Andrew P. Kowalczyk

Desmosomes: Intercellular Adhesive Junctions Specialized for Attachment of Intermediate Filaments

Cell-cell adhesion is thought to play important roles in development, in tissue morphogenesis, and in the regulation of cell migration and proliferation. Desmosomes are adhesive intercellular junctions that anchor the intermediate filament network to the plasma membrane. By functioning both as an adhesive complex and as a cell-surface attachment site for intermediate filaments, desmosomes integrate the intermediate filament cytoskeleton between cells and play an important role in maintaining tissue integrity. Recent observations indicate that tissue integrity is severely compromised in autoimmune and genetic diseases in which the function of desmosomal molecules is impaired. In addition, the structure and function of many of the desmosomal molecules have been determined, and a number of the molecular interactions between desmosomal proteins have now been elucidated. Finally, the molecular constituents of desmosomes and other adhesive complexes are now known to function not only in cell adhesion, but also in the transduction of intracellular signals that regulate cell behavior.

The head domain of plakophilin-1 binds to desmoplakin and enhances its recruitment to desmosomes. Implications for cutaneous disease.

The contribution of desmosomes to epidermal integrity is evident in the inherited blistering disorder associated with the absence of a functional gene for plakophilin-1. To define the function of plakophilin-1 in desmosome assembly, interactions among the desmosomal cadherins, desmoplakin, and the armadillo family members plakoglobin and plakophilin-1 were examined. In transient expression assays, plakophilin-1 formed complexes with a desmoplakin amino-terminal domain and enhanced its recruitment to cell-cell borders; this recruitment was not dependent on the equimolar expression of desmosomal cadherins. In contrast to desmoplakin-plakoglobin interactions, the interaction between desmoplakin and plakophilin-1 was not mediated by the armadillo repeat domain of plakophilin-1 but by the non-armadillo head domain, as assessed by yeast two-hybrid and recruitment assays. We propose a model whereby plakoglobin serves as a linker between the cadherins and desmoplakin, whereas plakophilin-1 enhances lateral interactions between desmoplakin molecules. This model suggests that epidermal lesions in patients lacking plakophilin-1 are a consequence of the loss of integrity resulting from a decrease in binding sites for desmoplakin and intermediate filaments at desmosomes.

Structure and function of desmosomal transmembrane core and plaque molecules

Desmosomes are intercellular junctions that function in cell-cell adhesion and attachment of intermediate filaments (IF) to the cell surface. Desmogleins and desmocollins are the major components of the transmembrane adhesion complex, whereas desmoplakins (DPs) are the most prominent components of the cytoplasmic plaque. Based on sequence similarity, desmogleins and desmocollins are related to the calcium-dependent homophilic adhesion molecules known as cadherins. Like the classical cadherins, the desmosomal cadherins contain four homologous extracellular domains bearing putative calcium-binding sites, a single transmembrane spanning domain, and a C-terminal cytoplasmic tail. Molecules in the desmoglein subclass contain a unique C-terminal extension within which is found a repeating motif that is predicted to form two beta-strands and two turns. Stable cell lines expressing desmoglein 1 have been generated from normally non-adherent L cell fibroblasts, to study the contribution of this cadherin to desmosomal adhesion. The predicted sequence of desmoplakin (DP) I suggests it will form homodimers comprising a central alpha-helical coiled-coil rod and two globular end domains. The C-terminus contains three regions with significant homology, each of which is made up of a 38-residue motif also found in two other molecules involved in organization of IF, bullous pemphigoid antigen and plectin. Ectopically expressed polypeptides including the C-terminus of DP I specifically align with keratin and vimentin IF in cultured cells, whereas those lacking this domain do not align with IF. The last 68 amino acids of DP are required for alignment along keratin but not vimentin IF, and residues 48-68 from the C-terminal end are critical for this interaction. These results suggest that the C-terminus of DP plays a role in the attachment of IF to the desmosome and that a specific site is necessary for interaction with keratin IF. A sequence at the most N-terminal end of DP appears to be required for efficient incorporation into the desmosomal plaque. Interestingly, this region has not been reported to be present in the homologous bullous pemphigoid antigen or plectin molecules and may represent a desmosomal targeting sequence.

Desmosomes: Integrators of Mechanical Integrity in Tissues

The most prominent cell surface attachment site for intermediate filaments (IF) at epithelial cell-cell interfaces is the desmosome (reviewed in Collins and Garrod, 1994; Schmidt et al., 1994; Garrod et al., 1996; Green and Jones, 1996); see Figure 1. By anchoring IF at sites of strong intercellular adhesion, desmosomes create a transcellular network throughout the tissue, and this network is thought to resist forces of mechanical stress. The importance of the IF-cell surface complex has been highlighted by the discovery of mutations in genes encoding IF structural proteins, as well as cell junction proteins that result in blistering diseases of the skin (Steinert and Bale, 1993; Fuchs, 1994; McLean and Lane, 1995). Furthermore, autoimmune antibodies that specifically attack the desmosoma1 cadherin component of desmosomes result in a family of blistering diseases of the skin and oral cavity known as pemphigus (Stanley, 1995). Thus, these cell-cell adhesive structures and their underlying cytoskeletal attachments are clearly important for the integrity of tissues. Desmosomes are related to another class of adhesive junctions called adherens junctions, which mediate attachment of the microfilament cytoskeleton to the cell surface (Kowalczyk and Green, 1996). In adherens junctions, classic calcium-dependent cell-cell adhesion molecules (e.g., E-cadherin) are anchored to the actin cytoskeleton through a complex that includes the armadillo protein family member p-catenin. ,0-catenin binds directly to both E-cadherin and to the actin-associated protein cu-catenin. In desmosomes, two classes of desmosomal cadherins,

Chapter 10 The Desmosome: A Component System for Adhesion and Intermediate Filament Attachment

Publisher Summary This chapter describes the organization of the desmosome as a component system for adhesion and intermediate filament attachment. The chapter reviews what is currently known about the molecular components of the desmosome, an intercellular junction that mediates cell–cell adhesion and couples this adhesion to the intermediate filament (IF) cytoskeleton. Emerging information on desmosomes as targets of intracellular-signaling pathways and as sites of signal initiation is discussed in the chapter. A major function of adhesive cell–cell and cell–matrix junctions is to couple the forces of adhesion to the cytoskeleton. In addition to this structural role, it is becoming increasingly apparent that these macromolecular complexes serve to integrate mechanical and chemical signaling pathways. The identification of disease states that involve desmosomal components and the generation of transgenic animals with disrupted desmosomal genes should further understanding of the function of these proteins on the tissue level.