Integrin connections to the cytoskeleton through talin and vinculin

IZKF Leipzig, Faculty of Medicine, University of Leipzig, Inselstrasse 22, D-04103 Leipzig, Germany.
Biochemical Society Transactions (Impact Factor: 3.19). 05/2008; 36(Pt 2):235-9. DOI: 10.1042/BST0360235
Source: PubMed


Integrins are alphabeta heterodimeric receptors that mediate attachment of cells to the extracellular matrix and therefore play important roles in cell adhesion, migration, proliferation and survival. Among the cytoskeletal proteins that interact directly with the beta-chain cytoplasmic domain, talin has emerged as playing a critical role in integrin activation and linkage to the actin cytoskeleton. Talin (2541 amino acids) is an elongated (60 nm) flexible antiparallel dimer, with a small globular head connected to an extended rod. The talin head contains a FERM (4.1/ezrin/radixin/moesin) domain (residues 86-400) with binding sites for several beta integrin cytodomains and the talin rod contains a second lower-affinity integrin-binding site, a highly conserved C-terminal actin-binding site and also several binding sites for vinculin. We have determined previously the crystal structures of two domains from the talin rod, spanning residues 482-789. Talin-(482-655), which contains a VBS (vinculin-binding site), folds into a five-helix bundle whereas talin-(656-789) is a four-helix bundle. We have also reported the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. In the present paper, we consider how binding sites buried within the folded helical bundles of talin and alpha-actinin form interactions with vinculin.

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    • "Moreover, experimental evidence has been presented in support of talin binding to the FAT domain of FAK via the talin-innate FERM domain, independently of FAK-paxillin binding (Lawson et al. 2012). Vinculin is essential for focal adhesions, since, on the one hand, vinculin interconnection with α-actinin yields the bonding of the β1- integrin with the filamentous-actin cytoskeleton and, on the other hand, the vinculin-talin interaction leads to membrane accumulation of activated β1-integrins concomitant with emerging focal adhesion growth (Humphries et al. 2007; Ziegler et al. 2008). Observations from mouse embryonic fibroblasts derived from vinculin knock-out animals reveal smaller focal adhesions, diminished adhesion on various ECM proteins, but faster migration as knock-out consequences (Xu et al. 1998), thereby suggesting that vinculin is important for the reinforcement of environmental cell attachment (Carisey and Ballestrem 2011). "
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    ABSTRACT: Mechanobiology is a scientific interface discipline emerging from engineering and biology. With regard to tissue-regenerative cell-based strategies, mechanobiological concepts, including biomechanics as a target for cell and human mesenchymal stem cell behaviour, are on the march. Based on the periodontium as a paradigm, this mini-review discusses the key role of focal-adhesion kinase (FAK) in mechanobiology, since it is involved in mediating the transformation of environmental biomechanical signals into cell behavioural responses via mechanotransducing signalling cascades. These processes enable cells to adjust quickly to environmental cues, whereas adjustment itself relies on the specific intramolecular phosphorylation of FAK tyrosine residues and the multiple interactions of FAK with distinct partners. Furthermore, interaction-triggered mechanotransducing pathways govern the dynamics of focal adhesion sites and cell behaviour. Facets of behaviour not only include cell spreading and motility, but also proliferation, differentiation and apoptosis. In translational terms, identified and characterized biomechanical parameters can be incorporated into innovative concepts of cell- and tissue-tailored clinically applied biomaterials controlling cell behaviour as desired.
    Full-text · Article · Jul 2014 · Cell and Tissue Research
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    • "Bundles of actin filaments often appear to terminate in focal adhesions, consistent with the notion that these sites provide a link between the actin cytoskeleton and the ECM (Chen et al. 2006; Geiger et al. 2009; Wolfenson et al. 2009; Yilmaz and Christofori 2009). Regulation of the activity of integrins potentially involves a number of signal transduction pathways plus key proteins that make up the cytoskeleton (Ziegler and Wolfgang 2008; Huveneers and Danen 2009; Guarino 2010). Structural and signaling proteins are aggregated in the focal adhesion sites on the cytoplasmic surface of the plasma membrane in association with actin stress fibers and integrin cytoplasmic domains. "
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    ABSTRACT: Arachidonic acid stimulates cell adhesion by activating α2β1 integrins in a process that depends on protein kinases, including p38 mitogen activated protein kinase. Here, we describe the interaction of cytoskeletal components with key signaling molecules that contribute to the spreading of, and morphological changes in, arachidonic acid-treated MDA-MB-435 human breast carcinoma cells. Arachidonic acid-treated cells showed increased attachment and spreading on collagen type IV, as measured by electric cell-substrate impedance sensing. Fatty acid-treated cells displayed short cortical actin filaments associated with an increased number of β1 integrin-containing pseudopodia, whereas untreated cells displayed elongated stress fibers and fewer clusters of β1 integrins. Confocal microscopy of arachidonic acid-treated cells showed that vinculin and phospho-p38 both appeared enriched in pseudopodia and at the tips of actin filaments, and fluorescence ratio imaging indicated the increase was specific for the phospho-(active) form of p38. Immunoprecipitates of phospho-p38 from extracts of arachidonic acid-treated cells contained vinculin, and GST-vinculin fusion proteins carrying the central region of vinculin bound phospho-p38, whereas fusion proteins expressing the terminal portions of vinculin did not. These data suggest that phospho-p38 associates with particular domains on critical focal adhesion proteins that are involved in tumor cell adhesion and spreading, and that this association can be regulated by factors in the tumor microenvironment.
    Full-text · Article · Dec 2013 · Biochemistry and Cell Biology
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    • "We also detected the expression of another important FACs protein, vinculin, in MARVELD1 overexpressing cells. Vinculin is a linkage protein to connect the integrin adhesion molecules to the actin cytoskeleton and the expression changes of vinculin directly related to cell-ECM adhesion and cell spreading (Ziegler et al., 2008). Thus, suppressed expression of vinculin in NIH3T3/MARVELD1 cells also contributed to recess cell spreading and microfilament disorder. "
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    ABSTRACT: Cell adhesion on an extracellular matrix (ECM) participates in cell motility, invasion, cell signal transduction and gene expression. Many nuclear proteins regulate cell-ECM adhesion through managing the transcription of cell adhesion-related genes. Here, we identified MARVEL [MAL (The myelin and lymphocyte protein) and related proteins for vesicle trafficking and membrane link] domain containing 1 (MARVELD1) that could suppress cell spreading and complicate actin organization. Over-expression of MARVELD1 in NIH3T3 cells decreased the expression level of integrin β1 and vinculin, and further led to dephosphorylation of focal adhesion kinase (FAK) at Tyr 397. We also found that MARVELD1 partially colocalized with serine/arginine-rich splicing factor 2 (SC35) and interacted with nuclear cap binding protein subunit 2 (CBP20). Finally, we demonstrated that pre-mRNA processing of integrin β1 was affected by MARVELD1. Taken together, our studies demonstrate that MARVELD1 plays a role in pre-mRNA processing of integrin β1, and thereby regulates cell adhesion and cell motility. These studies provide a novel regulatory mechanism of cell-ECM adhesion by nuclear protein in cells.
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