EGF protects prostate cancer cells from apoptosis by inducing BAD phosphorylation via redundant signaling pathways

doi:10.1074/jbc.M511485200

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Papers In Press, published online ahead of print July 17, 2006
J. Biol. Chem, 10.1074/jbc.M511485200
Submitted on October 24, 2005
Revised on July 14, 2006
Accepted on July 17, 2006

EGF protects prostate cancer cells from apoptosis by inducing BAD phosphorylation via redundant signaling pathways

Konduru S. R. Sastry, Yelena Karpova, and George Kulik

Dept. of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157

Corresponding Author: gkulik{at}wfubmc.edu

Protection from apoptosis by receptor tyrosine kinases, resistant to the inhibition of PI3K/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 EGF activates two anti-apoptotic signaling pathways that impinge on the pro-apoptotic protein BAD. One signaling cascade operates via the Ras/MEK module and induces BAD phosphorylation on S112. Another pathway predominantly relies on Rac/PAK1 signaling that leads to BAD phosphorylation on S136. Each of these two pathways is sufficient to protect cells from apoptosis and therefore both have to be inhibited simultaneously to block EGF-dependent survival. Redundancy of anti-apoptotic signaling pathways should be considered when therapies targeting anti-apoptotic mechanisms are designed.

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