The Phosphotyrosine Binding-like Domain of Talin Activates Integrins

Division of Vascular Biology, Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2002; 277(24):21749-58. DOI: 10.1074/jbc.M111996200
Source: PubMed


Cellular regulation of the ligand binding affinity of integrin adhesion receptors (integrin activation) depends on the integrin beta cytoplasmic domains (tails). The head domain of talin binds to several integrin beta tails and activates integrins. This head domain contains a predicted FERM domain composed of three subdomains (F1, F2, and F3). An integrin-activating talin fragment was predicted to contain the F2 and F3 subdomains. Both isolated subdomains bound specifically to the integrin beta3 tail. However, talin F3 bound the beta3 tail with a 4-fold higher affinity than talin F2. Furthermore, expression of talin F3 (but not F2) in cells led to activation of integrin alpha(IIb)beta3. A molecular model of talin F3 indicated that it resembles a phosphotyrosine-binding (PTB) domain. PTB domains recognize peptide ligands containing beta turns, often formed by NPXY motifs. NPX(Y/F) motifs are highly conserved in integrin beta tails, and mutations that disrupt this motif interfere with both integrin activation and talin binding. Thus, integrin binding to talin resembles the interactions of PTB domains with peptide ligands. These resemblances suggest that the activation of integrins requires the presence of a beta turn at NPX(Y/F) motifs conserved in integrin beta cytoplasmic domains.

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    • "Talin consists of a large C-terminal rod domain that contains bundles of alpha helices and an N-terminal FERM domain with three subdomains: F1, F2 and F3 (Rees et al., 1990). The F3 subdomain of the FERM domain contains the highest affinity integrin-binding site for integrin β tails and is sufficient to activate integrins (Calderwood et al., 2002). Talin interactions with PI(4,5)P 2 in vitro and lipid binding induce a conformational change in talin and enhance its interaction with integrins (Martel et al., 2001) (Figure 4). "
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    British Journal of Pharmacology 12/2014; 171(24). DOI:10.1111/bph.12777 · 4.84 Impact Factor
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    • "Talin binds to the cytoplasmic tail of integrins through its FERM (Four point one protein/Ezrin/Radixin/Moesin) domain, inducing integrin activation. Talin also binds to F-actin via its C-terminal rod domain (Calderwood et al., 2002; Kim et al., 2012a; Wang, 2012). The mechanosensory properties of talin are confined to the helix bundles present in its rod domain, containing 5 potential vinculin binding sites. "
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    European Journal of Cell Biology 10/2014; 93(10-12). DOI:10.1016/j.ejcb.2014.07.002 · 3.83 Impact Factor
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    • "The talin head domain (THD) contains four subdomains: F0, F1, F2, and F3. The F3 domain itself can bind to the β3 cytoplasmic domain and exert αIIbβ3 activation [5]. Other subdomains also have important roles in the activation [6-8]. "
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    ABSTRACT: Integrin-linked kinase (ILK) is an important signaling regulator that assembles into the heteroternary complex with adaptor proteins PINCH and parvin (termed the IPP complex). We recently reported that ILK is important for integrin activation in a Chinese hamster ovary (CHO) cell system. We previously established parental CHO cells expressing a constitutively active chimeric integrin (αIIbα6Bβ3) and mutant CHO cells expressing inactive αIIbα6Bβ3 due to ILK deficiency. In this study, we further investigated the underlying mechanisms for ILK-dependent integrin activation. ILK-deficient mutant cells had trace levels of PINCH and α-parvin, and transfection of ILK cDNA into the mutant cells increased not only ILK but also PINCH and α-parvin, resulting in the restoration of αIIbα6Bβ3 activation. In the parental cells expressing active αIIbα6Bβ3, ILK, PINCH, and α-parvin were co-immunoprecipitated, indicating the formation of the IPP complex. Moreover, short interfering RNA (siRNA) experiments targeting PINCH-1 or both α- and β-parvin mRNA in the parent cells impaired the αIIbα6Bβ3 activation as well as the expression of the other components of the IPP complex. In addition, ILK mutants possessing defects in either PINCH or parvin binding failed to restore αIIbα6Bβ3 activation in the mutant cells. Kindlin-2 siRNA in the parental cells impaired αIIbα6Bβ3 activation without disturbing the expression of ILK. For CHO cells stably expressing wild-type αIIbβ3 that is an inactive form, overexpression of a talin head domain (THD) induced αIIbβ3 activation and the THD-induced αIIbβ3 activation was impaired by ILK siRNA through a significant reduction in the expression of the IPP complex. In contrast, overexpression of all IPP components in the αIIbβ3-expressing CHO cells further augmented THD-induced αIIbβ3 activation, whereas they did not induce αIIbβ3 activation without THD. These data suggest that the IPP complex rather than ILK plays an important role and supports integrin activation probably through stabilization of the active conformation.
    PLoS ONE 12/2013; 8(12):e85498. DOI:10.1371/journal.pone.0085498 · 3.23 Impact Factor
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