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Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1

Author

Listed:
  • David Meiri

    (Technion Israel Institute of Technology)

  • Christopher B. Marshall

    (Princess Margaret Cancer Centre, University Health Network, University of Toronto, 101 College Street, Room 12-704, Toronto Medical Discovery Tower, Toronto, Ontario, Canada M5G 1L7)

  • Daphna Mokady

    (Princess Margaret Cancer Centre, University Health Network, University of Toronto, 101 College Street, Room 12-704, Toronto Medical Discovery Tower, Toronto, Ontario, Canada M5G 1L7)

  • Jose LaRose

    (Princess Margaret Cancer Centre, University Health Network, University of Toronto, 101 College Street, Room 12-704, Toronto Medical Discovery Tower, Toronto, Ontario, Canada M5G 1L7)

  • Michael Mullin

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Room 992A, Toronto, Ontario, Canada M5G 1X5)

  • Anne-Claude Gingras

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Room 992A, Toronto, Ontario, Canada M5G 1X5
    University of Toronto)

  • Mitsuhiko Ikura

    (Princess Margaret Cancer Centre, University Health Network, University of Toronto, 101 College Street, Room 12-704, Toronto Medical Discovery Tower, Toronto, Ontario, Canada M5G 1L7
    University of Toronto)

  • Robert Rottapel

    (Princess Margaret Cancer Centre, University Health Network, University of Toronto, 101 College Street, Room 12-704, Toronto Medical Discovery Tower, Toronto, Ontario, Canada M5G 1L7
    University of Toronto
    University of Toronto
    University of Toronto)

Abstract

The RhoGEF GEF-H1 can be sequestered in an inactive state on polymerized microtubules by the dynein motor light-chain Tctex-1. Phosphorylation of GEF-H1 Ser885 by PKA or PAK kinases creates an inhibitory 14-3-3-binding site. Here we show a new mode of GEF-H1 activation in response to the G-protein-coupled receptor (GPCR) ligands lysophosphatidic acid (LPA) or thrombin that is independent of microtubule depolymerization. LPA/thrombin stimulates disassembly of the GEF-H1:dynein multi-protein complex through the concerted action of Gα and Gβγ. Gα binds directly to GEF-H1 and displaces it from Tctex-1, while Gβγ binds to Tctex-1 and disrupts its interaction with the dynein intermediate chain, resulting in the release of GEF-H1. Full activation of GEF-H1 requires dephosphorylation of Ser885 by PP2A, which is induced by thrombin. The coordinated displacement of GEF-H1 from microtubules by G-proteins and its dephosphorylation by PP2A demonstrate a multistep GEF-H1 activation and present a unique mechanism coupling GPCR signalling to Rho activation.

Suggested Citation

  • David Meiri & Christopher B. Marshall & Daphna Mokady & Jose LaRose & Michael Mullin & Anne-Claude Gingras & Mitsuhiko Ikura & Robert Rottapel, 2014. "Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1," Nature Communications, Nature, vol. 5(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5857
    DOI: 10.1038/ncomms5857
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