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Functions and modes of action of small G proteins in cell adhesion and migration

小G蛋白在细胞粘附和迁移中的功能和作用方式

基本信息

批准号：
11680632
负责人：
SASAKI Takuya
金额：
$ 2.5万
依托单位：
The University of Tokushima School of Medicine (2000)Osaka University (1999)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

When epithelial cells start to migrate, cell-cell junctions are first disrupted. During migration, membrane protrusions, such as lamellipodia and filopodia, at the cell front, and retraction at the cell rear are externally observed, and dynamic reorganization of the actin cytoskeleton is internally observed. We have recently clarified that the Rho and Rab family small G proteins coordinately regulate cell adhesion and migration of cultured MDCK cells. The Rab family consists of over thirty members. We have found that some Rab family members are involved in HGF- or phorbol esterinduced endocytosis and recycling of cadherin and integrin. Rab11, a member of Rab family, has been implicated in vesicle recycling. During this support from 1999 to 2000, we have focused on studying the function and mode of action of Rab11 in cell migration. The results obtained are as follows :(1) We have isolated a downstream target of Rab11, named Rabphilin-11, from bovine brain. We have found that rabphilin-11 is localized at perinuclear regions, presumably the Golgi complex and recycling endosomes in MDCK cells.(2) We have found that Rabphilin-11 is localized not only at perinuclear regions but also along microtubules, which are oriented toward membrane lammelipodia in HeLa cells cultured on fibronectin. Overexpression of rabphilin-11 mutant reduces accumulation of transferrin at perinuclear regoins and cell migratoin.(3) We have found that rabphilin-11 directly binds the mammalian counterpart of yeast Sec13 proteins (mSec13) in cell-free and intact cell systems. Disruption of the rabphilin-11-mSec13 interaction by overexpression of the mSec13-binding region of rabphilin-11 impairs vesicle trafficking.

当上皮细胞开始迁移时，细胞-细胞连接首先被破坏。在迁移过程中，膜突起，如板状伪足和丝状伪足，在细胞前面，并在细胞后部的收缩外部观察，和动态重组的肌动蛋白细胞骨架内部观察。我们最近阐明，Rho和Rab家族小G蛋白协同调节培养的MDCK细胞的细胞粘附和迁移。拉布家族由30多名成员组成。我们已经发现，一些Rab家族成员参与HGF或佛波酯诱导的内吞和钙粘蛋白和整合素的再循环。Rab 11是Rab家族的一员，参与囊泡的再循环。在1999年至2000年的支持期间，我们重点研究了Rab 11在细胞迁移中的功能和作用方式。（1）从牛脑中分离到Rab 11的下游靶蛋白Rabphilin-11。我们发现rabphilin-11定位于核周区域，推测为高尔基复合体和MDCK细胞中的再循环内体。(2)我们已经发现Rabphilin-11不仅定位于核周区域，而且沿着微管定位，微管朝向在纤连蛋白上培养的HeLa细胞中的膜板状足。rabphilin-11突变体的过表达减少转铁蛋白在核周区蛋白和细胞移行蛋白的积累。(3)我们已经发现rabphilin-11在无细胞和完整细胞系统中直接结合酵母Sec 13蛋白（mSec 13）的哺乳动物对应物。通过rabphilin-11的mSec 13结合区的过表达破坏rabphilin-11-mSec 13相互作用损害囊泡运输。