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Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck

Nature volume 418, pages 790–793 (2002)Cite this article

Abstract

Rac signalling to actin—a pathway that is thought to be mediated by the protein Scar/WAVE (WASP (Wiskott–Aldrich syndrome protein)-family verprolin homologous protein)—has a principal role in cell motility. In an analogous pathway, direct interaction of Cdc42 with the related protein N-WASP stimulates actin polymerization1. For the Rac–WAVE pathway, no such direct interaction has been identified. Here we report a mechanism by which Rac and the adapter protein Nck activate actin nucleation through WAVE1. WAVE1 exists in a heterotetrameric complex that includes orthologues of human PIR121 (p53-inducible messenger RNA with a relative molecular mass (Mr) of 140,000), Nap125 (NCK-associated protein with an Mr of 125,000) and HSPC300. Whereas recombinant WAVE1 is constitutively active, the WAVE1 complex is inactive. We therefore propose that Rac1 and Nck cause dissociation of the WAVE1 complex, which releases active WAVE1–HSPC300 and leads to actin nucleation.

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Figure 1: Purification of a WAVE1-containing complex from bovine brain.
Figure 2: Rac1 or Nck induces Arp2/3 stimulation by the WAVE1 complex.
Figure 3: Disassembly of the WAVE1 complex by Rac1 and Nck enables activation.

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Acknowledgements

We thank H. Ho for HT–GST–WAVE1 baculovirus; B. Mayer for Nck constructs and proteins; R. Iggo for antibody to PIR121; J. Peterson and N. Ayad for discussions, technical help and critically reading the manuscript; and L. Ma for initial observations. This work was supported by the NIH (M.W.K.) the European Molecular Biology Organization (S.E.), the Human Frontier Science Program Organization (S.E.), the Danish National Research Foundation (M.M. and A.V.P.) and the Medical Sciences Training Program (MSTP) at Harvard Medical School (R.R.).

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  1. Alexandre V. Podtelejnikov

    Present address: MDS Proteomics, Staerosegaardsvej 6, DK-5230, Denmark,

Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Sharon Eden, Rajat Rohatgi & Marc W. Kirschner

  2. Protein Interaction Laboratory, University of Southern Denmark-Odense Campusvej 55, DK-5230 M, Odense, Denmark

    Alexandre V. Podtelejnikov & Matthias Mann

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Correspondence to Marc W. Kirschner.

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Eden, S., Rohatgi, R., Podtelejnikov, A. et al. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature 418, 790–793 (2002). https://doi.org/10.1038/nature00859

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