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Integrin β3 directly inhibits the Gα13-p115RhoGEF interaction to regulate G protein signaling and platelet exocytosis

Author

Listed:
  • 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
    Dupage Medical Technology, Inc.)

  • 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)

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.

Suggested Citation

  • Yaping Zhang & Xiaojuan Zhao & Bo Shen & Yanyan Bai & Claire Chang & Aleksandra Stojanovic & Can Wang & Andrew Mack & Gary Deng & Randal A. Skidgel & Ni Cheng & Xiaoping Du, 2023. "Integrin β3 directly inhibits the Gα13-p115RhoGEF interaction to regulate G protein signaling and platelet exocytosis," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40531-3
    DOI: 10.1038/s41467-023-40531-3
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    References listed on IDEAS

    as
    1. Bo Shen & Xiaojuan Zhao & Kelly A. O’Brien & Aleksandra Stojanovic-Terpo & M. Keegan Delaney & Kyungho Kim & Jaehyung Cho & Stephen C.-T. Lam & Xiaoping Du, 2013. "A directional switch of integrin signalling and a new anti-thrombotic strategy," Nature, Nature, vol. 503(7474), pages 131-135, November.
    2. Liang Zhu & Jun Yang & Thomas Bromberger & Ashley Holly & Fan Lu & Huan Liu & Kevin Sun & Sarah Klapproth & Jamila Hirbawi & Tatiana V. Byzova & Edward F. Plow & Markus Moser & Jun Qin, 2017. "Structure of Rap1b bound to talin reveals a pathway for triggering integrin activation," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
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