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质膜V-ATP酶调控致癌性RAS引起的巨胞饮
2019-12-12 19:35

美国纽约大学医学院Dafna Bar-Sagi研究团队发现,质膜V-ATP酶参与调控致癌性RAS引起的巨胞饮。 2019年12月11日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员确定液泡ATP酶(V-ATPase)是RAS诱导的巨胞饮作用的必要调节因子。致癌RAS通过需要通过碳酸氢盐依赖性可溶性腺苷酸环化酶激活蛋白激酶A的途径,促进V-ATP酶从细胞内膜向质膜的转运。V-ATP酶在质膜上积累对于RAC1的胆固醇依赖性血浆-膜结合是必需的,这是刺激膜起皱和巨胞饮作用的先决条件。这些观察结果建立了V-ATP酶运输与通过巨胞饮作用提供的养分之间的联系,可以利用这种联系来减少RAS突变肿瘤细胞的代谢适应能力。

据悉,RAS的致癌激活与一系列独特代谢依赖性物质的获取有关,从而有助于肿瘤细胞的适应性。表达致癌RAS的细胞能够通过称为巨胞饮的液相摄取机制来内化和降解细胞外蛋白质。人们越来越认识到这种RAS依赖性过程在游离氨基酸生成中的作用,其可在营养有限的条件下支持肿瘤细胞的生长。 然而,关于通过致癌RAS介导巨胞饮诱导的分子步骤仍知之甚少。

附:英文原文

Title: Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis

Author: Craig Ramirez, Andrew D. Hauser, Emily A. Vucic, Dafna Bar-Sagi

Issue&Volume: 2019-12-11

Abstract: Oncogenic activation of RAS is associated with the acquisition of a unique set of metabolic dependencies that contribute to tumour cell fitness. Cells that express oncogenic RAS are able to internalize and degrade extracellular protein via a fluid-phase uptake mechanism termed macropinocytosis1. There is increasing recognition of the role of this RAS-dependent process in the generation of free amino acids that can be used to support tumour cell growth under nutrient-limiting conditions2. However, little is known about the molecular steps that mediate the induction of macropinocytosis by oncogenic RAS. Here we identify vacuolar ATPase (V-ATPase) as an essential regulator of RAS-induced macropinocytosis. Oncogenic RAS promotes the translocation of V-ATPase from intracellular membranes to the plasma membrane via a pathway that requires the activation of protein kinase A by a bicarbonate-dependent soluble adenylate cyclase. Accumulation of V-ATPase at the plasma membrane is necessary for the cholesterol-dependent plasma-membrane association of RAC1, a prerequisite for the stimulation of membrane ruffling and macropinocytosis. These observations establish a link between V-ATPase trafficking and nutrient supply by macropinocytosis that could be exploited to curtail the metabolic adaptation capacity of RAS-mutant tumour cells.

DOI: 10.1038/s41586-019-1831-x

Source: https://www.nature.com/articles/s41586-019-1831-x

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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