Activation of the WAVE complex by coincident signals controls actin assembly.
WAVE proteins link upstream signals to actin nucleation by activating the Arp2/3 complex and are at the core of regulatory pathways driving membrane protrusion. They are found in heteropentameric complexes whose role in regulating WAVE function is presently unclear. Here we demonstrate that purified native WAVE complexes are basally inactive; previous reports of constitutive activity are artifacts of in vitro manipulation. Further, the native complexes are not activated by Rac alone. Activation of the WAVE2 complex requires simultaneous interactions with prenylated Rac-GTP and acidic phospholipids, as well as a specific state of phosphorylation. Together these signals promote full activation in a highly cooperative process on the membrane surface, by inducing an allosteric change in the complex rather than by simple recruitment or by dissociation of the subunits. These results explain how the WAVE complex can integrate coincident signals to promote localized actin nucleation during cell motility.
Lebensohn
Andres M
AM
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Kirschner
Marc W
MW
D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D006801:Humans; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation; D054876:Prenylation; D015398:Signal Transduction; D013552:Swine; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C078332:Nck protein; D015513:Oncogene Proteins; D010743:Phospholipids; C120152:WASF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D020744:rac GTP-Binding Proteins