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Molecular and Cellular Biology, October 2007, p. 6615-6628, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00367-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cdc42 and Phosphoinositide 3-Kinase Drive Rac-Mediated Actin Polymerization Downstream of c-Met in Distinct and Common Pathways ^,

Tanja Bosse,¹ Julia Ehinger,¹ Aleksandra Czuchra,⁴ Stefanie Benesch,^1, Anika Steffen,^2, Xunwei Wu,^4,¶ Kathrin Schloen,² Hartmut H. Niemann,³ Giorgio Scita,⁵ Theresia E. B. Stradal,² Cord Brakebusch,^4,|| and Klemens Rottner^1*

Cytoskeleton Dynamics Group,¹ Signalling and Motility Group,² Division of Structural Biology, Helmholtz Centre for Infection Research (HZI), Inhoffenstrasse 7, D-38124 Braunschweig, Germany,³ Heisenberg Group "Regulation of Cytoskeletal Organization," Max Planck Institute of Biochemistry, Am Klopferspitz 18A, D-82152 Martinsried, Germany,⁴ European Institute of Oncology (IEO) and The FIRC Institute for Molecular Oncology (IFOM), Via Adamello 16, 20139 Milan, Italy⁵

Received 28 February 2007/ Returned for modification 1 May 2007/ Accepted 23 July 2007

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.

Published ahead of print on 6 August 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Institute of Molecular Biotechnology, Dr. Bohr Gasse 3, A-1030 Vienna, Austria.

Present address: Cytoskeleton and Membrane Dynamics Group, Institut Curie, CNRS UMR 144, 26, rue d'Ulm, 75248 Paris, France.

^¶ Present address: Cutaneous Biology Research Center (CBRC), Massachusetts General Hospital, Harvard Medical School, Bldg. 149, 13th St., Charlestown, MA 02129.

^|| Present address: Department of Molecular Pathology, University of Copenhagen, Frederik V's Vej 11, 2100 Copenhagen, Denmark.

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