ReviewDesmosomal cadherins
Introduction
Desmosomes are adhesive intercellular junctions and linkers of the intermediate filament cytoskeleton in epithelia and cardiac muscle. The desmosomal cadherins, desmocollin (Dsc) and desmoglein (Dsg), are their adhesion molecules. Fig. 1 outlines the molecular structure of desmosomes as currently understood, and Table 1 shows the expression patterns and binding interactions of the desmosomal cadherin isoforms with other desmosomal cadherins and with their major cytoplasmic associates. Each Dsc isoform exhibits alternative splicing of the cytoplasmic domain giving rise to a longer ‘a’ form and a shorter ‘b’ form (not shown in Fig. 1). The carboxyl terminus of the ‘a’ form lies within the outer dense plaque (ODP), whereas that of the ‘b’ form is located at the extreme outer face of the ODP [1].
Several comprehensive reviews relating to desmosomes have appeared recently 2., 3., 4., 5., 6., 7., 8., 9.. We shall concentrate on desmosomal cadherins, emphasising their adhesive function, the regulation of adhesion and their role in tissue morphogenesis and disease.
Section snippets
Mechanism of adhesion
Direct demonstration of the adhesive function of the desmosomal cadherins is recent 10., 11., 12.. Two principal conclusions arose from these studies: Dsc and Dsg bind heterophilically; and Dsc, Dsg and plakoglobin (PG) represent the minimum complement of desmosomal components that can generate adhesion. Whether Dsc, Dsg and plakophilin (PP) would suffice has not yet been tested.
Dsc and Dsg show approximately 30% amino acid identity with each other and with the classical cadherins, and all have
Interdependence of desmosomes and adherens junctions
Desmosomal cadherins can initiate and maintain cell–cell adhesion in the absence of any contribution from classical cadherins [12]. However, adherens junctions arose earlier in evolution than desmosomes, are usually detected earlier in development of organisms and organ systems (for a recent example, see [19]), and assemble before desmosomes. During early adhesion of keratinocytes, filopodia of adjacent cells interdigitate, driven by actin polymerisation, generating a double row of punctate
Desmosome assembly and cytoplasmic interactions
It is not clear whether desmosome formation involves pre-assembly within the cytoplasm or takes place at the cell surface. A recent study of this issue [24•], showed that during desmosome assembly by squamous carcinoma cells, Dsg3 first forms simple clusters at the cell surface. Next, keratin intermediate filament attachment occurs and clusters are integrated into desmosomes. Ishii et al. [25] showed that incorporation of desmosomal cadherins into the desmosomes of squamous carcinoma cells was
Regulation of desmosomal adhesion
The dynamic regulation of desmosomal adhesion is not understood. Desmosomal adhesion in sub-confluent epithelial cell sheets in culture may be initiated or disrupted by raising or lowering the extracellular calcium concentration. However, in vivo extracellular calcium concentration is probably always well above that required to regulate desmosomes (about 0.1 mM). More conceivable is that intracellular calcium concentration directly or indirectly regulates desmosomal adhesion, which is perturbed
Desmosomal cadherins in cell positioning, morphogenesis and differentiation
Stratified epithelia show differentiation-related expression of different desmosomal cadherins isoforms (reviewed in [43]; Table 1). However, such expression is clearly not essential for stratification, since the corneal epithelium expresses only a single pair, Dsc2 and Dsg2 [44].
The differentiation-related expression of desmosomal cadherin isoforms raises the possibility that, in addition to their adhesive function, they may have a direct or indirect role in regulating differentiation [45].
Desmosomal cadherins and disease
In pemphigus vulgaris (PV) and pemphigus foliaceus, auto-antibodies target Dsg3 and Dsg1, respectively (reviewed in [53]). An active disease mouse model of PV has been described where splenocytes from Dsg3−/− mice immunised against Dsg3 were transferred to Rag2−/− mice, producing a PV phenotype [54••]. This model may provide a paradigm for the study of autoimmune disease. Epitope mapping studies using domain-swapped molecules revealed that both Dsg3 and Dsg1 auto-antibodies bind to specific
Conclusions
Evidence that CAR sites are functional in desmosomal cadherins raises many questions about the mechanism of desmosomal adhesion, necessitating biophysical and structural studies. The demonstration that desmosomal adhesion plays a role in morphogenesis by mammary gland cells predicts a wider involvement of desmosomes in development. Adhesion-blocking peptides may provide useful tools for investigating this. Indications that PKC and tyrosine phosphorylation regulate desmosomal adhesion may have
Acknowledgements
We thank Carolyn Byrne for helpful discussion and the Medical Research Council for financial support.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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