期刊
MOLECULAR CELL
卷 31, 期 6, 页码 835-849出版社
CELL PRESS
DOI: 10.1016/j.molcel.2008.07.019
关键词
-
资金
- NIH [HD08818, NURSA]
- Welch Foundation
SRC-3/AIB1 is a master growth coactivator and oncogene, and phosphorylation activates it into a powerful coregulator. Dephosphorylation is a potential regulatory mechanism for SRC-3 function, but the identity of such phosphatases remains unexplored. Herein, we report that, using functional genomic screening of human Ser/Thr phosphatases targeting SRC-3's known phosphorylation sites, the phosphatases PDXP, PP1, and PP2A were identified to be key negative regulators of SRC-3 transcriptional coregulatory activity in steroid receptor signalings. PDXP and PP2A dephosphorylate SIRC-3 and inhibit its ligand-dependent association with estrogen receptor. PP1 stabilizes SRC-3 protein by blocking its proteasome-dependent turnover through dephosphorylation of two previously unidentified phosphorylation sites (Ser101 and S102) required for activity. These two sites are located within a degron of SRC-3 and are primary determinants of SRC-3 turnover. Moreover, PP1 regulates the oncogenic cell proliferation and invasion functions of SRC-3 in breast cancer cells.
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