Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation
Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation
复制标题
DOI：
10.1002/j.1460-2075.1996.tb00571.x
复制
发表时间：
1996-05-01
期刊：
影响因子：
11.4
通讯作者：
Picard, D
中科院分区：
文献类型：
--
作者：
Bunone, G;Briand, PA;Picard, D
雌激素受体（ER）可以作为转录因子通过结合同源雌激素配体或间接地通过多种其他细胞外信号而被激活。作为阐明表皮生长因子（EGF）对ER的“类固醇非依赖性激活”机制的第一步，我们绘制了ER靶结构域并确定了信号传导途径，我们发现，N端转录激活功能AF-1，而不是C端AF-2，是EGF反应所必需的。EGF诱导的过度磷酸化和未配体ER的转录激活都依赖于118位可磷酸化的丝氨酸残基，然而，它的磷酸化是不够的，因此，必须有其他的靶结构域或蛋白质，以满足通过ER的EGF信号传导的额外要求，使用显性阴性Ras和MAP激酶（MAPK激酶）和组成型活性MAPK激酶突变体，我们表明EGF通过MAPK途径的信号传导激活ER，提示MAPK直接磷酸化关键的丝氨酸118，我们的研究结果还表明，类固醇非依赖性激活的各种ER突变体，出现在乳腺肿瘤的恶性进展，可能有助于他莫昔芬耐药。
The estrogen receptor (ER) can be activated as a transcription factor either by binding of cognate estrogenic ligand or, indirectly, by a variety of other extracellular signals, As a first step towards elucidating the mechanism of 'steroid-independent activation' of the ER by the epidermal growth factor (EGF), we have mapped the ER target domain and determined the signaling pathway, We show that the N-terminal transcriptional activation function AF-1, but not the C-terminal AF-2, is necessary for the EGF response, Both the EGF-induced hyperphosphorylation and the transcriptional activation of the unliganded ER depend on a phosphorylatable serine residue at position 118, However, its phosphorylation is not sufficient and, hence, there must be other target domains or proteins which fulfill an additional requirement for EGF signaling through the ER, Using dominant-negative Ras and MAP kinase kinase (MAPK kinase) and constitutively active MAPK kinase mutants, we show that EGF activates the ER by signaling through the MAPK pathway suggesting that MAPK directly phosphorylates the critical serine 118, Our results also imply that the steroid-independent activation of a variety of ER mutants, which arise during the malignant progression of breast tumors, may contribute to tamoxifen resistance.