Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling.
Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling.
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DOI：
10.1083/jcb.201307055
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发表时间：
2014-03-03
期刊：
影响因子：
--
通讯作者：
Parton RG
中科院分区：
文献类型：
--
作者：
Ariotti N;Fernández-Rojo MA;Zhou Y;Hill MM;Rodkey TL;Inder KL;Tanner LB;Wenk MR;Hancock JF;Parton RG
小窝将机械应力传递到质膜脂质改变中，以亚型特异性方式破坏Ras组织并调节下游信号转导。迄今为止，小窝控制细胞信号传导的分子机制仍然难以捉摸。因此，我们探索了小窝在调节Ras信号转导中的作用。脂质组学和基因阵列分析表明，窖蛋白-1（CAV 1）缺乏导致细胞脂质组成和质膜（PM）磷脂酰丝氨酸分布改变。这些变化与K-Ras表达增加和Ras空间组织的广泛亚型特异性扰动相关：在CAV 1缺陷细胞中，K-RasG 12 V纳米簇和MAPK活化增强，而GTP依赖的H-Ras侧向分离被废除，导致H-RasG 12 V纳米簇的信号输出受损。Ras纳米簇的这些变化是通过另一个关键小囊结构成分Cavin 1的下调以及渗透压增加导致小囊的急性丧失来表现的。因此，我们假设，小窝远程调节Ras纳米簇和信号转导通过控制PM组织。同样，小窝将机械应力转化为PM脂质改变，进而调节Ras PM组织。
Caveolae transduce mechanical stress into plasma membrane lipid alterations that disrupt Ras organization in an isoform-specific manner and modulate downstream signal transduction. The molecular mechanisms whereby caveolae exert control over cellular signaling have to date remained elusive. We have therefore explored the role caveolae play in modulating Ras signaling. Lipidomic and gene array analyses revealed that caveolin-1 (CAV1) deficiency results in altered cellular lipid composition, and plasma membrane (PM) phosphatidylserine distribution. These changes correlated with increased K-Ras expression and extensive isoform-specific perturbation of Ras spatial organization: in CAV1-deficient cells K-RasG12V nanoclustering and MAPK activation were enhanced, whereas GTP-dependent lateral segregation of H-Ras was abolished resulting in compromised signal output from H-RasG12V nanoclusters. These changes in Ras nanoclustering were phenocopied by the down-regulation of Cavin1, another crucial caveolar structural component, and by acute loss of caveolae in response to increased osmotic pressure. Thus, we postulate that caveolae remotely regulate Ras nanoclustering and signal transduction by controlling PM organization. Similarly, caveolae transduce mechanical stress into PM lipid alterations that, in turn, modulate Ras PM organization.
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