Activation of c-Met, the hepatocyte growth factor (HGF)/scatter factor receptor induces reorganization of the actin cytoskeleton, which drives epithelial cell scattering and motility and is exploited by pathogenic Listeria monocytogenes to invade nonepithelial cells. However, the precise contributions of distinct Rho-GTPases, the phosphatidylinositol 3-kinases, and actin assembly regulators to c-Met-mediated actin reorganization are still elusive. Here we report that HGF-induced membrane ruffling and Listeria invasion mediated by the bacterial c-Met ligand internalin B (InlB) were significantly impaired but not abrogated upon genetic removal of either Cdc42 or pharmacological inhibition of phosphoinositide 3-kinase (PI3-kinase). While loss of Cdc42 or PI3-kinase function correlated with reduced HGF- and InlB-triggered Rac activation, complete abolishment of actin reorganization and Rac activation required the simultaneous inactivation of both Cdc42 and PI3-kinase signaling. Moreover, Cdc42 activation was fully independent of PI3-kinase activity, whereas the latter partly depended on Cdc42. Finally, Cdc42 function did not require its interaction with the actin nucleation-promoting factor N-WASP. Instead, actin polymerization was driven by Arp2/3 complex activation through the WAVE complex downstream of Rac. Together, our data establish an intricate signaling network comprising as key molecules Cdc42 and PI3-kinase, which converge on Rac-mediated actin reorganization essential for Listeria invasion and membrane ruffling downstream of c-Met.
Cdc42 and phosphoinositide 3-kinase drive Rac-mediated actin polymerization downstream of c-Met in distinct and common pathways / T. Bosse, J. Ehinger, A. Czuchra, S. Benesch, A. Steffen, X. Wu, K. Schloen, H. H. Niemann, G. Scita, T. E. B. Stradal, C. Brakebusch, K. Rottner. - In: MOLECULAR AND CELLULAR BIOLOGY. - ISSN 0270-7306. - 27:19(2007 Oct), pp. 6615-28-6628.
|Titolo:||Cdc42 and phosphoinositide 3-kinase drive Rac-mediated actin polymerization downstream of c-Met in distinct and common pathways|
|Parole Chiave:||Animals; Listeria monocytogenes; Enzyme Activation; Wiskott-Aldrich Syndrome Protein Family; Humans; Proto-Oncogene Proteins c-met; Wiskott-Aldrich Syndrome Protein, Neuronal; Mice; Recombinant Fusion Proteins; Membrane Proteins; Phosphatidylinositol 3-Kinases; Mice, Knockout; Cell Surface Extensions; Bacterial Proteins; Actins; rac1 GTP-Binding Protein; cdc42 GTP-Binding Protein; Signal Transduction|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||ott-2007|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1128/MCB.00367-07|
|Appare nelle tipologie:||01 - Articolo su periodico|