Structure, Function, and Regulation of Desmosomes

Abstract

Summary Desmosomes are adhesive intercellular junctions that mechanically integrate adjacent cells by coupling adhesive interactions mediated by desmosomal cadherins to the intermediate filament cytoskeletal network. Desmosomal cadherins are connected to intermediate filaments by densely clustered cytoplasmic plaque proteins comprising members of the armadillo gene family, including plakoglobin and plakophilins, and members of the plakin family of cytolinkers, such as desmoplakin. The importance of desmosomes in tissue integrity is highlighted by human diseases caused by mutations in desmosomal genes, autoantibody attack of desmosomal cadherins, and bacterial toxins that selectively target desmosomal cadherins. In addition to reviewing the well-known roles of desmosomal proteins in tissue integrity, this chapter also highlights the growing appreciation for how desmosomal proteins are integrated with cell signaling pathways to contribute to vertebrate tissue organization and differentiation.

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…Desmosomes are intercellular junctions essential for mediating strong intercellular cohesion (Garrod 2010;Green et al 2010;Kowalczyk and Green 2013). They are composed of three protein families.…”

“…Despite their critical roles in maintaining epidermal adhesion and integrity, desmosomes are highly dynamic entities and undergo constant remodeling to allow for plasticity and cell migration within the epidermis during epidermal differentiation and regeneration (Green and Gaudry 2000;Garrod 2010;Kowalczyk and Green 2013). Desmosome adhesion can be regulated at several levels: Their composition, as well as size and number, vary among (A) Expression of keratins K5/14 and interaction with desmosomal protein isoforms forms stable cohesion among cells and protects basal keratinocytes against mechanical stress.…”

Desmosome assembly, homeostasis, and desmosomal disease

“…Large bundles of IFs extend from the nuclear surface and cell's interior out toward the plasma membrane, where they attach to desmosomes by interweaving with the cytoplasmic plaque of the adhesive complex. 12 Thus, the cytoskeletal IF network is attached to the plasma membrane at the desmosomal plaque, 13 and this multilevel structure is termed as desmosome/IF complex.…”

“…Thus, desmosomes are modular structures comprising adhesion molecules that bolt cells together, cytoskeletal cables that disperse forces, and linking molecules at the cytoplasmic plaque of the desmosome that carry mechanical load from the adhesion molecules to the IF cytoskeleton. 12 …”

“…61,62 Many of these molecules, such as PKC, Src, MAPK, epidermal growth factor receptor (EGFR), and caspase 2/3, are now known to be involved in the assembly and disassembly of desmosomes. 8,12,63,64 It is interesting to note that Pg, one of the main organizers of the desmosome that is crucial for adhesiveness, was highly connected to both protein kinases (n=5) and phosphatases (n=4), and this provided an in silico demonstration that the dynamic regulation of the desmosome may be orchestrated by this protein. 61 At the time that the desmo-adhesome was published in 2009, it was well accepted that adherens junctions cooperated with desmosomes in providing tight intercellular adhesion.…”