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Unconventional Rac-GEF activity is mediated through the Dock180–ELMO complex

Nature Cell Biology volume 4, pages 574582 (2002) | Download Citation

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Abstract

Mammalian Dock180 and ELMO proteins, and their homologues in Caenorhabditis elegans and Drosophila melanogaster, function as critical upstream regulators of Rac during development and cell migration. The mechanism by which Dock180 or ELMO mediates Rac activation is not understood. Here, we identify a domain within Dock180 (denoted Docker) that specifically recognizes nucleotide-free Rac and can mediate GTP loading of Rac in vitro. The Docker domain is conserved among known Dock180 family members in metazoans and in a yeast protein. In cells, binding of Dock180 to Rac alone is insufficient for GTP loading, and a Dock180–ELMO1 interaction is required. We can also detect a trimeric ELMO1–Dock180–Rac1 complex and ELMO augments the interaction between Dock180 and Rac. We propose that the Dock180–ELMO complex functions as an unconventional two-part exchange factor for Rac.

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Acknowledgements

We thank J. Casanova, T. Parsons and U. Lorenz for critically reading the manuscript and members of the Ravichandran laboratory for helpful suggestions and comments. We thank C. Der and T. Karnoub for generously providing us with the RacW56F mutant. This work was supported in part by an American Cancer Society grant to K.S.R.

Author information

Author notes

    • Enrico Brugnera
    •  & Lisa Haney

    These authors contributed equally to this work

Affiliations

  1. Beirne Carter Center for Immunology Research and the Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA

    • Enrico Brugnera
    • , Lisa Haney
    • , Cynthia Grimsley
    • , Mingjian Lu
    • , Scott F. Walk
    • , Annie-Carole Tosello-Trampont
    •  & Kodimangalam S. Ravichandran
  2. Department of Pharmacology and the Markey Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA

    • Ian G. Macara
  3. Department of Biochemistry and Biophysics, University of California-San Francisco, San Francisco, CA 94143, USA

    • Hiten Madhani
  4. Whitehead Institute, Nine Cambridge Center, Cambridge MA 02142, USA

    • Gerald R. Fink

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Kodimangalam S. Ravichandran.

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    Supplementary figure

    Supplemental Figure 1. Coprecipitation of Docker domain with GST-Rac.

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DOI

https://doi.org/10.1038/ncb824

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