Toca-1 mediates Cdc42-dependent actin nucleation by activating the N-WASP-WIP complex.
An important signaling pathway to the actin cytoskeleton links the Rho family GTPase Cdc42 to the actin-nucleating Arp2/3 complex through N-WASP. Nevertheless, these previously identified components are not sufficient to mediate Cdc42-induced actin polymerization in a physiological context. In this paper, we describe the biochemical purification of Toca-1 (transducer of Cdc42-dependent actin assembly) as an essential component of the Cdc42 pathway. Toca-1 binds both N-WASP and Cdc42 and is a member of the evolutionarily conserved PCH protein family. Toca-1 promotes actin nucleation by activating the N-WASP-WIP/CR16 complex, the predominant form of N-WASP in cells. Thus, the cooperative actions of two distinct Cdc42 effectors, the N-WASP-WIP complex and Toca-1, are required for Cdc42-induced actin assembly. These findings represent a significantly revised view of Cdc42-signaling and shed light on the pathogenesis of Wiskott-Aldrich syndrome.
Ho
Hsin-Yi Henry
HY
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Rohatgi
Rajat
R
Lebensohn
Andres M
AM
Le Ma
Li
Jiaxu
J
Gygi
Steven P
SP
Kirschner
Marc W
MW
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000096:biosynthesis / Q000378:metabolism*; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D002417:Cattle; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D019143:Evolution, Molecular; D050556:Fatty Acid-Binding Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D011485:Protein Binding / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000378:metabolism; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D029867:Xenopus Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; C488976:FNBP1L protein, Xenopus; C482527:FNBP1L protein, human; D050556:Fatty Acid-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D010750:Phosphoproteins; C495771:WASL protein, human; C109903:WIPF1 protein, human; C491670:Wipf1 protein, rat; C105364:Wipf3 protein, rat; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D029867:Xenopus Proteins; D020764:cdc42 GTP-Binding Protein