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

David Meiri, Christopher B. Marshall, Daphna Mokady, Jose LaRose, Michael Mullin, Anne-Claude Gingras, Mitsuhiko Ikura and Robert Rottapel ()
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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
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
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

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5857

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