Key Points
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Genetic-manipulation studies in mice, and work with human patients, has demonstrated key structural roles for several desmosomal proteins in the skin, heart and hair. As the molecular composition of desmosomes varies in different cell types, tissue-specific functional requirements for these intercellular junctions probably exist.
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High-resolution analysis has revealed molecular details of the organization of desmosomal cadherins at the cell surface and the structure of the subdomains of desmoplakin that are implicated in intermediate-filament binding. Short peptides that are specific to desmosomal cadherins can block adhesion, but interfering with the ability of desmoplakin to recruit intermediate filaments to desmosomes also reduces the adhesive strength of epithelial cells.
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Desmosomal cadherins have essential adhesive functions within desmosomes and are mutated in human disease. Recent work suggests that the desmogleins and desmocollins are also important in the cell-sorting and signalling events that drive tissue morphogenesis.
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Members of the armadillo-protein family, including plakoglobin, the plakophilins and p0071, are present within desmosomes, but, in some cases, might also function within the cytoplasm and the nucleus.
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Desmoplakin has been confirmed as an essential cytoskeletal linker protein in desmosomes and is required not only to maintain the integrity of epidermal and cardiac tissues, but also for the development of the microvasculature network. The factors that are required to regulate desmoplakin recruitment and function within junctions are still being identified.
Abstract
Desmosomes have long been regarded as essential 'spot welds' that externally glue together cells within a tissue, and internally anchor the cytoskeletal network of intermediate filaments. Inactivation of desmosomal components by mutation, autoimmune antibodies and bacterial toxins breaches the structural integrity of embryos and adult tissues. But desmosomes are also functionally flexible organelles that recruit molecules capable of instructing cells within a tissue to undergo proper morphogenesis and patterning.
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Acknowledgements
The authors would like to thank all of their colleagues who provided input and information prior to publication. Thanks go also to A. P. Kowalczyk, J. R. Stanley, W. I. Weis and members of the Green laboratory for critical reading of the manuscript. We regret that the work of many colleagues and authors could not be cited in this review because of space limitations. The authors are supported by grants from the National Institutes of Health (to K.J.G.) and a Canadian Institutes of Health Research postdoctoral fellowship (to S.G.).
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DATABASES
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Glossary
- INTERMEDIATE FILAMENT
-
A cytoskeletal filament, of typically 10 nm in diameter, that occurs in higher eukaryotic cells.
- ADHERENS JUNCTION
-
A cell–cell adhesion complex that contains classical cadherins and catenins that are attached to cytoplasmic actin filaments.
- TIGHT JUNCTION
-
A belt-like region of adhesion between adjacent epithelial or endothelial cells. Tight junctions regulate paracellular flux, and contribute to the maintenance of cell polarity by stopping molecules from diffusing within the plane of the membrane.
- APICAL-MEMBRANE DOMAIN
-
The surface of an epithelial cell that faces the lumen.
- BASOLATERAL-MEMBRANE DOMAIN
-
The surface of an epithelial cell that adjoins underlying tissue.
- GAP JUNCTION
-
A junction between two cells that consists of pores that allow passage of molecules (up to 1 kDa).
- DESMOSOMAL PLAQUE
-
An electron-dense region that is present beneath the plasma membrane of desmosomes, and which can be readily observed at the ultrastructural level.
- MENINGES
-
Three connective-tissue layers (dura, arachnoid and pia mater) that line the outer surface of the brain and spinal cord.
- TYPE I INTEGRAL MEMBRANE GLYCOPROTEIN
-
A single-pass transmembrane protein that contains an amino-terminal lumenal domain with sugar moieties and a carboxy-terminal cytoplasmic domain.
- ELECTRON TOMOGRAPHY
-
A technique for modelling three-dimensional (3D) objects using a series of two-dimensional electron-microscope images.
- KERATINOCYTE
-
A specialized epithelial cell that is present in the skin.
- PROTEASOME
-
A large multisubunit protease complex that selectively degrades intracellular proteins. Targeting to proteasomes most often occurs through the attachment of multi-ubiquitin tags.
- RHO-FAMILY GTPASE
-
A Ras-related GTPase that is involved in controlling the polymerization of actin.
- PDZ DOMAIN
-
(Postsynaptic-density protein of 95 kDa, Discs large, Zona occludens-1). A protein-interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family.
- MORULAE
-
A mulberry-like mass of early-stage embryonic cells.
- 14-3-3 PROTEIN
-
A protein that binds to two phosphoserine/phosphothreonine-containing polypeptides to form crosslinks.
- RNA INTERFERENCE
-
The process by which double-stranded RNA specifically silences the expression of genes by causing the degradation of their cognate mRNAs.
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Getsios, S., Huen, A. & Green, K. Working out the strength and flexibility of desmosomes. Nat Rev Mol Cell Biol 5, 271–281 (2004). https://doi.org/10.1038/nrm1356
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DOI: https://doi.org/10.1038/nrm1356
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