Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
Cell morphology and motility are governed largely by complex signaling networks that ultimately engage the actin cytoskeleton. Understanding how individual circuits contribute to the process of forming cellular structures would be aided greatly by the availability of specific chemical inhibitors. We have used a novel chemical screen in Xenopus cell-free extracts to identify compounds that inhibit signaling pathways regulating actin polymerization. Here we report the results of a high-throughput screen for compounds that inhibit phosphatidylinositol 4,5-bisphosphate (PIP(2))-induced actin assembly and the identification of the first compound, a cyclic peptide, known to block actin assembly by inhibiting an upstream signaling component. We identify the target of this compound as N-WASP, a protein that has been investigated for its role as a node interconnecting various actin signaling networks. We show that this compound prevents activation of the Arp2/3 complex by N-WASP by allosterically stabilizing the autoinhibited conformation of N-WASP.
Carlier,
GRB2 links signaling to actin assembly by enhancing interaction of neural Wiskott-Aldrich syndrome protein (N-WASp) with actin-related protein (ARP2/3) complex.
2000, Pubmed
Carlier,
GRB2 links signaling to actin assembly by enhancing interaction of neural Wiskott-Aldrich syndrome protein (N-WASp) with actin-related protein (ARP2/3) complex.
2000,
Pubmed Desai,
The use of Xenopus egg extracts to study mitotic spindle assembly and function in vitro.
1999,
Pubmed
,
Xenbase Devriendt,
Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia.
2001,
Pubmed Egile,
Activation of the CDC42 effector N-WASP by the Shigella flexneri IcsA protein promotes actin nucleation by Arp2/3 complex and bacterial actin-based motility.
1999,
Pubmed Frischknecht,
Actin-based motility of vaccinia virus mimics receptor tyrosine kinase signalling.
1999,
Pubmed Hall,
Rho GTPases and the actin cytoskeleton.
1998,
Pubmed Higgs,
Activation by Cdc42 and PIP(2) of Wiskott-Aldrich syndrome protein (WASp) stimulates actin nucleation by Arp2/3 complex.
2000,
Pubmed Janmey,
Phosphoinositides and calcium as regulators of cellular actin assembly and disassembly.
1994,
Pubmed Jones,
Principles of protein-protein interactions.
1996,
Pubmed Kim,
Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein.
2000,
Pubmed Ma,
The Arp2/3 complex mediates actin polymerization induced by the small GTP-binding protein Cdc42.
1998,
Pubmed
,
Xenbase Ma,
Corequirement of specific phosphoinositides and small GTP-binding protein Cdc42 in inducing actin assembly in Xenopus egg extracts.
1998,
Pubmed
,
Xenbase Miki,
N-WASP, a novel actin-depolymerizing protein, regulates the cortical cytoskeletal rearrangement in a PIP2-dependent manner downstream of tyrosine kinases.
1996,
Pubmed Miki,
Induction of filopodium formation by a WASP-related actin-depolymerizing protein N-WASP.
1998,
Pubmed Mullins,
Structure and function of the Arp2/3 complex.
1999,
Pubmed Mullins,
How WASP-family proteins and the Arp2/3 complex convert intracellular signals into cytoskeletal structures.
2000,
Pubmed Pantaloni,
Mechanism of actin-based motility.
2001,
Pubmed Prehoda,
Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex.
2000,
Pubmed Rohatgi,
Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4, 5-bisphosphate.
2000,
Pubmed
,
Xenbase Rohatgi,
The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly.
1999,
Pubmed
,
Xenbase Stites,
Proteinminus signProtein Interactions: Interface Structure, Binding Thermodynamics, and Mutational Analysis.
1997,
Pubmed Takenawa,
WASP and WAVE family proteins: key molecules for rapid rearrangement of cortical actin filaments and cell movement.
2001,
Pubmed Wright,
Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm.
1999,
Pubmed Zigmond,
How WASP regulates actin polymerization.
2000,
Pubmed
