Interaction of Ga13 With b3. GTPloaded Ga13 binds to b3 integrin. This interaction appears to regulate Src, resulting in the deactivation of RhoA and facilitating platelet spreading. Figure adapted from Flevaris P et al. J Cell Biol. 2007;179:553-65.
Interaction of Ga13 With b3. GTPloaded Ga13 binds to b3 integrin. This interaction appears to regulate Src, resulting in the deactivation of RhoA and facilitating platelet spreading. Figure adapted from Flevaris P et al. J Cell Biol. 2007;179:553-65.
The authors observed that silencing of Gα13 in platelets inhibited spreading on immobilized fibrinogen. In addition, depletion of Gα13 abolished autophosphorylation of Src, suggesting that Gα13 acts upstream of the kinase. Proof that Gα13 was interacting with the β3 cytoplasmic tail was derived from immunoprecipitation studies demonstrating an association of Gα13 and β3. Direct binding of Gα13 to the β3 cytoplasmic tail was shown using recombinant proteins. Of note, the association of Gα13 with β3 was substantially enhanced by either platelet activation or incubation with GTP-γ-S or AlF4- to drive the formation of GTP-loaded Gα13. The authors identified switch region I as the domain of Gα13 responsible for binding β3. With this knowledge, they designed a cell-penetrating synthetic peptide to interfere with the Gα13-β3 interaction. This peptide inhibited integrin-dependent Src phosphorylation, accelerated RhoA activation, prevented platelet spreading, and promoted clot retraction. These studies form the basis of a new model of dynamic regulation of RhoA during platelet spreading and demonstrate that a heterotrimeric Gprotein can interact directly with an integrin cytoplasmic tail.
In Brief
Although it is appreciated that signaling through G-protein coupled receptors can indirectly influence integrin function by acting through downstream effectors, the conventional wisdom has been that these receptor types use distinct secondary signaling machinery. The observation that Gα13 binds directly to β3 challenges this dogma. The implications of these findings are far-reaching. Several mouse models demonstrate that “outside-in” signaling contributes to hemostasis and thrombus formation following vascular injury.3,4 Targeting the Gα13-β3 interaction may be a viable strategy for antithrombotic therapy. More compelling, however, is the possibility that G protein-integrin interactions are not limited to platelets. Integrins and heterotrimeric G proteins are ubiquitous proteins, and it is possible that Gα13 interacts with other integrins in other cells. Indeed, the authors demonstrate an interaction between Gα13 and β1. The extent to which Gα13 — and perhaps other G proteins — bind to non-G-protein coupled receptors and contribute to downstream signaling of these other receptor types remains to be determined. This work, however, lays the foundation for future efforts to understand the degree to which G protein coupling to noncanonical receptors affects signal transduction.
