Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2012, PMID: 22139837

Androgen Receptor Enhances p27 Degradation in Prostate Cancer Cells through Rapid and Selective TORC2 Activation.

Fang, Zi; Zhang, Tao; Dizeyi, Nishtman; Chen, Sen; Wang, Hongyun; Swanson, Kenneth D; Cai, Changmeng; Balk, Steven P; Yuan, Xin

Androgen receptor (AR) plays a central role in prostate cancer (PCa) growth, with androgen deprivation or AR down-regulation causing cell-cycle arrest and accumulation of the p27 cyclin-dependent kinase inhibitor. The molecular basis for this AR regulation of cell-cycle progression remains unclear. Here we demonstrate that androgen can rapidly reduce p27 protein in PCa cells by increasing its proteasome-mediated degradation. This rapid androgen-stimulated p27 degradation was mediated by AKT through the phosphorylation of p27 T157. Significantly, androgen increased TORC2-mediated AKT S473 phosphorylation without affecting the PDK1-mediated AKT T308 phosphorylation or TORC1 activity. The TORC2 activation was further supported by enhanced mTOR/RICTOR association and increased phosphorylation of additional TORC2 substrates, SGK1 and PKCĪ±. The androgen-stimulated nuclear translocation of AR was associated with markedly-increased nuclear SIN1, a critical component of TORC2. Finally, the androgen-mediated TORC2/AKT activation targets a subset of AKT substrates including p27 and FOXO1, but not PRAS40. This study reveals a pathway linking AR to a selective activation of TORC2, the subsequent activation of AKT, and phosphorylation of a discrete set of AKT substrates that regulate cellular proliferation and survival. These findings establish that TORC2 can function as a central regulator of growth in response to signals that are distinct from those regulating TORC1, and support efforts to target TORC2 for cancer therapy.

Diseases/Pathways annotated by Medline MESH: Prostatic Neoplasms
Document information provided by NCBI PubMed

Text Mining Data

p27 → AKT: " This rapid androgen stimulated p27 degradation was mediated by AKT through the phosphorylation of p27 T157 "

TORC1 → PDK1: " Significantly, androgen increased TORC2 mediated AKT S473 phosphorylation without affecting the PDK1 mediated AKT T308 phosphorylation or TORC1 activity "

AKT → TORC2: " Significantly, androgen increased TORC2 mediated AKT S473 phosphorylation without affecting the PDK1 mediated AKT T308 phosphorylation or TORC1 activity "

AKT → PDK1: " Significantly, androgen increased TORC2 mediated AKT S473 phosphorylation without affecting the PDK1 mediated AKT T308 phosphorylation or TORC1 activity "

TORC2 → AKT: " This study reveals a pathway linking AR to a selective activation of TORC2 , the subsequent activation of AKT , and phosphorylation of a discrete set of AKT substrates that regulate cellular proliferation and survival "

Manually curated Databases

No curated data.