Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck.
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 polymerization. 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 (M(r)) of 140,000), Nap125 (NCK-associated protein with an M(r) 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.
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue Boston, Massachusetts 02115, USA.
Sharon
S
Eden
Rajat
R
Rohatgi
Alexandre V
AV
Podtelejnikov
Matthias
M
Mann
Marc W
MW
Kirschner
D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002417:Cattle; D006801:Humans; D046911:Macromolecular Substances; D008840:Microfilament Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D014923:Wiskott-Aldrich Syndrome; D051300:Wiskott-Aldrich Syndrome Protein Family; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D046911:Macromolecular Substances; D008840:Microfilament Proteins; C484362:NCKAP1 protein, human; C078332:Nck protein; D015513:Oncogene Proteins; D051300:Wiskott-Aldrich Syndrome Protein Family; D020830:rac1 GTP-Binding Protein