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J. Biol. Chem., Vol. 281, Issue 37, 27367-27377, September 15, 2006

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Epidermal Growth Factor Protects Prostate Cancer Cells from Apoptosis by Inducing BAD Phosphorylation via Redundant Signaling Pathways^*

From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Protection from apoptosis by receptor tyrosine kinases, resistant to the inhibition of phosphatidylinositol 3 '-kinase/Akt and Ras/MEK pathways, has been reported in several cell types, including fibroblasts and epithelial prostate cancer cells; however, mechanisms of this effect were not clear. Here we report that in prostate cancer cells, epidermal growth factor activates two antiapoptotic signaling pathways that impinge on the proapoptotic protein BAD. One signaling cascade operates via the Ras/MEK module and induces BAD phosphorylation on Ser¹¹². Another pathway predominantly relies on Rac/PAK1 signaling that leads to BAD phosphorylation on Ser¹³⁶. Each of these two pathways is sufficient to protect cells from apoptosis, and therefore both have to be inhibited simultaneously to block epidermal growth factor-dependent survival. Redundancy of antiapoptotic signaling pathways should be considered when therapies targeting antiapoptotic mechanisms are designed.

Received for publication, October 24, 2005 , and in revised form, July 14, 2006.

^* This work was supported by Department of Defense Grant DAMD17-02-1-0154, Grants from the Wake Forest University Comprehensive Cancer Center, and Wake Forest University School of Medicine Interim Funding. 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.

The on-line version of this article (available at http://www.jbc.org) contains Figs. S1-S8.

¹ To whom correspondence should be addressed. Tel.: 336-713-7650; Fax: 336-713-7661; E-mail: gkulik{at}wfubmc.edu.

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