Effects of integrin-mediated cell adhesion on plasma membrane lipid raft components and signaling.
Effects of integrin-mediated cell adhesion on plasma membrane lipid raft components and signaling.
复制标题
整联蛋白介导的细胞粘附对质膜脂质筏成分和信号传导的影响。
DOI：
10.1091/mbc.e11-04-0361
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发表时间：
2011-09
影响因子：
3.3
通讯作者：
Schwartz MA
中科院分区：
文献类型：
--
作者：
Norambuena A;Schwartz MA
已知整合素介导的细胞粘附的丧失诱导脂筏的内化，其改变质膜的物理和信号性质。现在对多种蛋白质的分析显示了广泛的行为，其中内化和从有序结构域到无序结构域的退出分别受到调节。细胞生长的锚定依赖性是抵抗肿瘤转移的关键，它由多种整合素调节的信号通路介导。细胞从细胞外基质的分离触发小窝蛋白-1依赖性的脂筏组分的内化，其介导悬浮细胞中Rho GTP酶、Erk和磷脂酰肌醇3-激酶的抑制。细胞脱离后环磷酸腺苷（cAMP）的升高也与悬浮细胞中生长信号的终止有关。整合素和脂筏的研究，但是，主要检查神经节苷脂GM 1和糖基磷脂酰肌醇连接的蛋白质作为脂筏标记。在这项研究中，我们研究了更广泛的脂筏组件。而许多筏组件内化与GM 1细胞脱离后，flotillin 2，连接蛋白43，和Gαs留在质膜。细胞粘附的损失引起的运动的许多组件从脂筏nonraft馏分蔗糖梯度，虽然flotillin 2，连接蛋白43，和H-Ras的抵抗。Gαs失去了筏结合，伴随着cAMP的产生。修饰Gαs的脂质尾部以增加其与有序结构域的结合，阻断了cAMP的增加。这些数据定义了整合素介导的粘附对各种脂筏组分的定位和行为的影响，并揭示了细胞脱离后cAMP升高的机制。
Loss of integrin-mediated cell adhesion is known to induce internalization of lipid rafts, which alters of the plasma membrane's physical and signaling properties. Analysis of multiple proteins now shows a wide range of behaviors in which internalization and exit from the ordered to disordered domains are regulated separately. Anchorage dependence of cell growth, which is mediated by multiple integrin-regulated signaling pathways, is a key defense against cancer metastasis. Detachment of cells from the extracellular matrix triggers caveolin-1–dependent internalization of lipid raft components, which mediates suppression of Rho GTPases, Erk, and phosphatidylinositol 3-kinase in suspended cells. Elevation of cyclic adenosine monophosphate (cAMP) following cell detachment is also implicated in termination of growth signaling in suspended cells. Studies of integrins and lipid rafts, however, examined mainly ganglioside GM1 and glycosylphosphatidylinositol-linked proteins as lipid raft markers. In this study, we examine a wider range of lipid raft components. Whereas many raft components internalized with GM1 following cell detachment, flotillin2, connexin43, and Gαs remained in the plasma membrane. Loss of cell adhesion caused movement of many components from the lipid raft to the nonraft fractions on sucrose gradients, although flotillin2, connexin43, and H-Ras were resistant. Gαs lost its raft association, concomitant with cAMP production. Modification of the lipid tail of Gαs to increase its association with ordered domains blocked the detachment-induced increase in cAMP. These data define the effects of that integrin-mediated adhesion on the localization and behavior of a variety of lipid raft components and reveal the mechanism of the previously described elevation of cAMP after cell detachment.