The Talin Head Domain Binds to Integrin β Subunit Cytoplasmic Tails and Regulates Integrin Activation

Calderwood, David A.; Zent, Roy; Grant, Richard P.; Rees, D. J. G.; Hynes, Richard O.; Ginsberg, Mark H.

doi:10.1074/jbc.274.40.28071

Cited by 637 publications

(622 citation statements)

References 23 publications

(34 reference statements)

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“…Structurally, the talin-binding site encompasses both the membrane proximal and central regions of the ␤ integrin cytoplasmic tails (11,38,39) The first NPXY (Tyr 747 in the ␤3 integrin tail) site located in the central region of the ␤ integrin tails is crucial for the formation of the talin⅐␤ integrin complexes. It has been shown, for example, that substitution of Tyr 747 with Ala abrogates the talin-binding activity (40,41). To test whether this site is required for the formation of the MIG-2⅐␤3 integrin complex, we incubated cell lysates with a GST-␤3 protein bearing the Y747A substitution mutation and precipitated it with glutathioneSepharose beads.…”

Section: Mig-2 Interacts With ␤1 and ␤3 Integrin Cytoplasmicmentioning

confidence: 99%

The MIG-2/Integrin Interaction Strengthens Cell-Matrix Adhesion and Modulates Cell Motility

Shi

Qing

et al. 2007

Journal of Biological Chemistry

158

175

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Integrin-mediated cell-matrix adhesion plays an important role in control of cell behavior. We report here that MIG-2, a widely expressed focal adhesion protein, interacts with ␤1 and ␤3 integrin cytoplasmic domains. Integrin binding is mediated by a single site within the MIG-2 FERM domain. Functionally, the MIG-2/integrin interaction recruits MIG-2 to focal adhesions. Furthermore, using ␣IIb␤3 integrin-expressing Chinese hamster ovary cells, a well described model system for integrin activation, we show that MIG-2 promotes integrin activation and enhances cell-extracellular matrix adhesion. Although MIG-2 is expressed in many cell types, it is deficient in certain colon cancer cells. Expression of MIG-2, but not of an integrin binding-defective MIG-2 mutant, in MIG-2-null colon cancer cells strengthened cell-matrix adhesion, promoted focal adhesion formation, and reduced cell motility. These results suggest that the MIG-2/integrin interaction is an important element in the cellular control of integrin-mediated cell-matrix adhesion and that loss of this interaction likely contributes to high motility of colon cancer cells.Cell-extracellular matrix (ECM) 3 adhesion is a fundamental process that is mediated by transmembrane receptors such as integrins (1-6). The interactions of integrins with ECM ligands can be controlled by integrin activation via "inside-out" signaling. Talin, a FERM (Band 4.1 (four point one)/ezrin/radixin/ moesin) domain-containing focal adhesion (FA) protein, can play a key role in this process (for recent reviews, see Refs. 7-10). Binding of the talin FERM domain to the ␤ integrin cytoplasmic domains results in separation of the ␣ and ␤ integrin cytoplasmic tails and consequently in an increase in integrin extracellular ligand-binding affinity (i.e. integrin activation) (11-13). Integrin extracellular ligand-binding affinity plays an important role in control of initial cell-ECM adhesion. Additionally, integrin-mediated cell-ECM adhesion can be enhanced through interactions with cytoskeletal proteins, a process that has been termed cytoskeletal strengthening (14 -16). The physical basis underlying the cytoskeletal strengthening of cell-ECM adhesion has been well described (16). However, the molecular interactions that mediate this process remain to be defined.MIG-2 (mitogen-inducible gene-2, also known as kindlin-2) is a widely expressed and evolutionarily conserved cytoplasmic protein (17-21). Genetic studies have shown that Caenorhabditis elegans UNC-112, a homolog of MIG-2, is required for attachment of body-wall muscle cells to the hypodermis (17,19). Loss of UNC-112 in C. elegans results in an embryonic lethal Pat (paralyzed, arrested elongation at two-fold) phenotype resembling that of ␣ or ␤ integrin loss (17, 19). In mammalian organisms, MIG-2 has been detected in many cell types, including fibroblasts, muscle cells, endothelial cells, and epithelial cells (20,22). In these cells, it concentrates at FAs. MIG-2 interacts with migfilin (20), a filamin-and VASP (vasodilatorstimulated p...

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Section: Mig-2 Interacts With ␤1 and ␤3 Integrin Cytoplasmicmentioning

confidence: 99%

The MIG-2/Integrin Interaction Strengthens Cell-Matrix Adhesion and Modulates Cell Motility

Shi

Qing

et al. 2007

Journal of Biological Chemistry

158

175

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“…5 The linkage of integrins to the cytoskeleton through talin-1 and kindlin-3 are essential in the regulation of integrin affinity. 6,7 Talin-1 binds with its head domain to the intracellular tail of β 1 , β 2 , and β 3 integrin. The talin-1 tail domain can also weakly bind to the integrin's intracellular tail, 8 but is also known to bind vinculin and actin.…”

Section: Integrin Affinity Regulationmentioning

confidence: 99%

Neutrophil integrin affinity regulation in adhesion, migration, and bacterial clearance

Langereis

2013

Cell Adhesion & Migration

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“…Because of its capacity to bind both integrin and actin, talin has long been recognized as a mechanical linker between the ECM and actin cytoskeleton to regulate cell adhesion and morphology [5]. However, about a decade ago, it was found that the binding of talin-FERM to integrin β CTs can also promote the conversion of integrins from a low-affinity into a high-affinity ligand-binding state, a dynamic process termed integrin inside-out signaling or integrin activation [6][7][8][9]. This finding suggests that the talin-FERM/ integrin interaction plays a multifunctional role in promoting integrin activation as well as integrin-actin coupling during dynamic cell adhesion processes [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion

et al. 2012

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The activation of heterodimeric (α/β) integrin transmembrane receptors by cytosolic protein talin is crucial for regulating diverse cell-adhesion-dependent processes, including blood coagulation, tissue remodeling, and cancer metastasis. This process is triggered by the coincident binding of N-terminal FERM (four-point-one-protein/ezrin/radixin/moesin) domain of talin (talin-FERM) to the inner membrane surface and integrin β cytoplasmic tail, but how these binding events are spatiotemporally regulated remains obscure. Here we report the crystal structure of a dormant talin, revealing how a C-terminal talin rod segment (talin-RS) self-masks a key integrin-binding site on talin-FERM via a large interface. Unexpectedly, the structure also reveals a distinct negatively charged surface on talin-RS that electrostatically hinders the talin-FERM binding to the membrane. Such a dual inhibitory topology for talin is consistent with the biochemical and functional data, but differs significantly from a previous model. We show that upon enrichment with phosphotidylinositol-4,5-bisphosphate (PIP2) -a known talin activator, membrane strongly attracts a positively charged surface on talin-FERM and simultaneously repels the negatively charged surface on talin-RS. Such an electrostatic "pull-push" process promotes the relief of the dual inhibition of talin-FERM, which differs from the classic "steric clash" model for conventional PIP2-induced FERM domain activation. These data therefore unravel a new type of membrane-dependent FERM domain regulation and illustrate how it mediates the talin on/off switches to regulate integrin transmembrane signaling and cell adhesion.

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The Talin Head Domain Binds to Integrin β Subunit Cytoplasmic Tails and Regulates Integrin Activation

Cited by 637 publications

References 23 publications

The MIG-2/Integrin Interaction Strengthens Cell-Matrix Adhesion and Modulates Cell Motility

The MIG-2/Integrin Interaction Strengthens Cell-Matrix Adhesion and Modulates Cell Motility

Neutrophil integrin affinity regulation in adhesion, migration, and bacterial clearance

A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion

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