Mediator of ERBB2-driven Cell Motility (MEMO) Promotes Extranuclear Estrogen Receptor Signaling Involving the Growth Factor Receptors IGF1R and ERBB2
Mediator of ERBB2-driven Cell Motility (MEMO) Promotes Extranuclear Estrogen Receptor Signaling Involving the Growth Factor Receptors IGF1R and ERBB2
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ERBB2 驱动的细胞运动介质 (MEMO) 促进涉及生长因子受体 IGF1R 和 ERBB2 的核外雌激素受体信号传导
DOI：
10.1074/jbc.m113.467837
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发表时间：
2013-08-23
影响因子：
4.8
通讯作者：
Ye, Qinong
中科院分区：
文献类型：
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作者：
Jiang, Kai;Yang, Zhihong;Ye, Qinong
除了核雌激素受体（nuclear estrogen receptor， ER）作为转录因子外，核外ER还通过激活激酶级联反应在癌细胞生长调节中发挥重要作用。然而，核外内质网发挥其功能的分子机制仍然知之甚少。在这里，我们报道erbb2驱动的细胞运动（MEMO）调节ER的核外功能。MEMO在物理上和功能上都与ER交互。通过与生长因子受体IGF1R和ERBB2的相互作用，MEMO介导内质网的核外功能，包括激活丝裂原活化蛋白激酶（MAPK）和蛋白激酶B/AKT这两种重要的生长调节蛋白激酶，以及与核内质网的功能整合。MAPK和AKT的激活负责备忘录调节内质网磷酸化和雌激素应答基因表达。此外，MEMO增加了体外er阳性乳腺癌细胞的锚定依赖性和非依赖性生长，并且是裸鼠雌激素诱导乳腺肿瘤生长所必需的。总之，我们的研究确定了MEMO是核外ER信号体的一个新组成部分，并表明MEMO在调节ER阳性乳腺癌细胞生长中起重要作用。
In addition to nuclear estrogen receptor (ER) acting as a transcription factor, extranuclear ER also plays an important role in cancer cell growth regulation through activation of kinase cascades. However, the molecular mechanisms by which extranuclear ER exerts its function are still poorly understood. Here, we report that mediator of ERBB2-driven cell motility (MEMO) regulates extranuclear functions of ER. MEMO physically and functionally interacted with ER. Through its interaction with the growth factor receptors IGF1R and ERBB2, MEMO mediated extranuclear functions of ER, including activation of mitogen-activated protein kinase (MAPK) and protein kinase B/AKT, two important growth regulatory protein kinases, and integration of function with nuclear ER. Activation of MAPK and AKT was responsible for MEMO modulation of ER phosphorylation and estrogen-responsive gene expression. Moreover, MEMO increased anchorage-dependent and -independent growth of ER-positive breast cancer cells in vitro and was required for estrogen-induced breast tumor growth in nude mice. Together, our studies identified MEMO as a new component of extranuclear ER signalosome and suggest an essential role for MEMO in the regulation of ER-positive breast cancer cell growth.