Two domains of the progesterone receptor interact with the estrogen receptor and are required for progesterone activation of the c-Src/Erk pathway in mammalian cells
Two domains of the progesterone receptor interact with the estrogen receptor and are required for progesterone activation of the c-Src/Erk pathway in mammalian cells
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DOI：
10.1128/mcb.23.6.1994-2008.2003
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发表时间：
2003-03-01
影响因子：
5.3
通讯作者：
Beato, M
中科院分区：
文献类型：
--
作者：
Ballaré, C;Uhrig, M;Beato, M
在乳腺癌细胞中，雌激素通过雌激素受体α（ER α）与c-Src的SH 2结构域的相互作用激活Src/Erk通路。据报道，孕激素也通过孕激素受体亚型B（PR B）与ER α的相互作用激活该途径，ER α本身激活c-Src，或者通过PR B与c-Src的SH 3结构域的直接相互作用激活该途径。在这里，我们确定了两个域的PRB，ERID-I和-II，介导的ER α的配体结合域的直接相互作用。ERID-I和ERID-II位于负责PRB与c-Src结合的脯氨酸簇的侧翼。在哺乳动物细胞中，通过缺失ERID-I或ERID-II，PRB与ER α的相互作用和Src/Erk级联的白蛋白激活被消除。这些区域对于胆固醇应答报告基因的反式激活是不需要的。突变的脯氨酸簇的PRB，防止直接与c-Src的相互作用不影响强激活的c-Src的孕激素在ER α的存在下。因此，在具有ER α的细胞中，ERID-I和ERID-II对于内源性Src/Erk途径的曲马斯登激活是必需的和足够的。
In breast cancer cells, estrogens activate the Src/Erk pathway through an interaction of the estrogen receptor alpha (ERalpha) with the SH2 domain of c-Src. Progestins have been reported to activate also this pathway either via an interaction of the progesterone receptor isoform B (PRB) with ERalpha, which itself activates c-Src, or by direct interaction of PRB with the SH3 domain of c-Src. Here we identify two domains of PRB, ERID-I and -II, mediating a direct interaction with the ligand-binding domain of ERalpha. ERID-I and ERID-II flank a proline cluster responsible for binding of PRB to c-Src. In mammalian cells, the interaction of PRB with ERalpha and the progestin activation of the Src/Erk cascade are abolished by deletion of either ERID-I or ERID-II. These regions are not required for transactivation of a progesterone-responsive reporter gene. Mutations in the proline cluster of PRB that prevent a direct interaction with c-Src do not affect the strong activation of c-Src by progestins in the presence of ERalpha. Thus, in cells with ERalpha, ERID-I and ERID-II are necessary and sufficient for progestin activation of the endogenous Src/Erk pathway.