Paxillin regulates androgen- and epidermal growth factor-induced MAPK signaling and cell proliferation in prostate cancer cells.

The Journal of Biological Chemistry
Aritro SenStephen R Hammes

Abstract

Although transcriptional effects of androgens have been extensively studied, mechanisms regulating transcription-independent (nongenomic) androgen actions are poorly understood. Previously, we have shown that paxillin, a multidomain adaptor protein, is a critical regulator of testosterone-induced MAPK-signaling during Xenopus oocyte maturation. Here we examine the nongenomic effects of dihydrotestosterone (DHT) in prostate cancer cells, focusing on how paxillin mediates Erk signaling and downstream physiologic actions. We show that in LnCAP cells DHT functions as a growth factor that indirectly activates the EGF-receptor (EGFR) via androgen receptor binding and matrix metalloproteinase-mediated release of EGFR ligands. Interestingly, siRNA-mediated knockdown of paxillin expression in androgen-dependent LnCAP cells as well as in androgen-independent PC3 cells abrogates DHT- and/or EGF-induced Erk signaling. Furthermore, EGFR-induced Erk activation requires Src-mediated phosphorylation of paxillin on tyrosines 31/118. In contrast, paxillin is not required for PKC-induced Erk signaling. However, Erk-mediated phosphorylation of paxillin on serines 83/126/130 is still needed for both EGFR and PKC-mediated cellular proliferation. Thu...Continue Reading

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Citations

Jul 19, 2012·The Journal of Biological Chemistry·Sungsoo M YooRichard A Cerione
Jun 12, 2012·The Journal of Clinical Investigation·Aritro SenStephen R Hammes
Oct 27, 2011·Endocrinology·Stephen R Hammes, Ellis R Levin
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Feb 12, 2014·Proceedings of the National Academy of Sciences of the United States of America·Aritro SenStephen R Hammes
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Aug 28, 2018·Frontiers in Endocrinology·Stephen Franks, Kate Hardy

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