Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actin Cytoskeleton / metabolism*
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Actins / biosynthesis
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Actins / metabolism*
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Amino Acid Sequence / genetics
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Animals
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Base Sequence / genetics
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Carrier Proteins / genetics
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Carrier Proteins / isolation & purification
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Carrier Proteins / metabolism*
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Cattle
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Cytoskeletal Proteins
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DNA, Complementary / analysis
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DNA, Complementary / genetics
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Evolution, Molecular
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Fatty Acid-Binding Proteins
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Humans
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Intracellular Signaling Peptides and Proteins
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Macromolecular Substances
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Molecular Sequence Data
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Phosphatidylinositol 4,5-Diphosphate / genetics
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Phosphatidylinositol 4,5-Diphosphate / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phylogeny
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Protein Binding / physiology
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Signal Transduction / genetics
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Wiskott-Aldrich Syndrome / genetics
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Wiskott-Aldrich Syndrome / metabolism
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Wiskott-Aldrich Syndrome Protein, Neuronal
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Xenopus Proteins / genetics
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Xenopus Proteins / isolation & purification
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Xenopus Proteins / metabolism*
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cdc42 GTP-Binding Protein / genetics
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cdc42 GTP-Binding Protein / metabolism*
Substances
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Actins
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Carrier Proteins
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Cytoskeletal Proteins
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DNA, Complementary
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FNBP1L protein, Xenopus
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FNBP1L protein, human
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Fatty Acid-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Macromolecular Substances
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Nerve Tissue Proteins
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Phosphatidylinositol 4,5-Diphosphate
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Phosphoproteins
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WASL protein, human
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WIPF1 protein, human
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Wipf1 protein, rat
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Wipf3 protein, rat
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Wiskott-Aldrich Syndrome Protein, Neuronal
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Xenopus Proteins
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cdc42 GTP-Binding Protein
Associated data
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GENBANK/AY514449
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GENBANK/AY640054