Key Points
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Plakins comprise a family of gigantic proteins that crosslink the cytoskeleton and that connect the cytoskeleton to cell junctions. The prototypical plakins BPAG1 (bullous pemphigoid antigen-1), desmoplakin and plectin were originally described by their association with desmosomes and hemidesmosomes, which are specific cell junctions in the epithelium that are linked to intermediate filaments.
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Plakins have important roles in the maintenance of epidermal tissue architecture. The characterization of shortstop and VAB-10 — the Drosophila melanogaster and Caenorhabditis elegans plakin orthologues, respectively — showed that the functions of plakins are evolutionarily conserved.
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Genetic analyses in mice and inverterbrates have revealed further roles for plakins in non-epidermal cells such as neurons, as well as roles that involve actin and microtubules. These studies highlight the functional importance of plakins in integrating two different cytoskeletal networks, which is vital for specific cellular functions.
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The plakin gene locus undergoes alterative splicing to encode numerous isoforms that show tissue-specific expression profiles. The isoforms have unique functions and display different domain organizations, some of which show similarity to the spectrin family of proteins.
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Mutations in the plakin genes are linked to several hereditary disorders of the skin and muscular system in humans. For example, mutations in plectin are implicated in a disorder called epidermolysis bullosa simplex with muscular dystrophy. Mice that lack plectin also exhibit the disease phenotype.
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Plakins are thought to organize and maintain multiprotein complexes in different cellular locations and to link them to the cytoskeleton. An important challenge for the future is to identify all the specific interaction partners of plakins in different cells.
Abstract
Plakins comprise a family of proteins that crosslink cytoskeletal filaments and attach them to membrane-associated complexes at cell junctions. They were originally found associated with intermediate filaments and were believed to function primarily in maintaining epithelial tissue integrity. However, new plakins with unique isoforms that are enormous in size have been identified in the past few years. These new plakins have highlighted further functions in all the cytoskeletal networks, as well as in non-epithelial cells.
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Acknowledgements
The authors are supported by grants from the National Institutes of Health and the Muscular Dystrophy Association. We thank K. Green and members of the Liem laboratory for their input in this manuscript. We apologize to many colleagues and authors whose work we could not cite here because of space limitations.
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Glossary
- CELL POLARITY
-
The asymmetric distribution of proteins, lipids and/or their complexes within the cell.
- BULLOUS PEMPHIGOID
-
A chronic autoimmune skin disorder that is characterized by the presence of large blisters.
- STRATIFIED SQUAMOUS EPITHELIA
-
A multilayered (stratified) epithelium such as is seen in the epidermis of the skin. It is formed by relatively flat (squamous) cells.
- DESMOSOMES
-
Specialized junctions between adjacent epithelial cells that are mediated by desmosomal cadherins (called desmocollins and desmogleins) and are linked to keratin intermediate filaments.
- HEMIDESMOSOMES
-
Specialized junctions between epithelial cells and the extracellular matrix that are mediated by α6β4-integrins and are associated with keratin intermediate filaments.
- CORNIFIED ENVELOPE
-
The outermost specialized layer of protein and lipid in terminally differentiating epidermal cells that has a protective barrier function.
- SPECTRIN REPEATS
-
Repeats of bundles of three α-helices that are found in the spectrin superfamily of proteins. Members of this superfamily function to organize the cytoskeleton in the cytoplasm and at the plasma membrane.
- SH3 DOMAIN
-
(Src-homology-3 domain). A protein–protein interaction domain that recognizes a unique proline-rich peptide motif. This domain is found in many proteins that are involved in signal transduction and membrane–cytoskeleton interactions.
- ARMADILLO-REPEAT FAMILY
-
A family of proteins that contain a repeat structure called an 'arm repeat' and that carry out dual roles in cell adhesion and signal transduction.
- EB1–APC COMPLEX
-
(Microtubule-plus-end-binding protein-1–adenomatous-polyposis-coli complex). A complex that is located at the plus end of microtubules and that has an important role in the dynamics and stability of microtubules.
- ADHERENS JUNCTIONS
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Actin-filament-associated, epithelial cell–cell junctions that have classical cadherins as their core component.
- FOLLICULAR EPITHELIA
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Refers to the thin layer of epithelial cells that surround the developing oocyte, which is a widely used model system to study the generation of cell polarity.
- DYNEIN–DYNACTIN COMPLEX
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Dynein is a minus-end-directed microtubule motor protein that is involved in several cellular processes such as cell division, migration and intracellular transport. Dynactin is an accessory complex of dynein that is important for the activation and interaction of dynein with its targets.
- ERM PROTEINS
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(ezrin, radixin and moesin proteins). Membrane-associated proteins of the Band-4.1 superfamily, which link the cytoskeleton to the plasma membrane and are found predominantly in actin-rich cortical structures such as microvilli and lamellopodia.
- FERM DOMAIN
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A clover-shaped structural feature that interacts with the cytoplasmic domain of transmembrane proteins and membrane lipids. Such domains are found in the amino terminus of the Band-4.1 superfamily of proteins that link the actin cytoskeleton to the plasma membrane.
- MICROTUBULE PLUS END
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Refers to the dynamic end of microtubules that alternates between periods of growth and shrinkage and that is directed towards the cell surface. The minus end is the less dynamic end that is associated with the centrosome in the cell interior.
- AXONAL TERMINAL ARBORIZATION
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An elaborate branching architecture at the end of an axon.
- GROWTH CONE
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A highly dynamic, motile structure at the tip of a growing axon.
- EXTRA-EMBRYONIC TISSUES
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The external embryonic structure that is integrated with the uterus, provides nourishment and support to the foetus, and is shed off during birth.
- HYPERKERATOSIS
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Refers to an abnormal thickening of the outer layer of the skin.
- CELL CORTEX
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The region underlying the plasma membrane that is rich in actin filaments and associated proteins.
- NEUREGULIN SIGNALLING PATHWAY
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A cell–cell signal-transduction system in which neuregulins function as ligands for the ErbB family of receptor tyrosine kinases. These receptors are involved in the development and function of several tissues such as the nervous system and heart.
- Rho
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A member of the family of small GTPases that includes Rac and Cdc42. Small GTPases participate in signalling pathways that modulate the cytoskeleton and regulate diverse cellular processes such as cell migration and cell adhesion.
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Jefferson, J., Leung, C. & Liem, R. Plakins: Goliaths that link cell junctions and the cytoskeleton. Nat Rev Mol Cell Biol 5, 542–553 (2004). https://doi.org/10.1038/nrm1425
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DOI: https://doi.org/10.1038/nrm1425
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