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J. Biol. Chem., Vol. 280, Issue 14, 14168-14176, April 8, 2005

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Systematic Evaluation of Anti-apoptotic Growth Factor Signaling in Vascular Smooth Muscle Cells

ONLY PHOSPHATIDYLINOSITOL 3'-KINASE IS IMPORTANT^*

Marius Vantler, Evren Caglayan, Wolfram H. Zimmermann¶, Anselm T. Bäumer, and Stephan Rosenkranz||

From the Klinik III für Innere Medizin, Universität zu Köln, D-50924 Köln, Germany, the Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, D-50924 Köln, Germany, and the ^¶Institut für Experimentelle und Klinische Pharmakologie, Universitätsklinikum Hamburg-Eppendorf, D-20246 Hamburg, Germany

Peptide growth factors contribute to the pathogenesis of cardiovascular diseases by inducing a variety of cellular responses including anti-apoptotic effects. Several of the signaling molecules that are activated by growth factor receptors such as Src family kinases (Src), phosphatidylinositol 3'-kinase (PI3K), phospholipase C (PLC), Ras, and SHP-2 were shown to mediate survival signals. We systematically investigated the relative contribution of each signaling molecule for growth factor-dependent cell survival in vascular smooth muscle cells (VSMC). Our approach was the use of mutated plateletderived growth factor (PDGF) -receptors (PDGFR) in which the tyrosine residues required for binding of each signaling molecule were individually mutated to phenylalanine. To bypass endogenous PDGFR in VSMC we used chimeric receptors (ChiRs), containing the extracellular domain of the macrophage colony-stimulating factor (M-CSF) receptor and the cytoplasmic domain of the wild type (WT) or mutated PDGFR. Selective activation of the ChiR-WT with M-CSF significantly reduced apoptosis to the same extent as PDGF-BB in non-transfected cells. Deletion of the binding site for PI3K, but not for Src, RasGAP, SHP-2, or PLC, completely abolished the anti-apoptotic effect. Consistently, a ChiR mutant that only binds PI3K was fully able to mediate cell survival as efficiently as the ChiR-WT. Furthermore, the PDGF-dependent anti-apoptotic effect in non-transfected cells was completely abolished by the PI3K inhibitor wortmannin, whereas inhibitors of Src, PLC, ERK, or p38 MAP kinase had no effect. The exploration of downstream signaling events revealed that PDGF-BB activates the anti-apoptotic Akt signaling pathway in a PI3K-dependent manner. Moreover, Akt phosphorylates and thus inactivates the pro-apoptotic proteins BAD and Forkhead transcription factors (FKHR, FKHRL1). We conclude that growth factor-dependent cell survival in VSMC is mediated only by activation of the PI3K/Akt pathway, whereas all other receptor-associated signaling molecules do not play a significant role.

Received for publication, November 26, 2004 , and in revised form, January 7, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft (DFG) (Ro 1306-2-1 (to S. R. and W. H. Z.)), the Center for Molecular Medicine of the University of Cologne (CMMC, TV84 (to S. R.)), and by the Marga and Walter Boll Stiftung, Germany (to M. V. and S. R.). 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.

^|| To whom correspondence should be addressed: Klinik III für Innere Medizin, Universität zu Köln, Kerpener Str. 62, D-50924 Köln, Germany, Tel.: 49-221-478-5159; Fax: 49-221-478-6490; E-mail: Stephan.Rosenkranz{at}medizin.uni-koeln.de.

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