Desmosomes: adhesive strength and signalling in health and disease

Biochem. J. (2010) 429, 419–433 (Printed in Great Britain) doi:10.1042/BJ20100567 419

REVIEW ARTICLEDesmosomes: adhesive strength and signalling in health and diseaseHelen A. THOMASON, Anthea SCOTHERN, Selina MCHARG and David R. GARROD1

Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, U.K.

Desmosomes are intercellular junctions whose primary functionis strong intercellular adhesion, known as hyperadhesion. In thepresent review, we discuss how their structure appears to supportthis function as well as how they are assembled and down-re-gulated. Desmosomal components also have signalling functionsthat are important in tissue development and remodelling. Theiradhesive and signalling functions are both compromised in geneticand autoimmune diseases that affect the heart, skin and mucous

membranes. We conclude that much work is required on structure–function relationships within desmosomes in vivo and on how theyparticipate in signalling processes to enhance our knowledge oftissue homoeostasis and human disease.

Key words: cell adhesion, desmosome, hyperadhesion, pemp-higus, tissue development, tissue remodelling.

INTRODUCTION

Desmosomes are intercellular junctions whose primary function isstrong adhesion, providing intercellular links in the desmosome–IF (intermediate filament) complex and lending great tensilestrength to tissues. They are most abundant in tissues that aresubject to mechanical stress, such as epidermis and myocardium.Their importance in maintaining tissue integrity is underlined bytheir contribution to a number of genetic diseases that affect skinand heart, and by the autoimmune blistering disease pemphigus.Desmosomes perform this essential function because, unlike otheradhesive junctions, they are able to adopt a strongly adhesivestate known as hyperadhesion. They have a characteristic andhighly organized structure that has been recognized since theearly days of EM (electron microscopy). This structure appears tobe fundamental to both their strong adhesion and their interactionwith the cytoskeleton. Although the major molecular componentshave been known for almost 30 years, details of how the moleculesare spatially arranged within and interact to form the structure areonly just beginning to emerge. This role of cementing togetherthe cellular building blocks of tissue architecture appears ratherstatic, yet the architectural analogy is essentially a poor oneas desmosomes are as dynamic as the tissues they support.The cell turnover that occurs in the course of normal tissuehomoeostasis and the more dramatic remodelling that occursduring embryonic development and wound re-epithelializationnecessitate desmosome assembly, adhesive modulation and down-regulation, processes into which there are insights, but whereenormous gaps in our understanding remain. In addition to theiradhesive role, desmosomes appear to participate in cell signallingduring development, tissue morphogenesis and wound healing.The present review examines our current knowledge of thestructural and functional dynamics of desmosomes, as well astheir role in genetic and autoimmune disease. Other excellentrecent reviews relating to these topics are [1–6].

MORPHOLOGY

Desmosomes are 0.2–0.5 μm in diameter in human epidermis andapprox. 0.22 μm in MDCK (Madin–Darby canine kidney) cells[7]. They consist of dense plaques arranged symmetrically on thecytoplasmic faces of the PM (plasma membrane) of adjoining cells(Figure 1). The membranes are separated by an ECD (extracellulardomain) approx. 30 nm wide and bisected by a dense midline.Each plaque comprises an ODP (outer dense plaque), 15–20 nmthick, adjacent to the PM (approx. 7 nm thick), an 8 nm electron-lucent zone and an IDP (inner dense plaque), less dense than theODP, but also 15–20 nm thick. Isolated desmosomes are irregularin shape (Figure 2).

The plaques show periodic organization perpendicular to thePM and lamellar organization parallel to it [8,9]. Cryo-EM ofrapidly frozen human epidermis showed the ODP as an 10–11 nm region of medium electron density adjacent to the PMfollowed by two electron-dense layers with a combined thicknessof 6.7 nm, showing a transverse periodicity of 6.6 nm [10,11].The midline and plaque can also be visualized by AFM (atomicforce microscopy) (Figure 2A) [12].

COMPONENT MOLECULES

Desmosomes have five major component proteins, the DCs(desmosomal cadherins) DSG (desmoglein) and DSC (desmo-collin), the plakin family cytolinker DP (desmoplakin), and thearm (armadillo) proteins PG (plakoglobin) and PKP (plakophilin).DSC and DSG are the desmosomal adhesion molecules, DP linksthe desmosomal plaque to the IF cytoskeleton, and PG and PKPare adaptor proteins that link between the adhesion molecules andDP (Figures 3 and 4).

DSC and DSG share 30% amino acid identity with each otherand with classical cadherins [13] and have five ECs (extracellular

Abbreviations used: AFM, atomic force microscopy; AJ, adherens junction; arm, armadillo; ARVC, arrhythmogenic right ventricular cardiomyopathy;CAR, cell-adhesion recognition; DC, desmosomal cadherin; DP, desmoplakin; DSC, desmocollin; DSG, desmoglein; E, embryonic day; EC, extracellularcadherin repeat; ECD, extracellular domain; ED-SFS, ectodermal dysplasia-skin fragility syndrome; EGF, epidermal growth factor; EGFR, EGF receptor;eIF4, eukaryotic initiation factor 4; EM, electron microscopy; ERK, extracellular-signal-regulated kinase; FRAP, fluorescence recovery after photobleaching;IDP, inner dense plaque; IF, intermediate filament; Lef-1, lymphoid enhancer factor 1; MAPK, mitogen-activated protein kinase; MDCK, Madin–Darby caninekidney; NF-κB, nuclear factor κB; ODP, outer dense plaque; PF, pemphigus foliaceus; PG, plakoglobin; PKC, protein kinase C; PKP, plakophilin; PM, plasmamembrane; PV, pemphigus vulgaris; SPPK, striate palmoplantar keratoderma; Tcf, T-cell factor; WT, wild-type.

1 To whom correspondence should be addressed (email [email protected]).

c© The Authors Journal compilation c© 2010 Biochemical Society

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420 H. A. Thomason and others

Figure 1 Electron micrograph of a desmosome from bovine nasal epidermis

DM, dense midline, PM, plasma membrane; ODP, outer dense plaque; IDP, inner dense plaque;IF, intermediate filaments. Scale bar, 160 nm.

Figure 2 Structure and shape of tissue desmosomes

(A) The desmosomal plaque and midline can be visualized by AFM. AFM scan of desmosomesin a cryo-section of bovine nasal epidermis (BNE). Phase data; scan size is 800 μm × 800 μm.Note the midlines (black arrows) and plaques (red arrows). Micrograph kindly supplied byDr Nigel Hodgson and Dr Michael Sharratt. (B) Desmosomes are irregular in shape. Electronmicrograph of desmosomes isolated from BNE deposited on to an EM grid and viewed from theinner aspect of the plaque. Scale bar, 500 nm.

cadherin repeats) containing Ca2+-binding sites and a CAR(cell-adhesion recognition) site [14,15]. Homology models forthe DSC2 and DSG2 EC domains were generated using thecrystal structure of Xenopus C-cadherin as a template [16,17].These models imply that the DCs, like the classical cadherins,undergo trans-adhesive binding by strand exchange between theirN-terminal domains. This is supported by inhibition of desmo-somal adhesion with CAR-site peptides and mutation of aconserved alanine residue (Ala80) within the adhesive interface[14,15] (Z. Nie, A.J. Merritt and D.R. Garrod, unpublished work).

The cytoplasmic domains of DSGs possess a membrane-proximal region containing an intracellular cadherin-typicalregion (catenin-binding domain) and a DSG-specific regioncontaining a proline-rich region, a series of unique 29-amino-acid repeats and a terminal domain. The DSG-specific regionis disordered in solution, but shows weak specific interactionswith PG, the plakin domain of DP, PKP1 and the cytoplasmicdomain of DSC1 [18]. Alternative splicing produces ‘a’ and ‘b’

Figure 3 Structure of desmosomal proteins

(A) All DCs, of which DSC2 and DSG2 are shown, are synthesized with N-terminal signal andpro-peptides (not shown) that are cleaved during protein maturation. The CAR site contributesto the adhesive function of DCs. DSC ‘a’ proteins and DSG cytoplasmic regions contain anintracellular cadherin-like sequence (ICS) domain. A truncated version of this domain, togetherwith a number of unique amino acids (11 in human DSC2b, white box), are found in DSC ‘b’proteins. EC1–EC4, extracellular cadherin repeats; EA, extracellular anchor; TM, transmembrane;IA, intracellular anchor; IPL, intracellular proline-rich linker; RUD, repeat unit domain; DTD,DSG terminal domain. Not drawn to scale. Reproduced from [4] with permission from Elsevier.(B) PG contains 12 arm repeats, whereas the PKPs have nine with an insert between repeats 5and 6 (box) that introduces a bend into the overall structure. The two known isoforms of PKP2are shown. (C) The two DP isoforms are shown. A, B and C are plakin repeat domains. GSR,glycine/serine/arginine-rich domain.

forms of DSCs, the ‘b’ form being shorter and generated byinsertion of a mini-exon containing a stop codon. The ‘a’ formbinds PG through its catenin-binding domain, which the truncatedcytoplasmic domain of the ‘b’ form lacks [19].

There are four DSG isoforms in humans (six in mice) and threeisoforms of DSC. DSG2 and DSC2 are ubiquitous, expressed inall desmosome-bearing tissues and the predominant isoformsin simple epithelia [20,21]. In stratified epithelia, the distri-bution of DSC2 mirrors that of DSC3 (see below), whereasexpression of DSG2 is confined to the basal cells. DSG1, DSG3and DSG4 and DSC1 and DSC3 are restricted to stratified epithelia[20,22–24]. Reflecting tissue differentiation, DSG1 and DSC1are strongly expressed in the granular and spinous layers of theepidermis, and more weakly in the lower layers, whereas DSG3and DSC3 are expressed strongly in the basal and immediatesuprabasal layers, decreasing towards the stratum granulosum[3,13,25]. When co-expressed, different isoforms occur withinthe same desmosomes [25].

PG has 12 arm repeats each consisting of three α-helices (twoin repeats 1 and 7) flanked by unstructured N- and C-termini[26]. These arm repeats share 65 % amino acid identity withβ-catenin that associates with AJs (adherens junctions). PG cansubstitute for β-catenin in AJs because both bind E-cadherin withsimilar affinity, but PG has higher affinity for DSG suggestingwhy it, rather than β-catenin, locates to desmosomes [26]. Thearm repeats of β-catenin form a superhelical positively chargedgroove, the cadherin-binding site, and PG binds to E-cadherin ina similar manner [26].

PKP contains nine arm repeats flanked by an N-terminal headand a small C-terminal region [27,28]. The arm repeat region of


Desmosomes: adhesive strength and signalling in health and disease 421

Figure 4 Schematic diagram of a desmosome showing the locations of the five major proteins

Note that the cytoplasmic domain of DSG is folded within the ODP and that DP is folded within the IDP where it binds to the IF. PKP and PG act as linkers between DP and the DCs.

Figure 5 Mapping the molecules on to the structure

(A) Molecular map of the desmosome adapted from [9] showing locations of the major desmosomal components generated by immunogold EM. (B) Schematic diagram of the desmosome asobserved in unfixed rapidly frozen skin observed by cryo-EM [10] with the locations of the desmosomal components observed by North et al. [9] mapped on to it. The 11 nm area of medium electrondensity corresponds to the location of the cytoplasmic domain of the shorter ‘b’ isoform of DSC and PKP. The location of the C-termini of DSC ‘a’, PG and PKP along with the N-terminus of DP alllocate to the 6.7 nm area of greatest density.

PKP1 is sickle-shaped because of an insert between repeats 5 and6, whereas PG and β-catenin are straight [29]. The N-terminalhead is responsible for all of the known binding interactions ofPKP, including the DCs, DP and PG. PKP also interacts withkeratin and actin [30,31]. There are three main isoforms, PKPs 1and 2 having ‘a’ and ‘b’ splice variants. In both cases, the shorter‘a’ variant predominates [32,33]. p0071 (PKP4) is a memberof this group, but its association with desmosomes is debatable[34,35].

PKP1 is restricted to the differentiated layers of stratified epi-thelia [27,28]. PKP2 is found in simple, complex and stratifiedepithelia, and in cardiac myocytes, where it is the only isoform[32]. PKP3 is found in most epithelia except for hepatocytes.PKP1 and PKP2 exhibit dual localization in the nucleus, as wellas at desmosomes [33,36]. The alternative splicing of the ‘b’ form,21 amino acids longer in PKP1b and 44 amino acids longer inPKP2b may target these proteins to the nucleus.

DP has two splice variants, I and II, both consisting of a coiled-coil α-helical rod domain, shorter in DPII, flanked by globular N-and C-terminal domains. DP is predicted to form homodimers viathe coiled-coil region [37]. The C-terminal domain contains threeregions, each consisting of 4.5 copies of a 38-amino-acid plakinrepeat. These C-terminal regions form discrete subdomains thatbind IFs [38].

A systems biology approach has characterized the ‘desmo-adhesome’ [39]. This includes 59 proteins of which 30 are intrinsic

and 29 are accessory. Apart from those above, the intrinsicproteins include the plakins, envoplakin and periplakin, theepidermal late differentiation antigens, involucrin and loricrin,and several keratin isoforms. Among the accessory proteins are14 protein kinases and four protein phosphatases, which may havea role in regulating desmosomal adhesion.

MAPPING THE MOLECULES ON TO THE STRUCTURE

The challenge to elucidating desmosomal plaque structure is itselectron density, but immunogold EM has produced a molecularmap of the plaque (Figure 5A) [9]. This showed that the armproteins interact with the N-terminus of DP and the cytoplasmicdomains of the DCs in the ODP, whereas the C-terminus ofDP binds to IFs in the IDP in accordance with functionaldata [40,41]. Mapping the localization data on to the cryo-EMstructure suggests that the densities in the plaque correspond tothis same region of substantial protein–protein interaction [9–11](Figure 5B).

The structure of the ECD is clearer because it is less electron-dense. Lanthanum infiltration of guinea pig heart showed thatthe ECD contained a regular staggered array of side arms witha periodicity of 75 Å (1 Å = 0.1 nm) linking the midline to thePM [42]. In en face view, the side arms were arranged in regularrows, a quadratic array. The homology models of the DCs [17]were used to generate a three-dimensional array that appeared



to account for the midline and showed remarkable agreementwith the periodicity noted by Rayns et al. [42]. Cryo-EM ofhuman epidermis supported such an arrangement [10,11] andET (electron tomography) indicated a regular array of 3 nmdiameter densities at 7 nm intervals along the midline with acurved shape resembling the crystal structure of C-cadherin[43]. Computational fitting of the C-cadherin crystal structureon to tomograms indicated that molecules interact at the midline,forming building blocks of alternate V-shaped cis dimers andW-shaped trans dimers, resulting in a highly packed regularorganization. Immunogold labelling of the ECD with a specificantibody showed that the N-terminus of DSG3 is localized tothe midline, consistent with current views of cadherin transinteraction and molecular models of the ECD [44].

THE SPECIFICITY OF DESMOSOMAL ADHESION

Desmosomal adhesion specificity has two aspects. First, candesmosomes form non-specifically between cells of differenttypes and even from different species? The answer is definitelyyes, in both respects [45,46]. Secondly, at the molecular level, doesDSG bind to DSC and do different isoforms of DSG and DSCbind to each other? Studies with transfected cells or recombinantproteins gave equivocal answers suggesting either heterophilic orboth heterophilic and homophilic interaction [47–49]. Amagaiet al. [50] found that DSG3 can mediate weak homophilicadhesion. Single-molecule AFM using the tethered EC domainof DSG1 has revealed homophilic multivalent Ca2+-dependentlow-affinity interactions [51]. AFM has also shown a homophilicDSC3-binding and heterophilic interaction between DSC3 andDSG1, but not between DSC3 and DSG3 [52]. Work withdesmosome-forming cells seems to suggest homophilic adhesivebinding between DCs. Thus anti-adhesion peptides of bothDSG and DSC were required to block desmosome assembly bymammary epithelial cells and de novo desmosome formation hasbeen demonstrated in non-desmosome-bearing cells expressingDSG only [15,53]. Cross-linking experiments with HaCaT cellsexpressing DSC2 and 3 and DSG2 and 3 suggested that adhesivebinding is both homophilic and isoform-specific (Z. Nie, A. J.Merritt and D. R. Garrod, unpublished work)

HYPERADHESION: ITS SIGNIFICANCE AND REGULATION

A property of desmosomes that distinguishes them from otherintercellular junctions is their ability to adopt a strongly adhesivestate known as hyperadhesion [17,54]. This is characterized byCa2+-independence and resistance to disruption by chelationof EC Ca2+ [55–57]. It is the normal state of desmosomesin mammalian tissues and appears to be of key functionalsignificance, permitting desmosomes to perform their primaryrole of maintaining tissue integrity [4,17,57].

Adoption of hyperadhesion is a remarkable property of theDCs. During the early stages of culture, desmosomal adhesionis Ca2+-dependent [54,56,57], chelating agents inducing lossof adhesion by splitting desmosomes into halves. This is whatwould be expected from classical cadherin-mediated adhesions.Maintained in confluent culture, epithelial desmosomes acquirehyperadhesion without changing their molecular compositionwith respect to their major components [54,57]. How can thechange from Ca2+-dependence to Ca2+-independence occur? Apossible answer comes from studies of epidermal wound healing,as follows.

Hyperadhesive mouse epidermal desmosomes have a prom-inent midline [17]. Wounding the epidermis causes desmosomes

near the wound edge to revert to Ca2+-dependence. They thenlose the midline and the intercellular space narrows by 10% [17].This suggests that hyperadhesion is associated with the orderedarrangement of the DCs, but that reversion to Ca2+-dependenceinvolves the loss of this order. Order is associated with strongadhesion and disorder with weak adhesion.

We speculate that the DCs become locked into an orderedarrangement possibly involving entrapment of Ca2+ ions [17,54].Furthermore, the desmosomal plaque may be crucial in regulatingthe adhesive state by transducing signals that order or disorder theDCs. In this regard, desmosomal adhesiveness may be regulatedby PKCα (protein kinase Cα), activation promoting Ca2+-dependence and inhibition promoting hyperadhesion [17,57].Phosphorylation of plaque components may cause rearrangementwithin the plaque and transmit a signal to the EC domains.However, desmosomal adhesiveness may be capable ofbeing regulated by different cytoplasmic signals becauseinhibition of tyrosine phosphatases (i.e. promotion of tyrosinephosphorylation) also promotes hyperadhesion [58].

DESMOSOME ASSEMBLY

The first essentials for desmosome assembly are cell–cellcontact and specific adhesive interaction. Prevention of these bymaintaining cells at low EC Ca2+ concentration, or by blockingwith antibodies or anti-adhesion peptides, inhibits desmosomeassembly [15,55,59]. Intercellular adhesion is normally initiatedby AJs, then stabilized by desmosomes [60]. PG, which bindsto both E-cadherin and DCs, may be crucial for interactionbetween AJs and desmosomes during assembly [61]. PKP2 andp120 catenin also associate with both desmosomal and classicalcadherins and may be involved in sorting AJ and desmosomalcomponents during junction assembly [28]. Nectin-1, which hasbeen shown to participate in AJ assembly, has now also beenshown to be involved in desmosome assembly in the enamel-forming epithelium of mouse incisors [62].

The DSC ‘a’ domain supports desmosomal plaque assembly,recruiting both PG and DP to the PM [63]. The ‘b’ form, however,cannot, leaving the function of the ‘b’ form unresolved. The ‘b’form has been shown to bind PKP3 [64], but zebrafish lacks a ‘b’form, yet can assemble apparently normal desmosomes (X.-M.Luan, A. Hurlstone and D. R. Garrod, unpublished work). DSGalso binds PG, and this binding is crucial for its incorporation intodesmosomes [65]. DSG, like DSC ‘a’, can support desmosomalplaque assembly because desmosomes assemble in cells lackingDSC [53]. All mammalian desmosomes appear to contain at leastone isoform of DSG and DSC ‘a’ and ‘b’.

PG and PKP are crucial for normal plaque assembly. Deletionor loss-of-function of either gives rise to diminished plaqueswith loss of DP and IF attachment [66–68] (Tables 1 and 2),demonstrating that these proteins link between the DCs and IFsvia DP. In the fatally defective hearts of mid-gestation PG−/−

mice, desmosomes were absent, but extended AJs containeddesmosomal components [69] (Table 1). The C-terminus of PGplays a role in regulating desmosome size; its deletion results inthe formation of extremely long junctions [70].

The arm repeat domain of PKP1 contains a basic patchthat could be responsible for ligand binding [38]. Nevertheless,expression studies suggest that the unstructured N-terminusrecruits DP to the desmosome, whereas the C-terminus recruitsPKP itself to the PM [30,71,72]. A role for PKP in mediatinglateral interactions between desmosomal components has beenpostulated [72].



Table 1 Desmosomal mutant mice

Desmosomal component Type of mutation Phenotype Reference

Dsp Global knockout Die at E6.5 [114]Display abnormalities in desmosomal assembly/stabilityShow a reduction in cell proliferation

Tetraploid rescue of Dsp knockout Die shortly after gastrulation (up to E10) [115]Exhibit major defects in the heart muscle, neuroepithelium, skin

epithelium and microvasculatureConditional knockout under control of the K14 promoter Show epidermal separation upon mechanical stress most prominent

in the basal layer[116]

Desmosomes lack attachment to intermediate filamentsOverexpression of Dsp V30M and Q90R mutations under control of

α-myosin heavy chain promoterDie before E13.5 displaying cardiac abnormalities [185]

Overexpression of mutant Dsp (R2834H) under control of theα-myosin heavy chain promoter

Develop cardiac defects with increased cardiomyocyte apoptosis,cardiac fibrosis and lipid accumulation

[185]

Disrupted DSP–desmin interaction at intercalated discsJup Global knockout Die between E10.5 and birth [117]

Develop severe heart defects, skin blistering and subcornealacantholysis

[69]

Show defects in desmosome number and morphologyOverexpression under control of the K14 promoter Stunted hair growth through the premature termination of anagen [189]

Reduced epidermal proliferation and apoptotic changesPkp2 Global knockout Die at E11 owing to altered heart morphogenesis [67]

DP dissociates from plaques of the AJs between cardiomyocytesDsg2 Global knockout Die shortly after implantation [126]

Desmosomal-independent changes in embryonic stem cellproliferation

Overexpression under control of the involucrin promoter Display epidermal hyperkeratosis with extensive epidermalhyperplasia, intra-epidermal skin lesions

[127]

More susceptible to chemically induced carcinogenesis [128]Dsg3 Global knockout Normal at birth, but develop suprabasilar acantholysis of the oral

mucosa leading to oral lesions[131]

Crusting and suprabasilar acantholysis of traumatized skinHair loss in telogen from postnatal day 20

Overexpression of �N-DSG3 under control of the K14 promoter Newborn pups develop swelling of their paws, flakiness on their backand blackening of the tail tip

[169]

Exhibit defects in desmosome number and morphologyHyperproliferative epidermis with thicker spinous and stratum

corneum layersMisexpression under control of the involucrin promoter Die shortly after birth from severe dehydration [132]

Abnormal stratum corneum with gross scaling and premature loss ofcohesion of corneocytes

Misexpression under control of the K1 promoter Exhibit flaky skin accompanied by epidermal pustules and thinninghair from 12 weeks of age

[133]

Acanthosis, hypergranulosis, hyperkeratosis, localized parakeratosisaffecting the epidermis and abnormal hair follicles observed

Dsg3 and P-cadherin Double knockout Normal size at birth, but notably smaller at 1 week of age and diebefore weaning

[186]

Severe oral lesions are more prevalent and occur earlier than inDsg3−/− mice

Dsc1 Global knockout Born with eyes open and develop flaky skin with punctate barrierdefects

[142]

Acantholysis in the granular layer, resulting in epidermal fragilityDevelop ulcerating lesions resembling chronic dermatitisExhibit localized hair loss from 6 weeks of age

C-terminal truncation of Dsc1a/b Mutant protein integrates into the desmosomal plaque [184]No abnormal phenotype detected

Dsc1a Misexpression under control of the K14 promoter No abnormal phenotype observed [187]Dsc3 Knockout Die before E2.5, before the formation of mature desmosomes [146]Dsc3a and Dsc3b Misexpression under control of the K1 promoter Develop ventral alopecia from the first postnatal hair cycle [170]

Exhibit a hyperproliferative epidermis and altered epidermaldifferentiation

Acanthosis, hypergranulosis and hyperkeratosis affects the epidermisDsg1 and Dsg3 Exfoliative toxin A inactivation of Dsg1 Loss of anagen hairs 4 h after Dsg1 inactivation [188]

Separation between the outer and inner root sheath of the hair follicle

DP mediates attachment between the plaque and the IFs, its N-terminus being associated with the ODP and its C-terminus withIF binding at the IDP [9,40,41,73]. During desmosome assembly,

DP can be recruited to contact zones from both diffusible andparticulate cytoplasmic pools by an actin-dependent mechanismand involving association with PKP2 [74].



Table 2 Human desmosomal mutations

AI, autoimmune disease; CH, compound heterozygosity; D, dominant; FS, frameshift; IGD, intragenic deletion; LV, left ventricular; M, missense; N, nonsense; R, recessive; S, splicing; VA, ventriculararrhythmias.

Desmosomalcomponent Disease OMIM entry Phenotype Inheritance Type(s) of mutation Reference(s)

DSP ARVC 607450 ARVC with or without LV involvement D M, N, FS, S [144,185,190]Carvajal syndrome 605676 Woolly hair, keratoderma and cardiomyopathy

predominantly affecting LVR FS [108,109]

Striate palmoplantar keratoderma 125647 Striate palmoplantar keratoderma D N [107]Lethal acantholytic epidermolysis

bullosa609638 Epidermolysis, generalized alopecia, absence

of nails and presence of neonatal teethR M, FS, CH [73]

Skin fragility woolly-hair syndrome 607655 Keratoderma woolly hair and nail dystrophy R M, N [110]Naxos-like disease Bullous dermatosis, plantar keratoderma,

woolly hair, alopecia and ARVC with orwithout LV involvement

R M, N, CH [111,113]

JUP Naxos disease 601214 ARVC, woolly hair and keratoderma R FS [119]PKP1 Ectodermal dysplasia-skin fragility

syndrome604536 Skin fragility, inflammation, scanty hair,

reduced sweating and astigmatismR FS, N, S, CH [66,99,100]

PKP2 ARVC VA, syncope and sudden cardiac death R FS, N, M, S [103,104]DSG1 Striate palmoplantar keratoderma 148700 Linear hyperkeratosis on the digits and

hyperkeratosis on the palms and solesD FS, N, M [120–122]

DSG2 ARVC VA, syncope and sudden cardiac death D and R FS, S, N, M, CH [124,125,144]DSG4 Autosomal-recessive hypotrichosis 607903 Fragile, short, sparse hairs on the scalp, trunk

and extremitiesR IGD, M [23,134,191]

Recessive monilethrix 252200 Fragile brittle hair resulting in dystrophicalopecia; hair-shaft abnormalities resemblemoniliform hair

R FS, S, M, N [136]

DSC2 ARVC VA, syncope and sudden cardiac death D M [143]ARVC, palmoplantar keratoderma,

woolly hairARVC with LV involvement associated with

palmoplantar keratoderma and woolly hairR FS [145]

DSC3 Hypotrichosis with recurrent skinvesicles

613102 Sparse, fragile hair on scalp, absent eyebrowsand eyelashes and large fluid-filledvesicles in the skin

R N [148]

DESMOSOME STABILITY AND TURNOVER

Maintenance of tissue integrity demands that desmosomes shouldbe both strongly adhesive and stable. Their remarkable stabilityin cultured cells was demonstrated by monitoring the behaviourof fluorescently labelled DSC2a incorporated into desmosomes[75]. Desmosomes were relatively immobile and maintained theirstructural integrity for long periods throughout the cell cycle.Only minor destabilization was evident during mitosis, confirmingearlier work [76]. However, significant turnover of DSC2a waspossible as FRAP (fluorescence recovery after photobleaching)showed a half-life of approx. 30 min [75].

However, there is a conflict between maintaining stability andtissue integrity and the continual need for tissue remodelling(e.g. embryonic development, wound re-epithelialization andcell renewal in the epidermis and the intestinal mucosa).Cells at different levels within the epidermis have desmosomeswith differing composition of DCs [25]. Given the FRAPresults of Windoffer et al. [75], this could occur by molecularexchange within existing desmosomes or may require completeddesmosomal turnover.

As far as we are aware, the only documented mechanism fordesmosome down-regulation in tissues is the internalization bycells of entire desmosomes. One cell of a pair internalizes thewhole desmosome, including the plaque and a small amount ofimmediately adjacent cytoplasm of its neighbour. This occurs inseveral situations, including wound healing and neoplasia [17].This may involve a type of phagocytosis where one cell of apair produces cytoplasmic processes that engulf the desmosomeand internalize it into a vacuole [77]. Consistent with this is the

observation that internalization of desmosomal halves formed byloss of desmosomal adhesion by cultured cells following Ca2+

depletion, a process which also involves engulfment in vacuoles,requires actin [78].

The fate of such desmosomes or desmosomal halves onceinternalized is far from clear. They are presumably degraded,although by what route is uncertain [79]. Although the evidenceis not entirely conclusive it seems unlikely that they disassembleand their components are reutilized [75,80].

Because of its importance in tissue remodelling, it seems thatfurther work on the mechanism of desmosome down-regulationin vivo is urgently required.

PHOSPHORYLATION AND DESMOSOME REGULATION

There are several ways in which phosphorylation is believed toregulate aspects of desmosome function. PKCα is a conventionalPKC isoenzyme and serine/threonine kinase. It localizes to theODP of wound-edge epidermal desmosomes, most of which areCa2+-dependent, but is absent from hyperadhesive desmosomes[17]. The PKC target proteins involved in this regulation arecurrently unknown. The ProteinPredict program of ExPASyindicates many potential PKC-target motifs, as follows: fourDSC2a cytoplasmic domain; 13 DSG2 cytoplasmic domain; 13PG; 21 PKP1; 64 DPI. All of these proteins (not necessarily thesame isoforms) have been shown to be serine-phosphorylatedunder certain circumstances [41,81–85]. To provide evidenceof how phosphorylation regulates hyperadhesion, we mutatedconserved sites in the cytoplasmic domains of DSG2 and DSC2a



and expressed the mutants in MDCK cells (see [86] for moredetails). This produced a modest increase in hyperadhesion, whichwas enhanced by depletion of the endogenous protein. It seemslikely that the regulation is complex, possibly involving multipletargets.

Activation of PKC has been reported to enhance bothdesmosome assembly and disassembly [87,88]. Recently,formation of a complex between PKP2, DP and PKCα wasdemonstrated during desmosome assembly in cultured cells [89].This may involve phosphorylation by PKCα of Ser2849 of DP, asite that had been shown previously, when phosphorylated, tonegatively regulate the DP–IF interaction [41]. It is not clearwhether this is relevant in vivo as PKCα−/− mice, which areviable, assemble normal desmosomes with attached IFs (T. E.Kimura and D. R. Garrod, unpublished work).

Phosphorylation of PG has been reported to affect itsdistribution between the soluble and insoluble pools, that in thesoluble pool being both serine- and threonine-phosphorylated,whereas insoluble PG was primarily phosphorylated on serine[83].

AJ adhesion is generally down-regulated by tyrosinephosphorylation by Src family kinases [90]. The situation withdesmosomes is less clear. Tyrosine phosphorylation can causea modest destabilization of desmosomes. Treatment of A431cells with EGF (epidermal growth factor) induces tyrosinephosphorylation of PG and DSG2, together with a modestdecrease in cytoskeletal association of PG [91,92]. Furthermore,tyrosine-phosphorylated PG does not associate with DP. Theseeffects are inhibited by treatment with EGFR (EGF receptor)inhibitor [93]. In contrast, treatment of cells with the tyrosinephosphatase inhibitor sodium pervanadate caused tyrosinephosphorylation of the major desmosomal components DSG2 andPG in both the soluble and the insoluble cell fractions, withoutaffecting their complex formation and, surprisingly, inducedhyperadhesion [58]. Collectively, these observations suggest thatthe role of tyrosine phosphorylation in regulating desmosomaladhesion is complex. Indeed tyrosine phosphorylation of PGat different sites by different kinases causes differential effects[94]. Thus Src phosphorylates Tyr643, decreasing PG binding toE-cadherin and α-catenin, whereas Fer phosphorylates Tyr549,increasing PG binding to α-catenin. Furthermore, PG suppressesSrc activity and cell motility [95].

Phosphorylation of desmosomal components may be importantin skin disease. Treatment of squamous carcinoma cells withPV (pemphigus vulgaris)-IgG induced serine phosphorylationof DSG3 and its dissociation from PG [96]. Furthermore arapid sustained increase in PKC activity occurred upon PV-IgG binding to DSG3, suggesting that PV-IgG is able to inducePKC activation [97]. However, PMA activation of PKC did notcause phosphorylation of DSG3 and the use of PKC inhibitorscaused only a partial inhibition of DSG3 phosphorylation at best,suggesting that another kinase may be responsible for PV-IgG-induced phosphorylation of DSG3 [84].

DISEASES AND MOUSE MODELS: THE FUNCTION OFDESMOSOMES AND THEIR COMPONENTS

As the primary function of desmosomes is that of strong adhesion,it is not surprising that mutations in genes encoding desmosomalproteins are responsible for diseases in which cell adhesionis compromised [98]. The identification of these mutationshas highlighted the importance of desmosomes in ectodermalintegrity, hair follicle development and cardiac function. Also,

striking similarities manifest between abnormalities in patientsand the phenotypes of mutant mice (Tables 1 and 2).

Plakophilins

The first disorder found to result from a desmosomal proteingene mutation was ED-SFS (ectodermal dysplasia-skin fragilitysyndrome) (OMIM 604536), characterized by skin fragility,inflammation and abnormalities in ectodermal development,including scant hair, reduced sweating and astigmatism [66].Ten cases of ED-SFS have now been reported, all resulting fromnonsense, frameshift or splice site mutations in PKP1 [99,100].

ED-SFS patients’ epidermis shows fewer, poorly formed,desmosomes [66]. Analysis of PKP1 mutations in culturedkeratinocytes indicates a role for PKP1 in desmosomal plaqueformation and stability [101]. Also, PKP1 may have a nuclearsignalling role, but whether defective signalling results in ED-SFS remains unclear [33,72].

Ablation of Pkp2 in mice resulted in embryonic lethalalterations in heart morphogenesis, caused by reduced associationof DP and PG with junctions in cardiomyocytes [67]. MutantPKP2 is unable to locate to the PM and, consequently, to recruitDP to the desmosomal plaque and IFs to cell–cell contacts [102].Subsequently, nonsense, frameshift, splice site and missensemutations in PKP2 have been identified as the major causeof ARVC (arrhythmogenic right ventricular cardiomyopathy),a disease which has a prevalence of 1/1000–1/5000 and ischaracterized by ventricular arrhythmias, syncope and suddendeath [103,104]. Some 10 % of deaths occur before the age of19, and 50% before the age of 35, making ARVC a leadingcause of cardiac sudden death in people under 35 years ofage.

Pkp3-deficient mice develop hair abnormalities and increasedsusceptibility to cutaneous inflammation [105] despite com-pensatory up-regulation of PKP1, PKP2 and DP. Whereas Pkp3−/−

mice raised in SPF (specific pathogen-free) facilities showedlimited skin alterations, Pkp3−/− mice raised in conventionalfacilities developed heightened inflammation, with large areasof epidermal hyperplasia, spongiosis, neutrophil-filled pustules,severe dermal and epidermal infiltration by immune cells, hairloss, scaling and wasting [105]. Culture experiments showedthat PKP3 associates with ribonucleoprotein particles and underenvironmental stress incorporates into ‘stress granules’ to stalltranslation initiation complexes [106]. Thus Pkp3−/− mice mayserve as a model for particular forms of dermatitis. However, nohuman PKP3 mutations have yet been reported.

Desmoplakin

In 1999, Armstrong et al. [107] mapped a disease-causingmutation of an autosomal dominant pedigree with SPPK(striate palmoplantar keratoderma) (OMIM 125647) to 6p24.3,where the DSP gene resides. Sequence analysis revealedheterozygous nonsense and splice site mutations in DSP leadingto haploinsufficiency [107]. These findings indicate that a 50 %loss of DP is sufficient for normal development and function ofnon-palmoplantar skin, but insufficient to maintain normal skinon the palms and soles.

The first reported autosomal recessive mutation in DSP, a dele-tion at the 3′ end of the gene, resulted in a DP protein lacking itsC-terminal domain [108]. This gave rise to Carvajal syndrome(OMIM 605676), a rare disorder comprising woolly hair,keratoderma and left ventricular cardiomyopathy [108,109].Subsequently, compound heterozygous nonsense–missense



mutations were found in patients exhibiting woolly hair andkeratoderma, but no cardiomyopathy, termed skin fragilitywoolly-hair syndrome (OMIM 607655) [110]. A compoundheterozygous nonsense frameshift mutation that truncates DSPhas been identified in a single case of lethal acantholysisepidermolysis bullosa (OMIM 609638) [73]. In addition,homozygous missense mutation in DSP have been identifiedin patients with isolated cardiomyopathy, whereas homozygousmissense mutations and compound heterozygous nonsensemutations have been identified in patients with a combinationof woolly hair, keratoderma and ARVC [111–113]. Thus thegenotype–phenotype correlation of DP mutations is complex andpoorly understood.

The lethality of Dsp−/− mice at E (embryonic day) 6.5 precludestheir use in determining the functional importance of DP in heartand skin development [114]. Partial rescue of Dsp−/− embryos upto E10 using the tetraploid aggregation approach revealed majordefects in heart muscle, neuroepithelium and skin epithelium, aswell as in the microvasculature [115]. Conditional ablation ofDsp using K14-Cre highlighted the role of DP in desmosomaladhesion in the epidermis. At birth, the epidermis of these mutantmice peels, leaving areas of denuded skin [116]. Desmosomes inaffected regions lacked an IDP and failed to attach to the kera-tin cytoskeleton, indicating the importance of DP in maintainingcytoskeletal architecture to reinforce stable intercellular adhesion.

Plakoglobin

As with DP, PG also plays an important role in heart, skin andhair development. Pg−/− mice display severe cardiac defects,causing death at E10.5. The few mutant pups that survive tobirth (on a C57BL/6 background) display skin blistering andsubcorneal acantholysis [117]. In addition, Coonar et al. [118]mapped Naxos disease (OMIM 601214), an autosomal recessivedisorder characterized by ARVC, woolly hair and keratoderma ina family originating from the Greek island of Naxos, to 17q21, alocus containing the JUP, the gene encoding PG. Subsequentlymutations in JUP were described; a homozygous 2 bp deletionwas found in 19 patients diagnosed with Naxos disease [119].The prevalence of Naxos disease on the Greek islands may be ashigh as 1/1000, but patients with Naxos disease have also beenidentified in Turkey, Israel and Saudi Arabia.

Desmogleins

A number of pathogenic splice site and frameshift DSG1mutations, believed to cause haploinsufficiency, cause SPPK(OMIM 148700) [120–123]. The patients’ skin exhibits fewer,smaller, desmosomes and loss of IF attachment.

In contrast with DSG1 mutations, patients harbouring mutationsin DSG2 exhibit cardiac defects, but no skin abnormalities.DSG2 mutations may account for 5–10% of ARVC andinclude dominantly inherited frameshift, splice site, nonsenseand missense mutations, mostly in the EC domain [124,125].Transgenic mice overexpressing the ARVC mutation DSG2N266S recapitulate the ARVC phenotype, including spontaneousventricular arrhythmias, cardiac dysfunction, biventriculardilatation, aneurysms and sudden premature death.

Global knockout of Dsg2 in mice is embryonic lethal shortlyafter implantation, indicating a non-desmosomal role for DSG2 inembryonic stem cell proliferation and embryonic survival [126].In contrast, overexpression of Dsg2 under control of the involucrinpromoter results in epidermal hyperplasia and hyperkeratosis,which developed into intra-epidermal skin lesions [127].

Although no human DSG3 mutations have been identified,autoantibodies against DSG3 are the cause of PV (discussedbelow). Dsg3−/− mice and the PV mouse model presentsimilar suprabasal acantholysis [128,129]. Dsg3−/− mice exhibitreduced PG levels in the desmosomal plaque. The acantholysisobserved in Dsg3−/− mice is therefore believed to arise throughfragility of desmosomes lacking DSG3 [130]. In contrast, thelevels of desmosomal components of the PV mouse modelare unaltered, indicating a different mechanism of acantholysispossibly involving altered DP localization and thus IF retraction[130]. In addition to its role in epidermal integrity, transgenicmouse models of Dgs3 have identified clear roles for thisprotein in hair-shaft anchorage and epithelial differentiation[131–133].

DSG4 mutations cause the rare disorders autosomal recessivehypotrichosis (OMIM 607903) and recessive monilethrix.Although listed as distinct entities, both result from mutationsin the DSG4 EC domain and there is considerable phenotypicoverlap. A homozygous intragenic deletion in a patient withhypotrichosis, a disease characterized by abnormal hair growth,has since been found in several Pakistani families [23,134]. Inaddition, a homozygous missense mutation has been identifiedin a conserved motif known to be important for cell adhesion[135]. Following on from this, a variety of mutations in DSG4,including frameshift, splice site, missense and nonsense mutationswere identified. In these cases, the patients were reported tosuffer from autosomal recessive monilethrix, a disease causedby structural defects of the hair shaft, usually inherited in anautosomal dominant fashion by mutations in the keratin geneshHb1, hHb3 and hHb6 [136–138].

Mutations in mouse and rat Dsg4 result in the lanceolate hairphenotype, characterized by sparse, fragile, broken hair shafts,ichthyosiform dermatitis and follicular dystrophy [139,140].Furthermore, a mutation in Dsg4 causes hypotrichosis inEODhage mice, an inbred strain characterized by the completeabsence of hair on the trunk and mast cell hyperplasia [141].These observations highlight an important role for DSG4 anddesmosomes in the regulation of hair growth.

Desmocollins

Dsc1 knockout in mice causes defects of the skin which becomeapparent 2 days after birth [142]. Affected skin is flaky withpunctate barrier defects that develop acantholysis in the granularlayer leading to localized lesions and epidermal fragility. By6 weeks of age, these lesions resemble chronic dermatitis andlocalized hair loss is observed. Unlike the global loss of Dsc1,mutant mice carrying a C-terminally truncated form of Dsc1a/bdo not display an abnormal phenotype despite the fact that themutant protein integrates into desmosomes, suggesting thatthe C-terminus is not required for desmosomal stability. No humanDSC1 mutations have been described.

DSC2 is the only DSC isoform expressed in cardiac tissue, andheterozygous mutations in DSC2 have been identified in patientswith isolated ARVC. Thus ARVC can result from mutations inat least five desmosomal protein components, JUP, DP, PKP2,DSG2 and DSC2 [143,144]. The N-terminal DSC2 mutant proteinexpressed in cultured cells resides predominantly in the cytoplasmand is unable to incorporate into desmosomes. However, it is yet tobe determined whether these mutations result in loss-of-functionnull alleles through cytoplasmic degradation or in a dominantgain-of-function manner [143]. More recently it was shown thatthe triad of ARVC associated with SPPK and woolly hair can alsoresult from frameshift mutations in DSC2 [145].



Dsc3−/− mice, which are embryonic lethal, die before theformation of mature desmosomes and therefore fail to providean insight into the importance of DSC3 in desmosomal adhesion[146]. To overcome this problem, Chen et al. [147] utilized K14-Cre to ablate Dsc3 in the epidermis and found that mutant pupsdevelop severe epithelial blisters induced by mild mechanicalstress and cyclic hair loss in adulthood. Acantholysis was observedbetween basal–basal and basal–suprabasal keratinocytes, withdesmosomes splitting in the midline. No differences wereobserved in the levels and localization of other desmosomalprotein components, suggesting that DSC3 in the epidermis isrequired for desmosome stability [147]. A homozygous nonsensemutation was identified in a family affected with hereditaryhypotrichosis. Affected individuals exhibited sparse and fragilehair on the scalp, absent eyebrows and eyelashes and large skinvesicles filled with watery fluid [148]. Thus DSC3 plays a role inepidermal integrity and hair development.

PF (pemphigus foliaceus) and PV

Autoantibodies against DSG1 appear to cause PF and fogoselvagem, and those against DSG3 or DSG3 and DSG1 cause PV[149–151]. Patients with PF and fogo selvagem have epidermalblisters within the granular layer or beneath the stratum corneum,whereas PV blisters occur just above the basal layer. Thesedefects correlate with the expression profile of the cadherins,with increased DSG1 in the upper epidermis and DSG3 highestin the basal layer [152].

How the autoantibodies cause acantholysis remains controver-sial. One argument is that autoantibodies bind to the EC domainsof the DCs impeding their adhesive function [51,153]. Heupelet al. [154] demonstrated that PV-IgG directly inhibits DSG3trans-interactions. Upon binding of PV-IgG, both DSG3 and PGwere rapidly internalized in a complex which does not containDP and retraction of the IFs from the cell borders occurred[155]. Caldelari et al. [156] demonstrated that PG is essentialfor PV-IgG to elicit this effect. Although both PG−/− and WT(wild-type) keratinocytes could bind the DSG IgG, onlyWT keratinocytes lost desmosomal adhesion and IF attachment.

In contrast, PF autoantibodies against DSG1 alter intracellularsignalling before reducing cell-surface levels of DSG1 [51].Waschke et al. [157] demonstrated that p38 MAPK (mitogen-activated protein kinase) phosphorylation facilitates the retractionof IFs and loss of adhesion observed following treatment withDSG3 autoantibodies. Investigations of PV murine models haveshown that inhibitors of tyrosine kinases, phospholipase C,calmodulin and PKC all impaired the development of acantholysisin mice, indicating that a broad range of signalling cascadesare involved [158]. Further studies have demonstrated that PG-mediated inhibition of c-Myc transcription is prevented by PV-IgGbinding, resulting in increased intracellular c-Myc concentrations[159].

Alternative views are that the primary cause of acantholysismay be induction of apoptosis or loss of interdesmosomaladhesion. Culture studies have shown that exposure to pemphigusautoantibodies induces apoptosis resulting in acantholysis [160–162]. In vivo studies of PF found apoptotic cells in the epidermis,increased expression of pro-apoptotic factors and reduced anti-apoptotic factors. Activated caspase 3 was detected in theepidermis before blister development and a peptide-based caspaseinhibitor blocks blister development [163].

A review of the literature on the EM of PV shows thatdirect disruption of desmosomal adhesion is not the primaryevent [164]. Rather, there is loss of cell–cell adhesion in

interdesmosomal regions and possible intracellular cleavagebehind the desmosomal plaque that might indicate a weakeningof the cytoskeleton, perhaps through a signalling mechanisminvolving PG [68,164].

Treatment of keratinocytes with PV autoantibodies in cultureshowed that desmosomes are down-regulated and that DSG3is depleted and internalized [124,165,166]. However, this workwas presumably carried out with keratinocytes possessing Ca2+-dependent desmosomes, which do not represent the in vivosituation. A study in which keratinocytes with Ca2+-dependentor hyperadhesive desmosomes were compared showed thathyperadhesion inhibited PV autoantibody-induced acantholysisand internalization of adhesion molecules, including DSG3 andE-cadherin [167]. These observations are consistent with the viewthat down-regulation of desmosomes is not the primary event.

It has been shown that PV autoantibodies activate Src [166].We hypothesize that autoantibodies may activate Src causing lossof inter-desmosomal adhesion in the epidermis by disrupting AJs,and that this may cause secondary loss of desmosomal adhesionand acantholysis.

OTHER ROLES FOR DESMOSOMES: DEVELOPMENT,DIFFERENTIATION, PROLIFERATION AND APOPTOSIS

In 1996, having demonstrated the remarkable reciprocal distri-butions of DSC1 and DSC3 in epidermis, we suggestedthat they may be responsible for regulating cell positioningand/or generating positional information that regulates celldifferentiation, the latter possibly involving PG or β-catenin [25].In the same year, targeted expression of �N-DSG3 was shownto cause changes in the epidermis, including hyperproliferation[169]. Subsequently, there have been several indications thatdesmosomes contribute to cellular development and behaviourthrough signalling processes.

Desmosomes are essential for embryonic development.Deletion of the genes for PG, PKP2 or DP in mice results inembryonic death principally because of failure of intercellularadhesion (see Table 1 and above). On the other hand, the earlyembryonic lethal effects caused by deletion of Dgs2 or Dsc3are more probably due to signalling defects. Deletion of Dsg2causes death at around the time of implantation because of adefect in embryonic stem cell proliferation, whereas deletionof Dsc3 causes death before E2.5, which precedes the time offirst desmosome assembly in the trophectoderm of the blastocyst[126,146]. Of further developmental significance may bethe demonstration that desmosomal adhesion regulates cellpositioning during mammary gland morphogenesis [15].

Several mouse desmosomal mutations give rise to cellproliferation changes. Thus failure of egg cylinder elongationin Dsp−/− mice was associated with hypoproliferation, whereasepidermal hyperproliferation was noted in Dsc1−/−, K1-Dsg3,K1-Dsc3 and Inv-Dsg2 mice [114,127,133,142,170] (Table 1).Whether such effects are primary, a direct consequenceof the desmosomal changes, or secondary, a response tothe effect on tissue caused by adhesive changes, is notcertain, but culture assays are consistent with the idea thatprimary Dsc1−/− keratinocytes are hyperprolifative (M.A.J.Chidgey, personal communication). Such mutations are alsoassociated with differentiative changes, including hyperkeratosis,abnormality of hair follicles and altered keratin expression[114,127,133,142,170] (Table 1). Inv-Dsg3 mice have anabnormal stratum corneum and lethal epidermal barrier defects,whereas Inv-Dsg2 keratinocytes show resistance to apoptosis



[127,132]. The latter mice also showed increased susceptibility tochemically induced carcinogenesis [127].

The above epidermal changes have been shown to be associatedwith activation of various signalling pathways. Hardman et al.[170] found increased β-catenin signalling in K1-Dsc3 mice andsimilar changes were subsequently found in Dsc1−/− and K1-Dsg3mice (A.J. Merritt, M.J. Hardman and D.R. Garrod, unpublishedwork). Brennan et al. [127] found enhanced activation of multiplegrowth and survival pathways in Inv-Dsg2 mice, includingPI3K (phosphoinositide 3-kinase)/Akt, MEK [MAPK/ERK(extracellular-signal-regulated kinase) kinase]/MAPK, STAT3(signal transducer and activator of transcription 3) and NF-κB (nuclear factor κB). In a culture model, DSG1 promoteskeratinocyte differentiation in an adhesion-independent mannerand through suppression of EGFR–ERK1/2 signalling [171]. Itwill be interesting to learn whether this mechanism is relevantin vivo. DP has been shown to play a role in differentiation-relatedreorganization of microtubules in epidermis through recruitmentof the centriolar protein ninein [172]

Inv-Dsg2 keratinocytes showed enhanced survival dependenton EGFR activation and NF-κB activity [127]. This may representan in vivo demonstration of previous results implicating DSGs inthe regulation of apoptosis. Both DSG1 and DSG2 are caspase 3targets and play apoptosis-promoting roles [173,174]. PG has alsobeen implicated in the regulation of apoptosis, but it is unclearwhether by promotion or inhibition. Dusek et al. [175] showedthat deletion of PG protected keratinocytes from apoptosis bysuppressing Bcl-XL expression, whereas Li et al. [176] showedthat overexpression of PG inhibited apoptosis by inducing Bcl-2expression.

PG has important and diverse roles in transcriptional regulationin addition to its above role in apoptosis. The role of its closerelative, β-catenin, is well known [177,178]. Activation of theWnt signalling pathway or mutation of members of the β-catenindegradation complex, e.g. in adenomatous polyposis coli, causeelevation of cytoplasmic levels of β-catenin, which then enters thenucleus and, in complex with Tcf (T-cell factor)/Lef-1 (lymphoidenhancer factor 1) transcription factors, regulates gene expression,for example up-regulation of the proto-oncogene c-Myc [179].PG can play a similar role. It is a strong activator of the c-Mycpromoter, indicating a possible role in cancer [180]. However, inother situations, PG represses c-Myc transcription [159,181]. Thisis important in relation to the initiation of keratinocyte terminaldifferentiation, with suppression of c-Myc promoting cell cycleexit [159]. Transcriptional repression by PG is mediated throughbinding to Lef-1 and involves a Tcf/Lef-1-binding site in thec-Myc promoter distinct from those involved in c-Myc activation,which is mediated by PG binding to Tcf-4 [159,181]. Whichfunction PG performs may depend upon the relative levels ofTcf/Lef-1 transcription factors [181].

PKP has both structural and signalling roles. In additionto their desmosomal localization, PKPs 1 and 2 localize tothe nucleus. The nuclear localization of PKP2 is regulated byCdc25C-associated kinase 1, which phosphorylates it, promotingits association with a 14-3-3 protein and nuclear entry [85].The nuclear role of PKPs is not entirely clear. PKP2 occursin complexes with RNA polymerase III in nuclear particlesand could play a role in regulating transcription of rRNA andtRNA [32]. PKP3 has been identified in cytoplasmic particlescontaining the RNA-binding proteins poly(A)-binding protein1, fragile-X-related protein and Ras-GAP (GTPase-activatingprotein)-SH3 (Src homology 3)-binding protein. In addition, theseproteins were found to be associated with PKP3 or PKP1 instress granules following heat shock along with eIF4 (eukaryoticinitiation factor 4) E and the ribosomal protein S6 [106]. The role

of PKP in the regulation of translation initiation has recentlybeen observed by Wolf et al. [182] who show that PKP1associates directly with eIF4A and stimulates eIF4A-dependenttranslation. Overexpression of PKP2 also up-regulates Wnt/β-catenin signalling in cultured cells [183].

Taken together, the above considerations indicate an importantrole for several desmosomal components in signalling events andit will be fascinating to discover how they contribute to tissuedevelopment and homoeostasis.

FUTURE PERSPECTIVES

Since the biochemical and molecular characterization ofdesmosomes began in the early 1980s, much has been learnedabout the interactions and functions of their component moleculesas well as their assembly, down-regulation and signalling roles,and their contributions to human disease. However, manyquestions remain. Of crucial importance is the realization thatdesmosomes in tissues exhibit Ca2+-independent adhesion, whichis strongly adhesive or ‘hyperadhesive’. This is fundamental totissue strength. Almost all studies in culture are done on weaklyadhesive Ca2+-dependent desmosomes, although hyperadhesioncan be readily obtained in confluent cell culture. Ca2+-dependenceis a default condition in vivo, found in wounds and embryonicdevelopment.

In order to understand the molecular basis of hyperadhesion, itwill be necessary to determine how the structure and molecularinteractions within desmosomes give rise to this adhesivestrength. Hyperadhesion appears to be associated with an orderedarrangement of the ECDs of the DCs, which gives rise to theintercellular midline identified in ultrastructural studies. We needto determine the specific properties of desmosomal componentsthat enable them to generate hyperadhesion and how theseproperties differ from those of the components of AJs, whichdo not become hyperadhesive. Two technical problems will haveto be solved in order to gain this information: first, how toresolve the structure of desmosomes with molecular resolution,and, secondly, how to analyse regulatory changes, primarilyphosphorylation events, that occur within desmosomes, giventheir extreme insolubility. Both of these will be helped by greaterknowledge of the structure of desmosomal molecules. In order tounderstand tissue dynamics, much more needs to be known aboutthe mechanisms of desmosome assembly and down-regulationin vivo.

With regard to the signalling roles of desmosomes, for whichevidence appears to be accumulating, we need to know whethersuch signals are generated from within intact hyperadhesivedesmosomes, or whether individual desmosomal componentshave a life outside of desmosomes. We also know virtuallynothing about the mechanisms involved. As with considerations ofadhesion, it is essential to focus on the situation in vivo. Increasedknowledge of structure–function relationships, its regulation andsignalling mechanisms will enhance our understanding of theroles of desmosomes in human disease leading in due course tothe development of novel therapies.

FUNDING

We thank the Medical Research Council [grant numbers G0700074 and G08000041] andthe Wellcome Trust [grant number 086167/Z/08/Z] for financial support.

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Received 22 April 2010/17 May 2010; accepted 1 June 2010Published on the Internet 14 July 2010, doi:10.1042/BJ20100567


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Desmosomes: adhesive strength and signalling in health and disease

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