Synergistic Activation of ERα by Estrogen and Prolactin in Breast Cancer Cells Requires Tyrosyl Phosphorylation of PAK1.
Synergistic Activation of ERα by Estrogen and Prolactin in Breast Cancer Cells Requires Tyrosyl Phosphorylation of PAK1.
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DOI：
10.1158/0008-5472.can-15-1758
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发表时间：
2016-05-01
期刊：
影响因子：
11.2
通讯作者：
Diakonova M
中科院分区：
文献类型：
--
作者：
Oladimeji P;Skerl R;Rusch C;Diakonova M
丝氨酸/苏氨酸激酶PAK 1被雌激素激活，在乳腺癌中起重要作用。然而，PAK 1整合到雌激素反应中并不完全清楚。本研究探讨了雌激素受体（ERα，ESR 1）激活的机制。我们发现雌激素通过ERα和GPER 1膜受体激活PAK 1。PAK 1的雌激素依赖性激活需要在组装的信号传导复合物内通过Etk/Bmx和蛋白激酶A（PKA）磷酸化酪氨酸残基，该信号传导复合物包括pTyr-PAK 1、Etk/Bmx、异源三聚体G蛋白亚基Gβ1、Gγ2和/或Gγ5、PAK相关鸟嘌呤核苷酸交换因子（βPIX、ARHGEF 7）和PKA。此外，PKA RIIβ亚基是PAK 1的直接靶点，因此在对雌激素的反应中，活化的pTyr-PAK 1复合物可增强PKA活性，表明正反馈机制。我们还证明，PKA磷酸化Ser 305-ERα响应雌激素，但pTyr-PAK 1磷酸化Ser 305-ERα响应催乳素（PRL），这意味着当细胞暴露于PRL和雌激素时，达到最大的ERα磷酸化。此外，S305-ERα的激活可导致Ser 118-ERα磷酸化水平的增加，从而促进细胞增殖和肿瘤生长。总之，这些数据强烈支持PRL和雌激素之间通过PAK 1的关键相互作用，并表明通过PRL/PAK 1的ERα的配体非依赖性激活可能会对抗雌激素治疗产生抗性。
Serine/threonine kinase PAK1 is activated by estrogen and plays an important role in breast cancer. However, the integration of PAK1 into the estrogen response is not fully understood. In this study, we investigated the mechanisms underlying hormone-induced activation of estrogen receptor (ERα, ESR1). We show that estrogen activated PAK1 through both the ERα and GPER1 membrane receptors. Estrogen-dependent activation of PAK1 required the phosphorylation of tyrosine residues by Etk/Bmx and protein kinase A (PKA) within an assembled signaling complex comprising pTyr-PAK1, Etk/Bmx, the heterotrimer G-protein subunits Gβ1, Gγ2 and/or Gγ5, PAK-associated guanine nucleotide exchange factor (βPIX, ARHGEF7), and PKA. Moreover, the PKA RIIβ subunit is a direct target of PAK1, and thus in response to estrogen, the activated pTyr-PAK1 complex reciprocally potentiated PKA activity, suggesting a positive feedback mechanism. We also demonstrate that PKA phosphorylated Ser305-ERα in response to estrogen, but pTyr-PAK1 phosphorylated Ser305-ERα in response to prolactin (PRL), implying that maximal ERα phosphorylation is achieved when cells are exposed to both PRL and estrogen. Furthermore, S305-ERα activation led to enhanced phosphorylation of Ser118-ERα and promoted cell proliferation and tumor growth. Together, these data strongly support a critical interplay between PRL and estrogen via PAK1, and suggest that ligand-independent activation of ERα through PRL/PAK1 may impart resistance to anti-estrogen therapies.