Integrin β3 directly inhibits the Gα13-p115RhoGEF interaction to regulate G protein signaling and platelet exocytosis
Yaping Zhang, Xiaojuan Zhao, Bo Shen, Yanyan Bai, Claire Chang, Aleksandra Stojanović, Can Wang, Andrew Mack, Gary G. Deng, Randal A. Skidgel, Ni Cheng, Xiaoping Du
Abstract
Abstract The integrins and G protein-coupled receptors are both fundamental in cell biology. The cross talk between these two, however, is unclear. Here we show that β 3 integrins negatively regulate G protein-coupled signaling by directly inhibiting the Gα 13 -p115RhoGEF interaction. Furthermore, whereas β 3 deficiency or integrin antagonists inhibit integrin-dependent platelet aggregation and exocytosis (granule secretion), they enhance G protein-coupled RhoA activation and integrin-independent secretion. In contrast, a β 3 -derived Gα 13 -binding peptide or Gα 13 knockout inhibits G protein-coupled RhoA activation and both integrin-independent and dependent platelet secretion without affecting primary platelet aggregation. In a mouse model of myocardial ischemia/reperfusion injury in vivo, the β 3 -derived Gα 13 -binding peptide inhibits platelet secretion of granule constituents, which exacerbates inflammation and ischemia/reperfusion injury. These data establish crucial integrin-G protein crosstalk, providing a rationale for therapeutic approaches that inhibit exocytosis in platelets and possibly other cells without adverse effects associated with loss of cell adhesion.