Paxillin regulates androgen- and epidermal growth factor-induced MAPK signaling and cell proliferation in prostate cancer cells.
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. Thus, paxillin serves as a specific upstream regulator of Erk in response to receptor-tyrosine kinase signaling but as a general regulator of downstream Erk actions regardless of agonist. Importantly, Erk-mediated serine phosphorylation of paxillin is also required for DHT-induced prostate-specific antigen mRNA expression in LnCAP cells as well as EGF-induced cyclin D1 mRNA expression in PC3 cells, suggesting that paxillin may regulate prostate cancer proliferation by serving as a liaison between extra-nuclear kinase signaling and intra-nuclear transcriptional signals. Thus, paxillin may prove to be a novel diagnostic or therapeutic target in prostate cancer.
Sen
Aritro
A
Department of Medicine, Division of Endocrinology, University of Rochester Medical Center, Rochester, New York 14642, USA.
O'Malley
Katherine
K
Wang
Zhou
Z
Raj
Ganesh V
GV
Defranco
Donald B
DB
Hammes
Stephen R
SR
D000728:Androgens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051419:Paxillin / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D000728:Androgens; C496061:PXN protein, human; D051419:Paxillin; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D017430:Prostate-Specific Antigen