Differential regulation of androgen receptor by P1M-1 kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases

Douglas E. Linn, Xi Yang, Yingqiu Xie, Alan Alfano, Dhanraj Deshmukh, Xin Wang, Hermela Shimelis, Hegang Chen, Wei Li, Kexin Xu, Mingyuan Chen, Yun Qiu

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30 Citations (Scopus)

Abstract

Androgen receptor (AR) plays a pivotal role in prostate cancer. Regulation of AR transcriptional activity by post-translational modifications, such as phosphorylation by multiple kinases, is well documented. Here, we report that two PIM-1 kinase isoforms which are up-regulated during prostate cancer progression, namely PIM-1S and PIM-1L, modulate AR stability and transcriptional activity through differentially phosphorylating AR at serine 213 (Ser-213) and threonine 850 (Thr-850). Although both kinases are capable of interacting with and phosphorylating AR at Ser-213, only PIM-1L could phosphorylate Thr-850. We also showed that PIM-1S induced Ser-213 phosphorylation destabilizes AR by recruiting the ubiquitin E3 ligase Mdm2 and promotes AR degradation in a cell cycle-dependent manner, while PIM-1L-induced Thr-850 phosphorylation stabilizes AR by recruiting the ubiquitin E3 ligase RNF6 and promotes AR-mediated transcription under low-androgen conditions. Furthermore, both PIM-1 isoforms could promote prostate cancer cell growth under low-androgen conditions. Our data suggest that these kinases regulate AR stability and transcriptional activity through recruitment of different functional partners in a phosphorylation-dependent manner. As AR turnover has been previously shown to be critical for cell cycle progression in prostate cancer cells, PIM-1 kinase isoforms may promote prostate cancer cell growth, at least in part, through modulating AR activity via distinct mechanisms.

Original languageEnglish
Pages (from-to)22959-22968
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number27
DOIs
Publication statusPublished - Jun 29 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Linn, D. E., Yang, X., Xie, Y., Alfano, A., Deshmukh, D., Wang, X., Shimelis, H., Chen, H., Li, W., Xu, K., Chen, M., & Qiu, Y. (2012). Differential regulation of androgen receptor by P1M-1 kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases. Journal of Biological Chemistry, 287(27), 22959-22968. https://doi.org/10.1074/jbc.M111.338350