Rab5 is a signalling GTPase involved in actin remodelling by receptor tyrosine kinases
Rab5 is a signalling GTPase involved in actin remodelling by receptor tyrosine kinases
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DOI：
10.1038/nature02542
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发表时间：
2004-05-20
期刊：
影响因子：
64.8
通讯作者：
Di Fiore, PP
中科院分区：
文献类型：
--
作者：
Lanzetti, L;Palamidessi, A;Di Fiore, PP
Rab5是一个小的GTP酶，在受体内吞和内体动力学水平上都参与控制细胞内的转运(1)。Rab5可以被受体酪氨酸激酶(RTK)激活的发现提出了一个问题，即它是否也参与了从这些受体发出的效应通路。在这里，我们证明了Rab5对于RTK诱导的肌动蛋白重塑是必不可少的，这种形式被称为环状褶皱。三个独立的信号，分别来自Rab5，磷脂酰肌醇-3-羟基激酶和Rac，是同时需要的诱导环形褶皱。Rab5通过RN-tre向肌动蛋白细胞骨架传递信号，RN-tre是一种先前发现的Rab5特异性GTP酶激活蛋白(GAP)(3)。在这里，我们证明了RN-TrE具有Rab(5)-GAP和Rab5效应器的双重功能。我们还表明，RN-TrE对巨噬细胞吞噬是关键的，这一过程以前与圆形褶皱的形成有关(4，5)。最后，RN-tre与F-肌动蛋白和肌动蛋白结合蛋白-4相互作用。我们认为RN-TrE与Rab5、F-肌动蛋白和肌动蛋白-4三管齐下。这可能有助于肌动蛋白纤维在质膜上形成肌动蛋白网络。因此，我们已经证明Rab5是一个信号转导的GTP酶，并阐明了其下游途径的主要分子元件。
Rab5 is a small GTPase involved in the control of intracellular trafficking, both at the level of receptor endocytosis and endosomal dynamics(1). The finding that Rab5 can be activated by receptor tyrosine kinases (RTK)(2) raised the question of whether it also participates in effector pathways emanating from these receptors. Here we show that Rab5 is indispensable for a form of RTK-induced actin remodelling, called circular ruffling. Three independent signals, originating from Rab5, phosphatidylinositol-3-OH kinase and Rac, respectively, are simultaneously required for the induction of circular ruffles. Rab5 signals to the actin cytoskeleton through RN-tre, a previously identified Rab5-specific GTPase-activating protein (GAP)(3). Here we demonstrate that RN-tre has the dual function of Rab(5)-GAP and Rab5 effector. We also show that RN-tre is critical for macropinocytosis, a process previously connected to the formation of circular ruffles(4,5). Finally, RN-tre interacts with both F-actin and actinin-4, an F-actin bundling protein. We propose that RN-tre establishes a three-pronged connection with Rab5, F-actin and actinin-4. This may aid crosslinking of actin fibres into actin networks at the plasma membrane. Thus, we have shown that Rab5 is a signalling GTPase and have elucidated the major molecular elements of its downstream pathway.