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Originally published In Press as doi:10.1074/jbc.M402924200 on July 29, 2004

J. Biol. Chem., Vol. 279, Issue 41, 43273-43284, October 8, 2004
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Involvement of Phosphoinositide 3-Kinase {gamma}, Rac, and PAK Signaling in Chemokine-induced Macrophage Migration*

Cornelia Weiss-Haljiti{ddagger}§, Christian Pasquali{ddagger}, Hong Ji{ddagger}, Corine Gillieron{ddagger}, Christian Chabert{ddagger}, Marie-Laure Curchod{ddagger}, Emilio Hirsch¶, Anne J. Ridley||, Rob Hooft van Huijsduijnen{ddagger}, Montserrat Camps{ddagger}, and Christian Rommel{ddagger}**

From the {ddagger}Serono Pharmaceutical Research Institute, Serono International S.A., 14 Chemin des Aulx, CH 1228 Plan-les-Ouates, Geneva, Switzerland, Dipartimento di Genetica, Biologia e Biochimica, Universita di Torino, 10126 Torino, Italy, ||Ludwig Institute for Cancer Research and Department of Biochemistry and Molecular Biology, University College London, W1W 7BS, United Kingdom

In macrophages, chemotactic stimuli cause the activation of Rac and PAK, but little is known about the signaling pathways involved and their role in chemotactic gradient sensing. Herein, we report that in macrophages, the chemokine RANTES (regulated on activation normal T cell expressed and secreted)/CCL5 activates the small GTPase Rac and its downstream target PAK2 within seconds. This response depends on Gi activation and largely on the subsequent triggering of phosphoinositide 3-kinase {gamma} (PI3K{gamma}) and Rac. Retroviral transduction of tagged Rac1 and -2 indicates that RANTES/CCL5-mediated activation of PI3K{gamma} triggers Rac1 but not Rac2. In agreement, silencing of Rac1 by shRNA blocks PAK2 activity and inhibits RANTES/CCL5-induced macrophage polarization and directional migration. On the other hand, the tyrosine kinase receptor agonist CSF-1 activates PAK2 independently of PI3K{gamma} and Rac. Our results thus demonstrate a chemokine-specific signaling pathway in which Gi and PI3K{gamma} coordinate to drive Rac1 and PAK2 activation that eventually controls the chemotactic response.

Received for publication, March 16, 2004 , and in revised form, July 22, 2004.

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: Cenix Bioscience GmbH, Tatzberg 47, 01307 Dresden, Germany.

** To whom correspondence should be addressed. Tel.: 0041-22-706-9627; Fax: 0041-22-706-9558; E-mail: christian.rommel{at}serono.com.


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