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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor α to the plasma membrane
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The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor α to the plasma membrane

机译：Shc和胰岛素样生长因子1受体在介导雌激素受体α转移到质膜中的作用

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摘要

Our previous studies demonstrated that 17β-estradiol (E2) rapidly induces the interaction of estrogen receptor α (ERα) with the adapter protein Shc, the translocation of ERa to the cell membrane, and the formation of dynamic membrane structures in MCF-7 breast cancer cells. The present study examined how E2 causes ERα to translocate to the region of the plasma membrane and focused on mechanisms whereby Shc and the insulin-like growth factor-1 receptor (IGF-1R) mediate this process. Shc physically interacts with IGF-1R in the plasma membrane, and E2 activates IGF-1R. We reasoned that ERα, when bound to Shc, would be directed to the region of the plasma membrane by the same processes, causing membrane translocation of Shc. We confirmed that E2 rapidly induced IGF-1R phosphorylation and demonstrated that E2 induced formation of a ternary protein complex among Shc, ERα, and IGF-1 R. Knock down of Shc with a specific small inhibitory RNA decreased the association of ERα with IGF-1R by 87%, suggesting that Shc is a crucial molecule in the formation of this ternary complex. Confocal microscopy studies provided further confirmation of the functional roles of Shc and the IGF-1R in the translocation of ERα to the region of the membrane. Down-regulation of Shc, ERα, or IGF-1R with specific small inhibitory RNAs all blocked E2-induced mitogen-activated protein kinase phosphorylation. Together, our results demonstrate that Shc and IGF-1R serve as key elements in the translocation of ERα to the cell membrane and in the facilitation of ERα-mediated rapid E2 action.
机译：我们先前的研究表明，MCF-7乳腺癌中17β-雌二醇（E2）迅速诱导雌激素受体α（ERα）与衔接蛋白Shc相互作用，ERa转运至细胞膜并形成动态膜结构细胞。本研究检查了E2如何引起ERα转运到质膜区域，并集中于Shc和胰岛素样生长因子-1受体（IGF-1R）介导此过程的机制。 Shc与质膜中的IGF-1R发生物理相互作用，而E2激活IGF-1R。我们认为，ERα当与Shc结合时，将通过相同的过程被导向质膜区域，从而导致Shc的膜移位。我们证实E2迅速诱导IGF-1R磷酸化，并证明E2诱导Shc，ERα和IGF-1 R之间形成三元蛋白复合物。用特定的小抑制性RNA敲除Shc降低了ERα与IGF-的结合。 1R降低了87％，表明Shc是这种三元复合物形成过程中的关键分子。共聚焦显微镜研究进一步证实了Shc和IGF-1R在ERα向膜区域转运中的功能作用。 Shc，ERα或IGF-1R的下调与特定的小抑制性RNA均能阻止E2诱导的丝裂原激活的蛋白激酶磷酸化。总之，我们的结果表明，Shc和IGF-1R在ERα向细胞膜移位和促进ERα介导的快速E2作用中起关键作用。

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