ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions.
ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions.
复制标题
DOI：
10.1210/mend.16.1.0757
复制
发表时间：
2002
影响因子：
--
通讯作者：
M. Razandi;P. Oh;A. Pedram;J. Schnitzer;E. Levin
中科院分区：
文献类型：
--
作者：
M. Razandi;P. Oh;A. Pedram;J. Schnitzer;E. Levin
最近的证据支持质膜内质网的存在。在许多细胞中，E2激活信号转导和细胞增殖，但类固醇抑制其他细胞的信号转导和生长。这些效应可能与内质网与膜上信号调节蛋白的相互作用有关。目前也不清楚内质网是如何运动到膜上的。在这里，我们展示了来自内皮细胞质膜的纯化小泡中的内质网，以及ERα与小窝结构外壳蛋白小窝-1的共存。在人血管平滑肌或MCF-7(人乳腺癌)细胞膜上，免疫共沉淀显示ER与小窝蛋白-1和-2结合。重要的是，雌二醇快速和差异性地刺激血管平滑肌细胞中ER-小窝蛋白的结合，但抑制MCF-7细胞中的这种结合。雌二醇还刺激小凹蛋白-1和小窝蛋白-2的蛋白质合成，并激活血管平滑肌细胞中的小窝蛋白-1启动子/荧光素酶报告。然而，类固醇抑制了MCF-7细胞中小窝蛋白的合成。为了确定小凹蛋白-内质网相互作用的功能，我们在MCF-7细胞中表达了小凹蛋白-1。这促进了ER向质膜的移位，也抑制了E2诱导的ERK(MAPK)的激活。这两种功能都需要小窝蛋白-1的支架结构域。根据靶细胞的不同，膜ER与小窝蛋白有不同的联系，而E2则不同地调节这种信号抑制支架蛋白的合成。这可能解释了E2在不同细胞类型中的不一致信号和作用。此外，小窝蛋白-1能够促进内质网向细胞膜的转位。
Recent evidence supports the existence of a plasma membrane ER. In many cells, E2 activates signal transduction and cell proliferation, but the steroid inhibits signaling and growth in other cells. These effects may be related to interactions of ER with signal-modulating proteins in the membrane. It is also unclear how ER moves to the membrane. Here, we demonstrate ER in purified vesicles from endothelial cell plasma membranes and colocalization of ERalpha with the caveolae structural coat protein, caveolin-1. In human vascular smooth muscle or MCF-7 (human breast cancer) cell membranes, coimmunoprecipitation shows that ER associates with caveolin-1 and -2. Importantly, E2 rapidly and differentially stimulates ER-caveolin association in vascular smooth muscle cells but inhibits association in MCF-7 cells. E2 also stimulates caveolin-1 and -2 protein synthesis and activates a caveolin-1 promoter/luciferase reporter in smooth muscle cells. However, the steroid inhibits caveolin synthesis in MCF-7 cells. To determine a function for caveolin-ER interaction, we expressed caveolin-1 in MCF-7 cells. This stimulated ER translocation to the plasma membrane and also inhibited E2-induced ERK (MAPK) activation. Both functions required the caveolin-1 scaffolding domain. Depending upon the target cell, membrane ERs differentially associate with caveolin, and E2 differentially modulates the synthesis of this signaling-inhibitory scaffold protein. This may explain the discordant signaling and actions of E2 in various cell types. In addition, caveolin-1 is capable of facilitating ER translocation to the membrane.