Competition for Talin Results in Trans-dominant Inhibition of Integrin Activation

Abstract

The ability of integrin adhesion receptors to undergo rapid changes in affinity for their extracellular ligands (integrin activation) is essential for the development and function of multicellular animals and is dependent on interactions between the integrin ␤ subunit-cytoplasmic tail and the cytoskeletal protein talin. Cross-talk among different integrins and between integrins and other receptors impacts many cellular processes including adhesion, spreading, migration, clot retraction, proliferation, and differentiation. One form of integrin cross-talk, transdominant inhibition of integrin activation, occurs when ligand binding to one integrin inhibits the activation of a second integrin. This may be relevant clinically in a number of settings such as during platelet adhesion, leukocyte trans-migration, and angiogenesis. Here we report that competition for talin underlies the trans-dominant inhibition of integrin activation. This conclusion is based on our observations that (i) ␤ tails selectively defective in talin binding are unable to mediate trans-dominant inhibition, (ii) trans-dominant inhibition can be reversed by overexpression of integrin binding and activating fragments of talin, and (iii) expression of another non-integrin talin-binding protein, phosphatidylinositol phosphate kinase type I␥-90, also inhibits integrin activation. Thus, the sequestration of talin by the suppressive species is both necessary and sufficient for trans-dominant inhibition of integrin activation.

Integrin-ECM interactions regulate the changes in cell shape driving the morphogenesis of theDrosophilawing epithelium

“…Here, we show that di␤ recruits the cytoplasmic protein Talin, opening the possibility that di␤ exerts its dominant-negative effect by competing for Talin. However, this does not seem to be the case because overexpression of Talin does not rescue the di␤ phenotype, contradicting data from CHO cells showing that competition for Talin underlies the trans-dominant inhibition exerted by isolated ␤ tails (Calderwood et al, 2004). Nevertheless, we recently demonstrated complementation between mutations in different motifs of the ␤PS cytoplasmic domain that eliminate the dominant-negative activity of di␤ (Tanentzapf et al, 2006).…”

β1-Integrin Signaling Mediates Premyelinating Oligodendrocyte Survival But Is Not Required for CNS Myelination and Remyelination

“…In other cell types (Calderwood et al, 2004), these dominant-negative approaches produced broader effects than those that are found when more physiological and stringent systems, such as conditional genetic loss-offunction, were used (Graus-Porta et al, 2001). One possible explanation is that the expression of ␤1-integrin dominantnegative constructs in oligodendroglial cells elicited a transdominant inhibitory effect impairing not only the function of ␤1-integrins but also the function of other oligodendrocyte integrin receptors.…”

Phospholipase D2 stimulates integrin-mediated adhesion via phosphatidylinositol 4-phosphate 5-kinase Iγb

“…The difference between these two splice variants is a 26 amino acid extension to the C-terminal of PIPkin Iγa, which has been shown to be responsible for its interaction with talin (Barsukov et al, 2003;Di Paolo et al, 2002;Ling et al, 2002). Di Paolo et al (Di Paolo et al, 2002), Ling et al (Ling et al, 2002;Ling et al, 2003), and Calderwood et al (Calderwood et al, 2004) showed that due to this interaction, high over-expression of PIPkin Iγa resulted in the loss of talin from integrin-based adhesions, while PIPkin Iγb had no effect. Therefore the small but significant, PIPkin Iγa dose-dependent decrease in adhesion shown in Fig.…”