The scaffolding protein GRASP/Tamalin directly binds to Dock180 as well as to cytohesins facilitating GTPase crosstalk in epithelial cell migration.
The scaffolding protein GRASP/Tamalin directly binds to Dock180 as well as to cytohesins facilitating GTPase crosstalk in epithelial cell migration.
复制标题
DOI：
10.1186/1471-2121-14-9
复制
发表时间：
2013-02-26
期刊：
影响因子：
--
通讯作者：
Santy LC
中科院分区：
文献类型：
--
作者：
Attar MA;Santy LC
上皮细胞从正常的非运动状态转变为运动状态需要许多小gtpase的协调作用。我们之前已经证明，上皮细胞迁移是由Arf和Rac gtpase的协同激活刺激的。这种串扰依赖于多蛋白复合物的组装，该复合物包含arf激活蛋白cytohesin 2/ARNO和Rac激活蛋白Dock180。两个支架蛋白直接结合到细胞内聚酶2组织这个复合体。我们现在已经发现Rac激活对肝细胞生长因子（HGF）的反应需要cytohesin 2和Dock180。GRASP/Tamalin是构建含有细胞分裂素2和Dock180复合物的支架之一。我们在这里确定了GRASP的富含Ala/Pro的区域直接与Dock180的SH3结构域相互作用。通过结合细胞素2/ARNO和Dock180， GRASP连接了激活Arf和Rac的鸟嘌呤核苷酸交换因子（gef），从而促进Arf到Rac的信号传导。此外，我们发现，低表达GRASP会损害肝细胞生长因子（HGF）刺激的Rac激活和HGF刺激的上皮细胞迁移。GRASP直接结合细胞素2和Dock180来协调它们的活动，并通过这样做促进Arf和Rac之间的串导。
The transition of epithelial cells from their normal non-motile state to a motile one requires the coordinated action of a number of small GTPases. We have previously shown that epithelial cell migration is stimulated by the coordinated activation of Arf and Rac GTPases. This crosstalk depends upon the assembly of a multi-protein complex that contains the Arf-activating protein cytohesin 2/ARNO and the Rac activating protein Dock180. Two scaffolding proteins that bind directly to cytohesin 2 organize this complex. We now have found that Rac activation in response to hepatocyte growth factor (HGF) requires cytohesin 2 and Dock180. GRASP/Tamalin is one of the scaffolds that builds the complex containing cytohesin 2 and Dock180. We determine here that the Ala/Pro rich region of GRASP directly interacts with the SH3 domain of Dock180. By binding to both cytohesin 2/ARNO and Dock180, GRASP bridges the guanine nucleotide exchange factors (GEFs) that activate Arf and Rac, thereby promoting Arf-to-Rac signaling. Furthermore, we find that knockdown of GRASP impairs hepatocyte growth factor (HGF)-stimulated Rac activation and HGF-stimulated epithelial migration. GRASP binds directly both cytohesin 2 and Dock180 to coordinate their activities, and by doing so promotes crosstalk between Arf and Rac.
登录
查看更多内容
影响因子：
3.3
作者：
Frank, SR;Hatfield, JC;Casanova, JE
通讯作者：
Casanova, JE
影响因子：
9.8
作者：
Beemiller P;Hoppe AD;Swanson JA
通讯作者：
Swanson JA
影响因子：
3.9
作者：
Donaldson, JG;Honda, A
通讯作者：
Honda, A
影响因子：
2.7
作者：
Kodama, Yutaka;Hu, Chang-Deng
通讯作者：
Hu, Chang-Deng
影响因子：
11.2
作者：
Muralidharan-Chari V;Hoover H;Clancy J;Schweitzer J;Suckow MA;Schroeder V;Castellino FJ;Schorey JS;D'Souza-Schorey C
通讯作者：
D'Souza-Schorey C