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Coordinated activation of the Rac-GAP β2-chimaerin by an atypical proline-rich domain and diacylglycerol

Author

Listed:
  • Alvaro Gutierrez-Uzquiza

    (Perelman School of Medicine, University of Pennsylvania)

  • Francheska Colon-Gonzalez

    (Perelman School of Medicine, University of Pennsylvania)

  • Thomas A. Leonard

    (Laboratory of Molecular Biology, National Institutes of Health)

  • Bertram J. Canagarajah

    (Laboratory of Molecular Biology, National Institutes of Health)

  • HongBin Wang

    (Perelman School of Medicine, University of Pennsylvania)

  • Bruce J. Mayer

    (University of Connecticut Health Center)

  • James H. Hurley

    (Laboratory of Molecular Biology, National Institutes of Health)

  • Marcelo G. Kazanietz

    (Perelman School of Medicine, University of Pennsylvania)

Abstract

Chimaerins, a family of GTPase activating proteins for the small G-protein Rac, have been implicated in development, neuritogenesis and cancer. These Rac-GTPase activating proteins are regulated by the lipid second messenger diacylglycerol generated by tyrosine kinases such as the epidermal growth factor receptor. Here we identify an atypical proline-rich motif in chimaerins that binds to the adaptor protein Nck1. Unlike most Nck1 partners, chimaerins bind to the third SH3 domain of Nck1. This association is mediated by electrostatic interactions of basic residues within the Pro-rich motif with acidic clusters in the SH3 domain. Epidermal growth factor promotes the binding of β2-chimaerin to Nck1 in the cell periphery in a diacylglycerol-dependent manner. Moreover, β2-chimaerin translocation to the plasma membrane and its peripheral association with Rac1 requires Nck1. Our studies underscore a coordinated mechanism for β2-chimaerin activation that involves lipid interactions via the C1 domain and protein–protein interactions via the N-terminal proline-rich region.

Suggested Citation

  • Alvaro Gutierrez-Uzquiza & Francheska Colon-Gonzalez & Thomas A. Leonard & Bertram J. Canagarajah & HongBin Wang & Bruce J. Mayer & James H. Hurley & Marcelo G. Kazanietz, 2013. "Coordinated activation of the Rac-GAP β2-chimaerin by an atypical proline-rich domain and diacylglycerol," Nature Communications, Nature, vol. 4(1), pages 1-13, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2834
    DOI: 10.1038/ncomms2834
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