Desmosomes: New Perspectives on a Classic

Abstract

Desmosomes are highly specialized anchoring junctions that link intermediate filaments to sites of intercellular adhesion, thus facilitating the formation of a supracellular scaffolding that distributes mechanical forces throughout a tissue. These junctions are thus particularly important for maintaining the integrity of tissues that endure physical stress, such as the epidermis and myocardium. The importance of the classic mechanical functions of desmosomal constituents is underscored by pathologies reported in animal models and an ever-expanding list of human mutations that target both desmosomal cadherins and their associated cytoskeletal anchoring proteins. However, the notion that desmosomes are static structures that exist simply to glue cells together belies their susceptibility to remodeling in response to environmental cues and their important tissue-specific roles in cell behavior and signaling. Here, we review the molecular blueprint of the desmosome and models for assembling its protein components to form an adhesive interface and the desmosomal plaque. We also discuss emerging evidence of supra-adhesive roles for desmosomal proteins in regulating tissue morphogenesis and homeostasis. Finally, we highlight the dynamic nature of these adhesive organelles, examining mechanisms in health and disease for modulating adhesive strength and stability of desmosomes.

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

“…In epithelia, adhesive intercellular junctional complexes, namely, the adherens junctions and desmosomes, function to connect neighboring cells to one another, as well as limit proliferation and migration, regulate tissue morphogenesis and maintain tissue integrity (Green and Simpson, 2007;Holthofer et al, 2007;Garrod and Chidgey, 2008;Garrod and Kimura, 2008;Hartsock and Nelson, 2008;Niessen and Gottardi, 2008). Cadherins are calcium-dependent transmembrane glycoproteins that mediate homotypic cell-cell interactions.…”

Intermediate filaments: versatile building blocks of cell structure

“…At the cell surface, IF interact with desmosomes, hemidesmosomes, focal adhesions and the extracellular matrix via a variety of linker proteins [3][4][5]. There is also evidence that IF associate with factors on the outer nuclear membrane which, in turn, connect to components of the nuclear lamina [4,6].…”

EGFR and ADAMs Cooperate to Regulate Shedding and Endocytic Trafficking of the Desmosomal Cadherin Desmoglein 2

“…In particular, members of cadherin family of calcium-dependent intercellular adhesion molecules have been demonstrated to both suppress (Frixen et al, 1991) and promote (Islam et al, 1996) cell migration and invasion. Although classic cadherins assemble into intercellular adhesive structures known as adherens junctions that associate with the cortical actin cytoskeleton, desmosomal cadherins, including desmogleins and desmocollins, make up the adhesive core of desmosomes, which anchor intermediate filaments (IF) to sites of strong intercellular adhesion (Green and Simpson, 2007).…”

“…Although our understanding of the role of desmosomal modulation in tissue homeostasis and remodeling is not well understood, changes in desmosomal cadherin expression, phosphorylation, and function are known to occur during tissue morphogenesis and tumor progression (Runswick et al, 2001;Chidgey and Dawson, 2007;Dusek et al, 2007;Green and Simpson, 2007;Muller et al, 2008). Our previous work suggested that epidermal growth factor receptor (EGFR), which is overexpressed in many tumor types (Rogers et al, 2005;Kalyankrishna and Grandis, 2006), regulates desmosome assembly and function in squamous cell carcinoma (SCC) cells, by decreasing the level and cell surface localization of desmosomal cadherins (Lorch et al, 2004).…”

“…In particular, members of cadherin family of calcium-dependent intercellular adhesion molecules have been demonstrated to both suppress (Frixen et al, 1991) and promote (Islam et al, 1996) cell migration and invasion. Although classic cadherins assemble into intercellular adhesive structures known as adherens junctions that associate with the cortical actin cytoskeleton, desmosomal cadherins, including desmogleins and desmocollins, make up the adhesive core of desmosomes, which anchor intermediate filaments (IF) to sites of strong intercellular adhesion (Green and Simpson, 2007).Anchorage to the IF cytoskeleton is established with the cooperation of the desmosomal cadherin-associated proteins plakoglobin and plakophilins, which in turn link the IF-associated protein desmoplakin (DP) to the membrane complex. Desmosomes provide mechanical integrity to epithelial and heart tissues by redistributing the forces of mechanical stress .…”