013. Desmosomal adhesion andpemphigus vulgaris: The first half of the story. Cell Com-mun Adhes 20: 1–10.

Cowley CM, Simrak D, Marsden MD, King IA, Arnemann J,Buxton RS. 1997a. AYAC contig joining the desmocollinand desmoglein loci on human chromosome 18 and or-dering of the desmocollin genes. Genomics 42: 208–216.

Cowley CM, Simrak D, Spurr NK, Arnemann J, Buxton RS.1997b. The plakophilin 1 (PKP1) and plakoglobin (JUP)genes map to human chromosomes 1q and 17, respec-tively. Hum Genet 100: 486–488.

Cui T, Chen Y, Yang L, Knosel T, Zoller K, Huber O, PetersenI. 2011. DSC3 expression is regulated by pp53, and meth-ylation of DSC3 DNA is a prognostic marker in humancolorectal cancer. Br J Cancer 104: 1013–1019.

Delva E, Tucker DK, Kowalczyk AP. 2009. The desmosome.Cold Spring Harb Perspect Biol 1: a002543.

Denning MF, Guy SG, Ellerbroek SM, Norvell SM, Kowalc-zyk AP, Green KJ. 1998. The expression of desmogleinisoforms in cultured human keratinocytes is regulatedby calcium, serum, and protein kinase C. Exp Cell Res239: 50–59.

Descargues P, Deraison C, Prost C, Fraitag S, Mazereeuw-Hautier J, D’Alessio M, Ishida-Yamamoto A, Bodemer C,Zambruno G, Hovnanian A. 2006. Corneodesmosomalcadherins are preferential targets of stratum corneumtrypsin- and chymotrypsin-like hyperactivity in Nether-ton syndrome. J Invest Dermatol 126: 1622–1632.

Dong JT, Chen C. 2009. Essential role of KLF5 transcrip-tion factor in cell proliferation and differentiation and itsimplications for human diseases. Cell Mol Life Sci 66:2691–2706.

Dubash AD, Koetsier JL, Amargo EV, Najor NA, HarmonRM, Green KJ. 2013. The GEF Bcr activates RhoA/MALsignaling to promote keratinocyte differentiation via des-moglein-1. J Cell Biol 202: 653–666.

Dusek RL, Attardi LD. 2011. Desmosomes: New perpetra-tors in tumour suppression. Nat Rev Cancer 11: 317–323.

J.L. Johnson et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Dusek RL, Getsios S, Chen F, Park JK, Amargo EV, Cryns VL,Green KJ. 2006. The differentiation-dependent desmoso-mal cadherin desmoglein 1 is a novel caspase-3 target thatregulates apoptosis in keratinocytes. J Biol Chem 281:3614–3624.

Dusek RL, Godsel LM, Chen F, Strohecker AM, Getsios S,Harmon R, Muller EJ, Caldelari R, Cryns VL, Green KJ.2007. Plakoglobin deficiency protects keratinocytes fromapoptosis. J Invest Dermatol 127: 792–801.

Elias PM, Matsuyoshi N, Wu H, Lin C, Wang ZH, Brown BE,Stanley JR. 2001. Desmoglein isoform distribution affectsstratum corneum structure and function. J Cell Biol 153:243–249.

Eshkind L, Tian Q, Schmidt A, Franke WW, Windoffer R,Leube RE. 2002. Loss of desmoglein 2 suggests essentialfunctions for early embryonic development and prolifer-ation of embryonal stem cells. Eur J Cell Biol 81: 592–598.

Ferone G, Mollo MR, Thomason HA, Antonini D, Zhou H,Ambrosio R, De Rosa L, Salvatore D, Getsios S, van Bok-hoven H, et al. 2013. p63 control of desmosome geneexpression and adhesion is compromised in AEC syn-drome. Hum Mol Genet 22: 531–543.

Franzen CA, Todorovic V, Desai BV, Mirzoeva S, Yang XJ,Green KJ, Pelling JC. 2012. The desmosomal armadilloprotein plakoglobin regulates prostate cancer cell adhe-sion and motility through vitronectin-dependent Src sig-naling. PLoS ONE 7: e42132.

Frydman AS, Fairley JA. 2011. New and innovative interven-tions in the management of pemphigus. G Ital DermatolVenereol 146: 211–224.

Funakoshi S, Ezaki T, Kong J, Guo RJ, Lynch JP. 2008. Re-pression of the desmocollin 2 gene expression in humancolon cancer cells is relieved by the homeodomain tran-scription factors Cdx1 and Cdx2. Mol Cancer Res 6:1478–1490.

Gallicano GI, Kouklis P, Bauer C, Yin M, Vasioukhin V,Degenstein L, Fuchs E. 1998. Desmoplakin is requiredearly in development for assembly of desmosomes andcytoskeletal linkage. J Cell Biol 143: 2009–2022.

Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT,Schneider MD, Khoury DS, Marian AJ. 2006. Suppres-sion of canonical Wnt/b-catenin signaling by nuclearplakoglobin recapitulates phenotype of arrhythmogen-ic right ventricular cardiomyopathy. J Clin Invest 116:2012–2021.

Gardel ML, Kasza KE, Brangwynne CP, Liu J, Weitz DA.2008. Chapter 19: Mechanical response of cytoskeletalnetworks. Methods Cell Biol 89: 487–519.

Garrod DR, Fisher C, Smith A, Nie Z. 2008. Pervanadatestabilizes desmosomes. Cell Adh Migr 2: 161–166.

Getsios S, Simpson CL, Kojima S, Harmon R, Sheu LJ, Du-sek RL, Cornwell M, Green KJ. 2009. Desmoglein 1-de-pendent suppression of EGFR signaling promotes epi-dermal differentiation and morphogenesis. J Cell Biol185: 1243–1258.

Godsel LM, Dubash AD, Bass-Zubek AE, Amargo EV, Kless-ner JL, Hobbs RP, Chen X, Green KJ. 2010. Plakophilin 2couples actomyosin remodeling to desmosomal plaqueassembly via RhoA. Mol Biol Cell 21: 2844–2859.

Grando SA. 2012. Pemphigus autoimmunity: Hypothesesand realities. Autoimmunity 45: 7–35.

Green KJ, Gaudry CA. 2000. Are desmosomes more thantethers for intermediate filaments? Nat Rev Mol Cell Biol1: 208–216.

Green KJ, Simpson CL. 2007. Desmosomes: New perspec-tives on a classic. J Invest Dermatol 127: 2499–2515.

Green KJ, Getsios S, Troyanovsky S, Godsel LM. 2010. In-tercellular junction assembly, dynamics, and homeosta-sis. Cold Spring Harb Perspect Biol 2: a000125.

Groot KR, Sevilla LM, Nishi K, DiColandrea T, Watt FM.2004. Kazrin, a novel periplakin-interacting protein as-sociated with desmosomes and the keratinocyte plasmamembrane. J Cell Biol 166: 653–659.

Hanakawa Y, Matsuyoshi N, Stanley JR. 2002. Expression ofdesmoglein 1 compensates for genetic loss of desmoglein3 in keratinocyte adhesion. J Invest Dermatol 119: 27–31.

Hardman MJ, Liu K, Avilion AA, Merritt A, Brennan K,Garrod DR, Byrne C. 2005. Desmosomal cadherin mis-expression alters b-catenin stability and epidermal dif-ferentiation. Mol Cell Biol 25: 969–978.

Harmon RM, Simpson CL, Johnson JL, Koetsier JL, DubashAD, Najor NA, Sarig O, Sprecher E, Green KJ. 2013. Des-moglein-1/Erbin interaction suppresses ERK activationto support epidermal differentiation. J Clin Invest 123:1556–1570.

Hartlieb E, Kempf B, Partilla M, Vigh B, Spindler V, WaschkeJ. 2013. Desmoglein 2 is less important than desmoglein 3for keratinocyte cohesion. PLoS ONE 8: e53739.

Henkler F, Strom M, Mathers K, Cordingley H, Sullivan K,King I. 2001. Trangenic misexpression of the differentia-tion-specific desmocollin isoform 1 in basal keratino-cytes. J Invest Dermatol 116: 144–149.

Hobbs RP, Amargo EV, Somasundaram A, Simpson CL,Prakriya M, Denning MF, Green KJ. 2011. The calciumATPase SERCA2 regulates desmoplakin dynamics andintercellular adhesive strength through modulation ofPKC-a signaling. FASEB J 25: 990–1001.

Hofmann I, Casella M, Schnolzer M, Schlechter T, Spring H,Franke WW. 2006. Identification of the junctional plaqueprotein plakophilin 3 in cytoplasmic particles containingRNA-binding proteins and the recruitment of plakophi-lins 1 and 3 to stress granules. Mol Biol Cell 17: 1388–1398.

Hovnanian A. 2013. Netherton syndrome: Skin inflamma-tion and allergy by loss of protease inhibition. Cell TissueRes 351: 289–300.

Humphries JD, Parry EJ, Watson RE, Garrod DR, GriffithsCE. 1998. All-trans retinoic acid compromises desmo-some expression in human epidermis. Br J Dermatol139: 577–584.

Ihrie RA, Attardi LD. 2005. A new Perp in the lineup: Link-ing p63 and desmosomal adhesion. Cell Cycle 4: 873–876.

Johnson JL, Koetsier JL, Sirico A, Agidi AT, Antonini D,Missero C, Green KJ. 2014. The desmosomal proteindesmoglein 1 aids recovery of epidermal differentiationafter acute ultraviolet light exposure. J Invest Dermatoldoi: 10.1038/jid.2014.124.

Kalantari-Dehaghi M, Anhalt GJ, Camilleri MJ, Chernyav-sky AI, Chun S, Felgner PL, Jasinskas A, Leiferman KM,Liang L, Marchenko S, et al. 2013. Pemphigus vulgaris



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



autoantibody profiling by proteomic technique. PLoSONE 8: e57587.

Kaz AM, Luo Y, Dzieciatkowski S, Chak A, Willis JE, UptonMP, Leidner RS, Grady WM. 2012. Aberrantly methylat-ed PKP1 in the progression of Barrett’s esophagus toesophageal adenocarcinoma. Genes Chromosomes Cancer51: 384–393.

Kenchegowda D, Harvey SA, Swamynathan S, Lathrop KL,Swamynathan SK. 2012. Critical role of Klf5 in regulatinggene expression during post-eyelid opening maturationof mouse corneas. PLoS ONE 7: e44771.

Khapare N, Kundu ST, Sehgal L, Sawant M, Priya R, GosaviP, Gupta N, Alam H, Karkhanis M, Naik N, et al. 2012.Plakophilin3 loss leads to an increase in PRL3 levelspromoting K8 dephosphorylation, which is requiredfor transformation and metastasis. PLoS ONE 7: e38561.

Kim MY, Lee SE, Chang JY, Kim SC. 2011. Retinoid inducesthe degradation of corneodesmosomes and downregula-tion of corneodesmosomal cadherins: Implications onthe mechanism of retinoid-induced desquamation. AnnDermatol 23: 439–447.

Kimura TE, Merritt AJ, Lock FR, Eckert JJ, Fleming TP,Garrod DR. 2012. Desmosomal adhesiveness is develop-mentally regulated in the mouse embryo and modulatedduring trophectoderm migration. Dev Biol 369: 286–297.

Klessner JL, Desai BV, Amargo EV, Getsios S, Green KJ. 2009.EGFR and ADAMs cooperate to regulate shedding andendocytic trafficking of the desmosomal cadherin des-moglein 2. Mol Biol Cell 20: 328–337.

Kljuic A, Bazzi H, Sundberg JP, Martinez-Mir A, O’Shaugh-nessy R, Mahoney MG, Levy M, Montagutelli X, AhmadW, Aita VM, et al. 2003. Desmoglein 4 in hair follicledifferentiation and epidermal adhesion: Evidence frominherited hypotrichosis and acquired pemphigus vulga-ris. Cell 113: 249–260.

Kolegraff K, Nava P, Helms MN, Parkos CA, Nusrat A. 2011.Loss of desmocollin-2 confers a tumorigenic phenotypeto colonic epithelial cells through activation of Akt/b-catenin signaling. Mol Biol Cell 22: 1121–1134.

Koulu L, Kusumi A, Steinberg MS, Klaus-Kovtun V, StanleyJR. 1984. Human autoantibodies against a desmosomalcore protein in pemphigus foliaceus. J Exp Med 160:1509–1518.

Kowalczyk AP, Green KJ. 2013. Structure, function, andregulation of desmosomes. Prog Mol Biol Transl Sci 116:95–118.

Kroger C, Loschke F, Schwarz N, Windoffer R, Leube RE,Magin TM. 2013. Keratins control intercellular adhesioninvolving PKC-a-mediated desmoplakin phosphoryla-tion. J Cell Biol 201: 681–692.

Lebeau S, Masouye I, Berti M, Augsburger E, Saurat JH,Borradori L, Fontao L. 2005. Comparative analysis ofthe expression of ERBIN and Erb-B2 in normal humanskin and cutaneous carcinomas. Br J Dermatol 152: 1248–1255.

Lechler T, Fuchs E. 2007. Desmoplakin: An unexpectedregulator of microtubule organization in the epidermis.J Cell Biol 176: 147–154.

Leclerc EA, Huchenq A, Mattiuzzo NR, Metzger D, Cham-bon P, Ghyselinck NB, Serre G, Jonca N, Guerrin M. 2009.Corneodesmosin gene ablation induces lethal skin-bar-

rier disruption and hair-follicle degeneration related todesmosome dysfunction. J Cell Sci 122: 2699–2709.

Leitner L, Shaposhnikov D, Mengel A, Descot A, Julien S,Hoffmann R, Posern G. 2011. MAL/MRTF-A controlsmigration of non-invasive cells by upregulation of cyto-skeleton-associated proteins. J Cell Sci 124: 4318–4331.

Li D, Turi TG, Schuck A, Freedberg IM, Khitrov G, Blumen-berg M. 2001. Rays and arrays: The transcriptional pro-gram in the response of human epidermal keratinocytesto UVB illumination. FASEB J 15: 2533–2535.

Li D, Zhang W, Liu Y, Haneline LS, Shou W. 2012. Lack ofplakoglobin in epidermis leads to keratoderma. J BiolChem 287: 10435–10443.

Lin S, Gordon K, Kaplan N, Getsios S. 2010. Ligand target-ing of EphA2 enhances keratinocyte adhesion and differ-entiation via desmoglein 1. Mol Biol Cell 21: 3902–3914.

Loffek S, Bruckner-Tuderman L, Magin TM. 2012. Involve-ment of the ubiquitin-proteasome system in the stabili-zation of cell-cell contacts in human keratinocytes. ExpDermatol 21: 791–793.

Lopez-Pajares V, Yan K, Zarnegar BJ, Jameson KL, KhavariPA. 2013. Genetic pathways in disorders of epidermaldifferentiation. Trends Genet 29: 31–40.

Lorch JH, Klessner J, Park JK, Getsios S, Wu YL, Stack MS,Green KJ. 2004. Epidermal growth factor receptor inhi-bition promotes desmosome assembly and strengthensintercellular adhesion in squamous cell carcinoma cells.J Biol Chem 279: 37191–37200.

Maatta A, Ruhrberg C, Watt FM. 2000. Structure and regu-lation of the envoplakin gene. J Biol Chem 275: 19857–19865.

MacRae CA, Birchmeier W, Thierfelder L. 2006. Arrhyth-mogenic right ventricular cardiomyopathy: Moving to-ward mechanism. J Clin Invest 116: 1825–1828.

Mannan T, Jing S, Foroushania SH, Fortune F, Wan H. 2011.RNAi-mediated inhibition of the desmosomal cadherin(desmoglein 3) impairs epithelial cell proliferation. CellProlif 44: 301–310.

Mao X, Nagler AR, Farber SA, Choi EJ, Jackson LH, Leifer-man KM, Ishii N, Hashimoto T, Amagai M, Zone JJ,et al. 2010. Autoimmunity to desmocollin 3 in pemphi-gus vulgaris. Am J Pathol 177: 2724–2730.

Mao X, Sano Y, Park JM, Payne AS. 2011. p38 MAPK acti-vation is downstream of the loss of intercellular adhesionin pemphigus vulgaris. J Biol Chem 286: 1283–1291.

Mao X, Li H, Sano Y, Gaestel M, Mo Park J, Payne AS. 2013.MAPKAP kinase 2 (MK2)-dependent and independentmodels of blister formation in pemphigus vulgaris. J In-vest Dermatol 134: 68–76.

Marsden MD, Collins JE, Greenwood MD, Adams MJ,Fleming TP, Magee AI, Buxton RS. 1997. Cloning andtranscriptional analysis of the promoter of the humantype 2 desmocollin gene (DSC2). Gene 186: 237–247.

Matsuda M, Hoshino T, Yamashita Y, Tanaka K, Maji D, SatoK, Adachi H, Sobue G, Ihn H, Funasaka Y, et al. 2013.Prevention of UVB radiation-induced epidermal damageby expression of heat shock protein 70. J Biol Chem 285:5848–5858.

Merritt AJ, Berika MY, Zhai W, Kirk SE, Ji B, Hardman MJ,Garrod DR. 2002. Suprabasal desmoglein 3 expression inthe epidermis of transgenic mice results in hyperprolif-

J.L. Johnson et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



eration and abnormal differentiation. Mol Cell Biol 22:5846–5858.

Miralles F, Posern G, Zaromytidou AI, Treisman R. 2003.Actin dynamics control SRF activity by regulation of itscoactivator MAL. Cell 113: 329–342.

Mizukoshi K, Matsumoto K, Hirose R, Fujita T, Ishida-Ya-mamoto A, Iizuka H. 2011. Effects of serine palmitoyl-transferase inhibitor ISP-I on the stratum corneum ofintact mouse skin. Biol Pharm Bull 34: 1383–1389.

Mucke N, Kreplak L, Kirmse R, Wedig T, Herrmann H, AebiU, Langowski J. 2004. Assessing the flexibility of interme-diate filaments by atomic force microscopy. J Mol Biol335: 1241–1250.

Murakami T, Fujimoto M, Ohtsuki M, Nakagawa H. 2001.Expression profiling of cancer-related genes in humankeratinocytes following non-lethal ultraviolet B irradia-tion. J Dermatol Sci 27: 121–129.

Nachat R, Cipolat S, Sevilla LM, Chhatriwala M, Groot KR,Watt FM. 2009. KazrinE is a desmosome-associated li-prin that colocalises with acetylated microtubules. J CellSci 122: 4035–4041.

Nava P, Laukoetter MG, Hopkins AM, Laur O, Gerner-Smidt K, Green KJ, Parkos CA, Nusrat A. 2007. Desmo-glein-2: A novel regulator of apoptosis in the intestinalepithelium. Mol Biol Cell 18: 4565–4578.

Nguyen VT, Arredondo J, Chernyavsky AI, Kitajima Y,Grando SA. 2003. Keratinocyte acetylcholine receptorsregulate cell adhesion. Life Sci 72: 2081–2085.

Nguyen B, Dusek RL, Beaudry VG, Marinkovich MP, AttardiLD. 2009. Loss of the desmosomal protein perp enhancesthe phenotypic effects of pemphigus vulgaris autoanti-bodies. J Invest Dermatol 129: 1710–1718.

Ning S, Hahn GM. 1994. Formation of tight junctions anddesmosomes protects MDCK cells against hyperthermickilling. J Cell Physiol 160: 249–254.

Oji V, Eckl KM, Aufenvenne K, Natebus M, Tarinski T, Ac-kermann K, Seller N, Metze D, Nurnberg G, Folster-HolstR, et al. 2010. Loss of corneodesmosin leads to severe skinbarrier defect, pruritus, and atopy: Unraveling the peel-ing skin disease. Am J Hum Genet 87: 274–281.

Oshiro MM, Watts GS, Wozniak RJ, Junk DJ, Munoz-Ro-driguez JL, Domann FE, Futscher BW. 2003. Mutant p53and aberrant cytosine methylation cooperate to silencegene expression. Oncogene 22: 3624–3634.

Owens P, Bazzi H, Engelking E, Han G, Christiano AM,Wang XJ. 2008. Smad4-dependent desmoglein-4 expres-sion contributes to hair follicle integrity. Dev Biol 322:156–166.

Pan H, Gao F, Papageorgis P, Abdolmaleky HM, Faller DV,Thiagalingam S. 2007. Aberrant activation of g-cateninpromotes genomic instability and oncogenic effects dur-ing tumor progression. Cancer Biol Ther 6: 1638–1643.

Parker HR, Li Z, Sheinin H, Lauzon G, Pasdar M. 1998.Plakoglobin induces desmosome formation and epider-moid phenotype in N-cadherin-expressing squamouscarcinoma cells deficient in plakoglobin and E-cadherin.Cell Motil Cytoskeleton 40: 87–100.

Petrof G, Mellerio JE, McGrath JA. 2012. Desmosomal gen-odermatoses. Br J Dermatol 166: 36–45.

Potter E, Braun S, Lehmann U, Brabant G. 2001. Molecularcloning of a functional promoter of the human plakoglo-bin gene. Eur J Endocrinol 145: 625–633.

Rawlings A, Harding C, Watkinson A, Banks J, Ackerman C,Sabin R. 1995. The effect of glycerol and humidity ondesmosome degradation in stratum corneum. Arch Der-matol Res 287: 457–464.

Reczek EE, Flores ER, Tsay AS, Attardi LD, Jacks T. 2003.Multiple response elements and differential p53 bindingcontrol Perp expression during apoptosis. Mol Cancer Res1: 1048–1057.

Roberts BJ, Pashaj A, Johnson KR, Wahl JK III. 2011. Des-mosome dynamics in migrating epithelial cells requiresthe actin cytoskeleton. Exp Cell Res 317: 2814–2822.

Roemer K. 2012. Notch and the p53 clan of transcriptionfactors. Adv Exp Med Biol 727: 223–240.

Ruhrberg C, Hajibagheri MA, Parry DA, Watt FM. 1997.Periplakin, a novel component of cornified envelopesand desmosomes that belongs to the plakin family andforms complexes with envoplakin. J Cell Biol 139: 1835–1849.

Rundhaug JE, Hawkins KA, Pavone A, Gaddis S, Kil H, KleinRD, Berton TR, McCauley E, Johnson DG, Lubet RA,et al. 2005. SAGE profiling of UV-induced mouse skinsquamous cell carcinomas, comparison with acute UVirradiation effects. Mol Carcinog 42: 40–52.

Ryan KR, Lock FE, Heath JK, Hotchin NA. 2012. Plakoglo-bin-dependent regulation of keratinocyte apoptosis byRnd3. J Cell Sci 125: 3202–3209.

Saito M, Stahley SN, Caughman CY, Mao X, Tucker DK,Payne AS, Amagai M, Kowalczyk AP. 2012. Signaling de-pendent and independent mechanisms in pemphigusvulgaris blister formation. PLoS ONE 7: e50696.

Samady L, Faulkes DJ, Budhram-Mahadeo V, Ndisang D,Potter E, Brabant G, Latchman DS. 2006. The Brn-3bPOU family transcription factor represses plakoglobingene expression in human breast cancer cells. Int J Cancer118: 869–878.

Samuelov L, Sarig O, Harmon RM, Rapaport D, Ishida-Yamamoto A, Isakov O, Koetsier JL, Gat A, Goldberg I,Bergman R, et al. 2013. Desmoglein 1 deficiency results insevere dermatitis, multiple allergies and metabolic wast-ing. Nat Genet 45: 1244–1248.

Sato J, Denda M, Nakanishi J, Koyama J. 1998. Dry condi-tion affects desquamation of stratum corneum in vivo.J Dermatol Sci 18: 163–169.

Savagner P, Kusewitt DF, Carver EA, Magnino F, Choi C,Gridley T, Hudson LG. 2005. Developmental transcrip-tion factor slug is required for effective re-epithelializa-tion by adult keratinocytes. J Cell Physiol 202: 858–866.

Sesto A, Navarro M, Burslem F, Jorcano JL. 2002. Analysis ofthe ultraviolet B response in primary human keratino-cytes using oligonucleotide microarrays. Proc Natl AcadSci 99: 2965–2970.

Sevilla LM, Nachat R, Groot KR, Klement JF, Uitto J, Djian P,Maatta A, Watt FM. 2007. Mice deficient in involucrin,envoplakin, and periplakin have a defective epidermalbarrier. J Cell Biol 179: 1599–1612.

Sevilla LM, Nachat R, Groot KR, Watt FM. 2008. Kazrinregulates keratinocyte cytoskeletal networks, intercellularjunctions and differentiation. J Cell Sci 121: 3561–3569.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Sheu HM, Kitajima Y, Yaoita H. 1989. Involvement of pro-tein kinase C in translocation of desmoplakins from cy-tosol to plasma membrane during desmosome formationin human squamous cell carcinoma cells grown in low tonormal calcium concentration. Exp Cell Res 185: 176–190.

Shim JS, Kim DH, Kwon HJ. 2004. Plakoglobin is a newtarget gene of histone deacetylase in human fibrosarcomaHT1080 cells. Oncogene 23: 1704–1711.

Silos SA, Tamai K, Li K, Kivirikko S, Kouba D, ChristianoAM, Uitto J. 1996. Cloning of the gene for human pem-phigus vulgaris antigen (desmoglein 3), a desmosomalcadherin. Characterization of the promoter region andidentification of a keratinocyte-specific cis-element. J BiolChem 271: 17504–17511.

Simpson CL, Kojima S, Cooper-Whitehair V, Getsios S,Green KJ. 2010. Plakoglobin rescues adhesive defects in-duced by ectodomain truncation of the desmosomal cad-herin desmoglein: 1. Implications for exfoliative toxin-mediated skin blistering. Am J Pathol 177: 2921–2937.

Simrak D, Cowley CM, Buxton RS, Arnemann J. 1995. Tan-dem arrangement of the closely linked desmoglein geneson human chromosome 18. Genomics 25: 591–594.

Smith C, Zhu K, Merritt A, Picton R, Youngs D, Garrod D,Chidgey M. 2004. Regulation of desmocollin gene expres-sion in the epidermis: CCAAT/enhancer-binding pro-teins modulate early and late events in keratinocyte dif-ferentiation. Biochem J 380: 757–765.

Sonnenberg A, Liem RK. 2007. Plakins in development anddisease. Exp Cell Res 313: 2189–2203.

Spindler V, Waschke J. 2011. Role of Rho GTPases in des-mosomal adhesion and pemphigus pathogenesis. AnnAnat 193: 177–180.

Spindler V, Rotzer V, Dehner C, Kempf B, Gliem M, RadevaM, Hartlieb E, Harms GS, Schmidt E, Waschke J. 2013.Peptide-mediated desmoglein 3 cross-linking preventspemphigus vulgaris autoantibody-induced skin blister-ing. J Clin Invest 123: 800–811.

Steinert PM, Marekov LN. 1999. Initiation of assembly ofthe cell envelope barrier structure of stratified squamousepithelia. Mol Biol Cell 10: 4247–4261.

Sumigray KD, Lechler T. 2011. Control of cortical microtu-bule organization and desmosome stability by centroso-mal proteins. Bioarchitecture 1: 221–224.

Sumigray KD, Lechler T. 2012. Desmoplakin controls mi-crovilli length but not cell adhesion or keratin organiza-tion in the intestinal epithelium. Mol Biol Cell 23: 792–799.

Sumigray KD, Chen H, Lechler T. 2011. Lis1 is essentialfor cortical microtubule organization and desmosomestability in the epidermis. J Cell Biol 194: 631–642.

Swamynathan S, Kenchegowda D, Piatigorsky J. 2011. Reg-ulation of corneal epithelial barrier function by Kruppel-like transcription factor 4. Invest Ophthalmol Vis Sci 52:1762–1769.

Szegedi A, Payer E, Czifra G, Toth BI, Schmidt E, Kovacs L,Blumberg PM, Biro T. 2009. Protein kinase C isoenzymesdifferentially regulate the differentiation-dependent ex-pression of adhesion molecules in human epidermal ker-atinocytes. Exp Dermatol 18: 122–129.

Tachikawa T, Kohno Y, Matsui Y, Yoshiki S. 1986. In vitroearly changes in intercellular junctions by treatment witha chemical carcinogen. Carcinogenesis 7: 885–892.

Tada H, Hatoko M, Tanaka A, Kuwahara M, Muramatsu T.2000. Expression of desmoglein I and plakoglobin in skincarcinomas. J Cutan Pathol 27: 24–29.

Teh MT, Parkinson EK, Thurlow JK, Liu F, Fortune F, Wan H.2011. A molecular study of desmosomes identifies a des-moglein isoform switch in head and neck squamous cellcarcinoma. J Oral Pathol Med 40: 67–76.

Thomason HA, Scothern A, McHarg S, Garrod DR. 2010.Desmosomes: Adhesive strength and signalling in healthand disease. Biochem J 429: 419–433.

Thomason HA, Cooper NH, Ansell DM, Chiu M, Merrit AJ,Hardman MJ, Garrod DR. 2012. Direct evidence thatPKC-a positively regulates wound re-epithelialization:Correlation with changes in desmosomal adhesiveness.J Pathol 227: 346–356.

Todorovic V, Desai BV, Patterson MJ, Amargo EV, DubashAD, Yin T, Jones JC, Green KJ. 2010. Plakoglobin regu-lates cell motility through Rho- and fibronectin-depen-dent Src signaling. J Cell Sci 123: 3576–3586.

Tokonzaba E, Chen J, Cheng X, Den Z, Ganeshan R, MullerEJ, Koch PJ. 2013. Plakoglobin as a regulator of desmo-collin gene expression. J Invest Dermatol 133: 2732–2740.

Tsang SM, Liu L, Teh MT, Wheeler A, Grose R, Hart IR,Garrod DR, Fortune F, Wan H. 2010. Desmoglein 3, viaan interaction with E-cadherin, is associated with activa-tion of Src. PLoS ONE 5: e14211.

Tsang SM, Brown L, Gadmor H, Gammon L, Fortune F,Wheeler A, Wan H. 2012a. Desmoglein 3 acting as anupstream regulator of Rho GTPases, Rac-1/Cdc42 inthe regulation of actin organisation and dynamics. ExpCell Res 318: 2269–2283.

Tsang SM, Brown L, Lin K, Liu L, Piper K, O’Toole EA, GroseR, Hart IR, Garrod DR, Fortune F, et al. 2012b. Non-junctional human desmoglein 3 acts as an upstream reg-ulator of Src in E-cadherin adhesion, a pathway possiblyinvolved in the pathogenesis of pemphigus vulgaris. JPathol 227: 81–93.

Twiss F, de Rooij J. 2013. Cadherin mechanotransduction intissue remodeling. Cell Mol Life Sci 70: 4101–4116.

Vandewalle C, Comijn J, De Craene B, Vermassen P, Bruy-neel E, Andersen H, Tulchinsky E, Van Roy F, Berx G.2005. SIP1/ZEB2 induces EMT by repressing genes ofdifferent epithelial cell-cell junctions. Nucleic Acids Res33: 6566–6578.

Wallis S, Lloyd S, Wise I, Ireland G, Fleming TP, Garrod D.2000. The a isoform of protein kinase C is involved insignaling the response of desmosomes to wounding incultured epithelial cells. Mol Biol Cell 11: 1077–1092.

Walsh R, Blumenberg M. 2011. Eph-2B, acting as an extra-cellular ligand, induces differentiation markers in epider-mal keratinocytes. J Cell Physiol 227: 2330–2340.

Wan H, South AP, Hart IR. 2007. Increased keratino-cyte proliferation initiated through downregulation ofdesmoplakin by RNA interference. Exp Cell Res 313:2336–2344.

Wang Y, Amagai M, Minoshima S, Sakai K, Green KJ, Nish-ikawa T, Shimizu N. 1994. The human genes for desmo-

J.L. Johnson et al.


ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



gleins (DSG1 and DSG3) are located in a small region onchromosome 18q12. Genomics 20: 492–495.

Wanner R, Wolff B, Glowacki F, Kolde G, Wittig B. 1999. Theloss of desmosomes after retinoic acid treatment resultsin an apparent inhibition of HaCaT keratinocyte differ-entiation. Arch Dermatol Res 291: 346–353.

Waschke J, Spindler V, Bruggeman P, Zillikens D, Schmidt G,Drenckhahn D. 2006. Inhibition of Rho A activity causespemphigus skin blistering. J Cell Biol 175: 721–727.

White FH, Gohari K. 1984. A qualitative ultrastructuralstudy of the intercellular spaces between epithelial cellstreated in vivo with DMBA. J Oral Pathol 13: 231–243.

Whittock NV, Bower C. 2003. Genetic evidence for a novelhuman desmosomal cadherin, desmoglein 4. J InvestDermatol 120: 523–530.

Wilanowski T, Caddy J, Ting SB, Hislop NR, Cerruti L,Auden A, Zhao LL, Asquith S, Ellis S, Sinclair R, et al.2008. Perturbed desmosomal cadherin expression ingrainy head-like 1-null mice. EMBO J 27: 886–897.

Wolf A, Rietscher K, Glass M, Huttelmaier S, SchutkowskiM, Ihling C, Sinz A, Wingenfeld A, Mun A, Hatzfeld M.2013. Insulin signaling via Akt2 switches plakophilin 1

function from stabilizing cell adhesion to promoting cellproliferation. J Cell Sci 126: 1832–1844.

Wong MP, Cheang M, Yorida E, Coldman A, Gilks CB,Huntsman D, Berean K. 2008. Loss of desmoglein 1 ex-pression associated with worse prognosis in head andneck squamous cell carcinoma patients. Pathology 40:611–616.

Yamazaki S, Uchiumi A, Katagata Y. 2012. Hsp40 regulatesthe amount of keratin proteins via ubiquitin-proteasomepathway in cultured human cells. Int J Mol Med 29: 165–168.

Yang L, Chen Y, Cui T, Knosel T, Zhang Q, Albring KF, HuberO, Petersen I. 2012. Desmoplakin acts as a tumor sup-pressor by inhibition of the Wnt/b-catenin signalingpathway in human lung cancer. Carcinogenesis 33:1863–1870.

Yin T, Getsios S, Caldelari R, Kowalczyk AP, Muller EJ, JonesJC, Green KJ. 2005. Plakoglobin suppresses keratinocytemotility through both cell–cell adhesion-dependentand-independent mechanisms. Proc Natl Acad Sci 102:5420–5425.

Yong AA, Tey HL. 2012. Paraneoplastic pemphigus. Aus-tralas J Dermatol 54: 241–250.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



2014; doi: 10.1101/cshperspect.a015297Cold Spring Harb Perspect Med Jodi L. Johnson, Nicole A. Najor and Kathleen J. Green Epidermal Health and DiseaseDesmosomes: Regulators of Cellular Signaling and Adhesion in

Subject Collection The Skin and Its Diseases

InsightsMelanoma: Clinical Features and Genomic

Elena B. Hawryluk and Hensin TsaoDevelopment in the MouseModeling Cutaneous Squamous Carcinoma

Phillips Y. Huang and Allan BalmainWound Healing and Skin Regeneration

Makoto Takeo, Wendy Lee and Mayumi ItoNatural and Sun-Induced Aging of Human Skin

Laure Rittié and Gary J. Fisher

Development and Regeneration of the Hair FollicleEpithelial Stem and Progenitor Cells in The Dermal Papilla: An Instructive Niche for

Bruce A. Morgan

Advanced Treatment for Basal Cell Carcinomas

OroScott X. Atwood, Ramon J. Whitson and Anthony E.

Immunology and Skin in Health and DiseaseJillian M. Richmond and John E. Harris

Epidermal Polarity Genes in Health and Disease

M. NiessenFrederik Tellkamp, Susanne Vorhagen and Carien

and Adhesion in Epidermal Health and DiseaseDesmosomes: Regulators of Cellular Signaling

GreenJodi L. Johnson, Nicole A. Najor and Kathleen J.

Potentials, Advances, and LimitationsInduced Pluripotent Stem Cells in Dermatology:

Ganna Bilousova and Dennis R. Roop

in Adult Mammalian SkinMarkers of Epidermal Stem Cell Subpopulations

Kai Kretzschmar and Fiona M. Watt

The Genetics of Human Skin DiseaseGina M. DeStefano and Angela M. Christiano

Psoriasis

NestlePaola Di Meglio, Federica Villanova and Frank O. Disease

p53/p63/p73 in the Epidermis in Health and

Vladimir A. Botchkarev and Elsa R. FloresCell Therapy in Dermatology

McGrathGabriela Petrof, Alya Abdul-Wahab and John A. Receptors in Skin

Diversification and Specialization of Touch

David M. Owens and Ellen A. Lumpkin

http://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see

Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved


http://perspectivesinmedicine.cshlp.org/cgi/collection/

http://perspectivesinmedicine.cshlp.org/cgi/collection/


desmosomes: regulators of cellular signaling and adhesion...

Documents