Essential phosphatases and a phospho-degron are critical for regulation of SRC-3/AIB1 coactivator function and turnover.
Essential phosphatases and a phospho-degron are critical for regulation of SRC-3/AIB1 coactivator function and turnover.
复制标题
DOI：
10.1016/j.molcel.2008.07.019
复制
发表时间：
2008-09-26
期刊：
影响因子：
16
通讯作者：
O'Malley, Bert W.
中科院分区：
文献类型：
--
作者：
Li, Chao;Liang, Yao-Yun;Feng, Xin-Hua;Tsai, Sophia Y.;Tsai, Ming-Jer;O'Malley, Bert W.
SRC-3/AIB 1是一个主要的生长辅激活因子和癌基因，磷酸化激活它成为一个强大的辅调节因子。去磷酸化是SRC-3功能的潜在调节机制，但这些磷酸酶的身份仍未被探索。在此，我们报告，使用功能基因组筛选的人丝氨酸/苏氨酸磷酸酶靶向SRC-3的已知的磷酸化位点，磷酸酶PDXP，PP 1和PP 2A被确定为关键的负调控SRC-3转录共调节活性的类固醇受体信号。PDXP和PP 2A使SRC-3去磷酸化并抑制其与雌激素受体的配体依赖性缔合。PP 1通过阻断SRC-3蛋白的蛋白酶体依赖性周转来稳定SRC-3蛋白，所述蛋白酶体依赖性周转通过活性所需的两个先前未鉴定的磷酸化位点（Ser 101和S102）的去磷酸化来进行。这两个位点位于SRC-3的降解决定子内，并且是SRC-3周转的主要决定因素。此外，PP 1调节乳腺癌细胞中SRC-3的致癌细胞增殖和侵袭功能。
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 SRC-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.
登录
查看更多内容
影响因子：
4.8
作者：
LEFEBVRE, P;GAUB, MP;FORMSTECHER, P
通讯作者：
FORMSTECHER, P
影响因子：
4.6
作者：
Liu, Cathy W. Y.;Wang, Rui-Hong;Berndt, Norbert
通讯作者：
Berndt, Norbert
影响因子：
4.8
作者：
Lu, Q;Surks, HK;Karas, RH
通讯作者：
Karas, RH
影响因子：
5.3
作者：
Feng, Qin;Yi, Ping;O'Malley, Bert W.
通讯作者：
O'Malley, Bert W.
影响因子：
--
作者：
Lee, SK;Kim, HJ;Lee, JW
通讯作者：
Lee, JW