NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin.
NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin.
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DOI：
10.1083/jcb.201503081
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发表时间：
2015-10-26
期刊：
影响因子：
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通讯作者：
McClatchey AI
中科院分区：
文献类型：
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作者：
Chiasson-MacKenzie C;Morris ZS;Baca Q;Morris B;Coker JK;Mirchev R;Jensen AE;Carey T;Stott SL;Golan DE;McClatchey AI
膜突蛋白（Merlin）和埃兹蛋白（Ezrin）在一种机制中起着核心作用，通过该机制，从细胞连接跨顶端肌动球蛋白细胞骨架转导的机械力控制着表皮生长因子受体（EGFR）的移动性和内化，这为细胞如何响应细胞接触抑制促有丝分裂信号传导提供了新的见解。
正常细胞在汇合时增殖受到抑制，但这种被称为接触依赖性增殖抑制现象的分子基础尚不清楚。我们之前确定了2型神经纤维瘤病（NF2）肿瘤抑制因子膜突蛋白是接触依赖性增殖抑制的关键调节因子，并特别发现膜突蛋白响应细胞接触抑制表皮生长因子受体（EGFR）的内化及其信号传导。膜突蛋白与膜 - 细胞骨架连接蛋白埃兹蛋白、根蛋白（Radixin）和膜收缩蛋白（Moesin）密切相关，并且膜突蛋白定位于皮质细胞骨架是EGFR接触依赖性调节所必需的。我们表明，膜突蛋白和埃兹蛋白是一种机制的重要组成部分，通过该机制，与细胞 - 细胞连接建立相关的机械力通过皮质肌动球蛋白细胞骨架跨细胞皮层转导，以控制EGFR的侧向移动性和活性，为细胞如何响应细胞接触抑制促有丝分裂信号传导提供了新的见解。
Merlin and Ezrin are central to a mechanism whereby mechanical forces transduced across the apical actomyosin cytoskeleton from cell junctions control the mobility and internalization of EGFR, providing novel insight into how cells inhibit mitogenic signaling in response to cell contact. The proliferation of normal cells is inhibited at confluence, but the molecular basis of this phenomenon, known as contact-dependent inhibition of proliferation, is unclear. We previously identified the neurofibromatosis type 2 (NF2) tumor suppressor Merlin as a critical mediator of contact-dependent inhibition of proliferation and specifically found that Merlin inhibits the internalization of, and signaling from, the epidermal growth factor receptor (EGFR) in response to cell contact. Merlin is closely related to the membrane–cytoskeleton linking proteins Ezrin, Radixin, and Moesin, and localization of Merlin to the cortical cytoskeleton is required for contact-dependent regulation of EGFR. We show that Merlin and Ezrin are essential components of a mechanism whereby mechanical forces associated with the establishment of cell–cell junctions are transduced across the cell cortex via the cortical actomyosin cytoskeleton to control the lateral mobility and activity of EGFR, providing novel insight into how cells inhibit mitogenic signaling in response to cell contact.