The Phosphotyrosine Binding-like Domain of Talin Activates Integrins

Calderwood, David A.; Yan, Boxu; Pereda, José M. de; Alvarez, Begoña Garcı́a; Fujioka, Yohsuke; Liddington, Robert; Ginsberg, Mark H.

doi:10.1074/jbc.m111996200

Cited by 356 publications

(375 citation statements)

References 46 publications

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“…47). Interestingly, among all the cytoplasmic ␤ integrin-binding proteins that had been tested, only talin had been shown to be able to promote integrin activation (24,41,48). The results presented in this study demonstrate that MIG-2 can also play a role in this process.…”

Section: Discussionmentioning

confidence: 64%

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

Shi

Qing

et al. 2007

Journal of Biological Chemistry

158

176

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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: Discussionmentioning

confidence: 64%

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

Shi

Qing

et al. 2007

Journal of Biological Chemistry

158

176

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“…The latter possibility is suggested by biochemical studies of ␤ integrin cytoplasmic tails demonstrating that the Y-A mutation disrupts interaction with the cytoskeletal protein talin (Calderwood et al 2002) and the observation that talin-deficient ES cells lose surface expression of ␤1 integrins (Priddle et al 1998). To address this question, mutant ␤1 integrin expression and function were next studied in homozy- Figure 1.…”

Section: Resultsmentioning

confidence: 99%

In vivo β1 integrin function requires phosphorylation-independent regulation by cytoplasmic tyrosines

Chen

Zou²,

Sarratt³

et al. 2006

Genes Dev.

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Integrins are heterodimeric adhesion receptors associated with bidirectional signaling. In vitro studies support a role for the binding of evolutionarily conserved tyrosine motifs (NPxY) in the ␤ integrin cytoplasmic tail to phosphotyrosine-binding (PTB) domain-containing proteins, an interaction proposed to be dynamically regulated by tyrosine phosphorylation. Here we show that replacement of both ␤1 integrin cytoplasmic tyrosines with alanines, resulting in the loss of all PTB domain interaction, causes complete loss of ␤1 integrin function in vivo. In contrast, replacement of ␤1 integrin cytoplasmic tyrosines with phenylalanines, a mutation that prevents tyrosine phosphorylation, conserves in vivo integrin function. These results have important implications for the molecular mechanism and regulation of integrin function.Supplemental material is available at http://www.genesdev.org.Received January 9, 2006; revised version accepted February 17, 2006. Integrin receptors bridge extracellular matrix proteins and intracellular cytoskeletal and signaling proteins and are essential regulators of cellular behavior and function (for review, see Hynes 2002). Since the cytoplasmic tails of integrin receptors are relatively short and lack intrinsic enzymatic activity, integrin signals are believed to be mediated by protein-protein interactions. Biochemical studies have identified a large number of intracellular cytoskeletal and signaling proteins that are capable of binding integrin cytoplasmic tails, but a clear picture of how these many potential protein-protein interactions result in bidirectional integrin signals has not yet emerged.A highly recognizable motif in the integrin cytoplasmic tail is NPxY, two of which are found in the cytoplasmic tails of ␤ integrin subunits. Biochemical and structural studies have demonstrated that NPxY motifs bind phosphotyrosine-binding (PTB) domains and that the specificity of NPxY-PTB domain interactions is conferred by both the NPxY motif and the PTB domain (for review, see Uhlik et al. 2005). Some PTB domains (e.g., the Shc [Src homology 2 domain-containing] transforming protein 1 PTB domain) require phosphotyrosines for high-affinity interaction with NPxY motifs, while others (e.g., the talin PTB domain) bind through hydrophobic interaction with nonphosphorylated tyrosine or phenylalanine residues. The specificity and diversity of NPxY-PTB domain interactions have recently been proposed as a molecular mechanism by which integrin cytoplasmic tails transmit a variety of bidirectional signals . Biochemical studies performed in vitro suggest that distinct ␤ integrin cytoplasmic tails bind distinct PTB domain-containing proteins, and that tyrosine phosphorylation can alter these interactions through addition of a charged phosphate group to the hydrophobic tyrosine aromatic ring Garcia-Alvarez et al. 2003). Dynamic regulation of NPxY-PTB domain binding by tyrosine phosphorylation is therefore a potentially elegant means of explaining how short integrin cytoplasmic tails transmit di...

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“…The ERM proteins bind via their FERM domains to the cytoplasmic domains of transmembrane proteins, e.g., CD44 (3). Other examples of FERM domain-mediated intermolecular interactions include binding of the talin FERM domain to the β subunit of integrins and the interaction of the FERM domains of Janus-activated kinases with the γc and gp130 subunits of cytokine receptors (6,7). Second, FERM domains function in either intramolecular or homophilic intermolecular interactions.…”

Section: Introductionmentioning

confidence: 99%

Clinical Implications of the Influence of Ehm2 on the Aggressiveness of Breast Cancer Cells through Regulation of Matrix Metalloproteinase-9 Expression

Ye²,

Mansel³

et al. 2010

Molecular Cancer Research

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Ehm2, a member of NF2/ERM/4.1 superfamily, has been indicated in disease progression and metastasis of prostate cancer. However, its function and implication in malignancies remain largely unknown. The present study aimed to examine the role of Ehm2 in breast cancer. We first constructed a hammerhead ribozyme transgene to knock down Ehm2 expression in breast cancer cells. The effect on growth, cell matrix adhesion, motility, and invasion following knockdown of Ehm2 was then investigated using in vitro models. Reduction of Ehm2 had inhibitory effects on in vitro growth and invasion of breast cancer cells. Flow cytometric analysis showed that knockdown of Ehm2 induced apoptosis. Knockdown of Ehm2 also significantly decreased matrix metalloproteinase 9 mRNA and protein levels, as well as the corresponding enzymatic activity, and consequently led to a reduction of the invasion. The expression pattern of Ehm2 in a cohort of breast specimens (normal, n = 33; cancer, n = 127) was analyzed using both quantitative real-time PCR and immunohistochemical staining. Increased expression of Ehm2 in breast cancer was seen at both mRNA and protein levels. Higher levels of Ehm2 transcripts were correlated with disease progression, metastasis, and poor prognosis. Disease-free survival of the patients with lower levels of Ehm2 was 135.8 (95% confidence interval, 125.1-146.5) months, significantly longer compared with 102.5 (95% confidence interval, 78.7-126.4) months of patients with higher levels of Ehm2 expression (P = 0.039). Taken together, increased Ehm2 expression correlates with poor prognosis and metastasis. Ehm2 may promote the invasive ability of breast cancer cells via regulation of matrix metalloproteinase 9. Mol Cancer Res; 8(11); 1501-12.

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The Phosphotyrosine Binding-like Domain of Talin Activates Integrins

Cited by 356 publications

References 46 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

In vivo β1 integrin function requires phosphorylation-independent regulation by cytoplasmic tyrosines

Clinical Implications of the Influence of Ehm2 on the Aggressiveness of Breast Cancer Cells through Regulation of Matrix Metalloproteinase-9 Expression

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