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 Stojanovic, Can Wang, Andrew Mack, Gary Deng, Randal A. Skidgel, Ni Cheng and Xiaoping Du ()
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Yaping Zhang: University of Illinois at Chicago
Xiaojuan Zhao: University of Illinois at Chicago
Bo Shen: University of Illinois at Chicago
Yanyan Bai: University of Illinois at Chicago
Claire Chang: University of Illinois at Chicago
Aleksandra Stojanovic: University of Illinois at Chicago
Can Wang: University of Illinois at Chicago
Andrew Mack: University of Illinois at Chicago
Gary Deng: Eli Lilly
Randal A. Skidgel: Dupage Medical Technology, Inc.
Ni Cheng: University of Illinois at Chicago
Xiaoping Du: University of Illinois at Chicago

Nature Communications, 2023, vol. 14, issue 1, 1-12

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 β3 integrins negatively regulate G protein-coupled signaling by directly inhibiting the Gα13-p115RhoGEF interaction. Furthermore, whereas β3 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 β3-derived Gα13-binding peptide or Gα13 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 β3-derived Gα13-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.

Date: 2023
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DOI: 10.1038/s41467-023-40531-3

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