RalA-exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling.
RalA-exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling.
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DOI：
10.1016/j.cub.2009.11.016
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发表时间：
2010-01-12
期刊：
影响因子：
--
通讯作者：
Schwartz MA
中科院分区：
文献类型：
--
作者：
Balasubramanian N;Meier JA;Scott DW;Norambuena A;White MA;Schwartz MA
细胞生长的锚定依赖性是一种关键的转移抑制机制，其机制是通过整合素对生长信号通路的影响而介导的。小的GTP酶Rala在转移性癌症中通过多种机制被激活，并特异性地诱导锚定独立。整合素介导的黏附丧失触发小窝蛋白依赖的富含胆固醇和鞘磷脂的脂筏微域内化到循环内小体；这些微域作为许多信号通路的平台，在细胞分离抑制生长信号后从质膜(PM)清除。相反，重新粘连会触发它们返回PM并恢复生长信号。整合素激活Arf6介导RAFT标记从RE退出，但不足以返回PM我们现在证明Rala而不是RalB通过胞囊复合体介导整合素依赖的膜筏的胞吐作用。体质活性的Rala恢复膜筏靶向，以促进锚定非依赖性生长信号。RAS转化的胰腺癌细胞也显示Rala依赖的组成性PM RAFT靶向。这些结果确定Rala是整合素依赖的膜筏运输和生长信号调节的关键决定因素。因此，他们定义了Rala调节锚定依赖性的机制，并在整合素信号和癌症之间提供了新的联系。
Anchorage-dependence of cell growth is a key metastasis-suppression mechanism that is mediated by effects of integrins on growth signaling pathways. The small GTPase RalA is activated in metastatic cancers through multiple mechanisms and specifically induces anchorage independence. Loss of integrin-mediated adhesion triggers caveolin-dependent internalization of cholesterol- and sphingolipid- rich lipid raft microdomains to the recycling endosomes; these domains serve as platforms for many signaling pathways and their clearance from the plasma membrane (PM) after cell detachment suppresses growth signaling. Conversely, re-adhesion triggers their return to the PM and restores growth signaling. Activation of Arf6 by integrins mediates exit of raft markers from the RE but is not sufficient for return to the PM. We now show that RalA but not RalB mediates integrin-dependent membrane raft exocytosis through the exocyst complex. Constitutively active RalA restores membrane raft targeting to promote anchorage independent growth signaling. Ras-transformed pancreatic cancer cells also show RalA-dependent constitutive PM raft targeting. These results identify RalA as a key determinant of integrin-dependent membrane raft trafficking and regulation of growth signaling. They therefore define a mechanism by which RalA regulates anchorage dependence and provide a new link between integrin signaling and cancer.
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