Involvement of the Ras-Ras-activated rab5 guanine nucleotide exchange factor RIN2-Rab5 pathway in the hepatocyte growth factor-induced endocytosis of E-cadherin
Involvement of the Ras-Ras-activated rab5 guanine nucleotide exchange factor RIN2-Rab5 pathway in the hepatocyte growth factor-induced endocytosis of E-cadherin
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DOI：
10.1074/jbc.m510531200
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发表时间：
2006-04-14
影响因子：
4.8
通讯作者：
Takai, Y
中科院分区：
文献类型：
--
作者：
Kimura, T;Sakisaka, T;Takai, Y
E-钙粘蛋白是粘附连接（AJs）处的关键细胞-细胞粘附分子，并且当AJs被细胞外信号（例如肝细胞生长因子（HGF）/散射因子）的作用破坏时，E-钙粘蛋白经历内吞作用。Rab 5小G蛋白参与了HGF诱导的E-cadherin的内吞作用，但Rab 5活性调节的分子机制尚不清楚。我们首先研究了这一机制，通过使用无细胞测定系统的内吞的E-钙粘蛋白的AJ-enriched馏分从大鼠肝脏。HGF诱导Ras小G蛋白激活，然后与RIN 2（具有Vps 9 p样鸟苷酸交换因子和Ras结合结构域的Rab 5 GDP/GTP交换因子）结合并激活它。激活的RIN 2然后激活Rab 5，最终诱导E-cadherin的内吞作用。然后，我们研究了RIN 2是否参与了完整Madin-Darby犬肾细胞中HGF诱导的E-钙粘蛋白的内吞。RIN 2定位于细胞间粘附位点，其鸟嘌呤核苷酸交换因子活性是HGF诱导的Madin-Darby犬肾细胞中E-钙粘蛋白内吞所需的。这些结果表明，RIN 2连接Ras Rab 5在HGF诱导的E-钙粘蛋白的内吞。
E-cadherin is a key cell-cell adhesion molecule at adherens junctions (AJs) and undergoes endocytosis when AJs are disrupted by the action of an extracellular signal, such as hepatocyte growth factor (HGF)/scatter factor. Rab5 small G protein has been implicated in the HGF-induced endocytosis of E-cadherin, but the molecular mechanism for the regulation of Rab5 activity remains unknown. We first studied this mechanism by using the cell-free assay system for the endocytosis of E-cadherin of the AJ-enriched fraction from rat livers. HGF induced activation of Ras small G protein, which then bound to RIN2, a Rab5 GDP/GTP exchange factor with the Vps9p-like guanine nucleotide exchange factor and Ras association domains, and activated it. Activated RIN2 then activated Rab5, eventually inducing the endocytosis of E-cadherin. We then studied whether RIN2 was involved in the HGF-induced endocytosis of E-cadherin in intact Madin-Darby canine kidney cells. RIN2 localized at the cell-cell adhesion sites, and its guanine nucleotide exchange factor activity was required for the HGF-induced endocytosis of E-cadherin in Madin-Darby canine kidney cells. These results indicate that RIN2 connects Ras to Rab5 in the HGF-induced endocytosis of E-cadherin.