Key Points
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Expressed abundantly and differentially, intermediate filaments provide each cell type with a unique cytoskeletal architecture, thereby providing a mechanism for cell-type-specific cytoskeletal crosstalk. Intermediate filaments form extensive networks within the cytoplasm that extend radially in all directions from the nucleus to the cell surface, conferring an obvious advantage for intermediate filaments in coordinating cytoskeletal crosstalk in all areas of the cytoplasm.
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Different intermediate-filament types have preferential interactions with either microtubules or microfilaments. Among the main mediators of crosstalk between intermediate filaments and the other cytoskeletal systems are the molecular motors kinesin, dynein and myosin Va. The assembly and maintenance of an intermediate-filament network depends on microtubule- and microfilament-based motility and this motility can be regulated by phosphorylation of intermediate filaments as well as by intermediate-filament-associated proteins, such as plectin and bullous pemphigoid antigens, and microtubule-associated proteins like tau.
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Intermediate-filament-mediated cytoskeletal crosstalk might provide specialized cells with mechanisms that are related to their different physiological activities and might be related to the determination and maintenance of the diverse cell shapes. Different types of intermediate filament are expressed during the development and regeneration of nerve cells, at which time the shape of the cells undergoes rapid and numerous changes. Targeted disruption of intermediate filaments, which leads to significant alterations in both microtubule and microfilament networks, also causes marked changes in cell shape.
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The severely compromised wound-healing capacity of vimentin-deficient (vim−/−) mice and the reduction in motility of their fibroblasts imply a role for intermediate filaments and intermediate-filament-based cytoskeletal crosstalk in cell motility. With findings that vimentin interacts with adhesion-complex components such as fimbrin and plectin, both of which are known to interact with other cytoskeletal elements like actin, there is increasing evidence for a role for intermediate filaments in mediating cytoskeletal crosstalk at these crucial cellular structures. Plectin-deficient cells also have impaired motility.
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Phosphorylation is intimately linked to the assembly/disassembly of intermediate-filament networks, indicating a role for intermediate filaments as highly sensitive mediators of cytoskeletal crosstalk through signalling. Intermediate filaments are important factors in signalling pathways that regulate both microtubule and microfilament function and organization during various cellular processes such as cell movement and cell division. This appears to be related to the regulation of certain activities involving key components in signal transduction such as Rho kinase α and the 14-3-3 proteins.
Abstract
Intermediate filaments, actin-containing microfilaments and microtubules are the three main cytoskeletal systems of vertebrate and many invertebrate cells. Although these systems are composed of distinctly different proteins, they are in constant and intimate communication with one another. Understanding the molecular basis of this cytoskeletal crosstalk is essential for determining the mechanisms that underlie many cell-biological phenomena. Recent studies have revealed that intermediate filaments and their associated proteins are important components in mediating this crosstalk.
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Acknowledgements
Figure 2 was kindly provided by H. Herrmann (German Cancer Research Center, Heidelberg, Germany) and U. Aebi (Maurice E. Müller Institute for Structural Biology, Biozentrum Basel, Switzerland). The authors would like to acknowledge the support of a MERIT Award from the National Institute of General Medical Sciences, and grants from the National Institute of Dental Research, and the National Heart, Lung and Blood Institute.
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Glossary
- KERATIN
-
Obligate heteropolymer intermediate filaments that are composed of type-I and type-II intermediate-filament proteins, which are expressed mainly in epithelial cells.
- VIMENTIN
-
Type-III, homopolymer intermediate filaments that are expressed in mesenchymal and some ectodermal cells.
- NEUROFILAMENT
-
Type-IV, heteropolymer intermediate filaments that are composed of three neurofilament subunits (NF-L, NF-M and NF-H), which are expressed mainly in neurons.
- SPREADING PROCESS
-
The process of cells spreading after trypsinization and re-plating. Visualization of intermediate-filament particles and squiggles in the peripheral regions of the cells is optimized during the early stages of cell spreading.
- CYTOPLASMIC DYNEIN
-
A microtubule motor that can bind to and move towards the minus end of microtubules.
- FRAP
-
(fluorescence recovery after photobleaching). A live-cell imaging technique used to study the mobility of fluorescent molecules. A pulse of high intensity light is used to irreversibly photobleach a population of fluorophores in a target region. Recovery of fluorescence in the bleached region represents movement of fluorophores into that region.
- PERIPHERIN
-
Type-III, homopolymer intermediate filaments that are expressed in peripheral and enteric neurons, as well as in PC12 cells.
- CONVENTIONAL KINESIN
-
A microtubule motor that can bind to and move towards the plus ends of microtubules.
- DYNAMITIN
-
A component of dynactin, a large complex thought to be involved in dynein–cargo interactions. Overexpression of dynamitin leads to disruption of dynein function.
- WOUND-SCRAPE ASSAY
-
An assay used to assess cell migration. A scrape is made in a confluent monolayer of cells, leaving an area devoid of cells, followed by microscopy to monitor the migration of cells into the wound.
- FOCAL COMPLEXES
-
Small (1 μm diameter), dot-like adhesion structures that are present mainly at the edges of the lamellipodium.
- LAMELLIPODIA
-
Broad, flat protrusions at the leading edge of a moving cell that are enriched with a branched network of actin filaments.
- FILOPODIA
-
Thin cellular processes containing long, unbranched, parallel bundles of actin filaments.
- PODOSOMES
-
Extracellular-matrix adhesions that are found in various malignant cells and in some normal cells, including macrophages and osteoclasts. Podosomes are small (0.5 μm diameter) cylindrical structures containing typical focal-adhesion proteins, such as vinculin and paxillin.
- 14-3-3 PROTEINS
-
A family of proteins and protein domains that bind to serine/threonine-phosphorylated residues in a context-specific manner. They bind and regulate key proteins involved in various physiological processes.
- RHO-GTPase FAMILY
-
Ras-related small GTPases that function as molecular switches to control signal-transduction pathways. They have been traditionally characterized to function as regulators of actin and, to a lesser extent, microtubule dynamics.
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Chang, L., Goldman, R. Intermediate filaments mediate cytoskeletal crosstalk. Nat Rev Mol Cell Biol 5, 601–613 (2004). https://doi.org/10.1038/nrm1438
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DOI: https://doi.org/10.1038/nrm1438
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