Temporal and spatial regulation of signal transduction by Rab family small G proteins

Rab 家族小 G 蛋白对信号转导的时空调节

基本信息

批准号：
18390089
负责人：
SASAKI Takuya
金额：
$ 10.26万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390089/
关键词：
Signal transduction Rab proteins neurotransmission cell-cell adhesion cell growth Rab3A Rab12 Rab7 Rabファミリー低分子量G蛋自質 JRAB タイトジャンクションアドヘレンスジャンクション Rab3 GAP

项目摘要

The Rab family small G proteins, which consist of more than 60 different members in mammalian cells, are key regulators in membrane trafficking. Since each member recognizes distinct subsets on intracellular membranes, this family may contribute to temporal and spatial regulation of signal transduction in various cellular functions. In this project, we analyzed the functions of Rab proteins in neurotransmission, cell-cell adhesion, and cell growth. As to neurotransmission, we focused on the process of neurotransmitter release, which Rab3A and its related proteins regulate. We generated Rab3 GAP p130-deficient mice and showed using the mice that this protein plays important roles in neurotransmitter release and synaptic plasticity through regulation of the activity and translocation of Rab3A at the nerve endings. As to the cell-cell adhesion, we focused on the transport of the adhesion proteins to the cell-cell adhesion sites of the epithelial cells. We had previously found that Rabl3 regulates the transport of the integral adhesion proteins, claudins and occludin, to the tight junctions. In this project, we identified JRAB/MICAL-L2 as a novel Rabl3 effector protein, which localized to the tight junctions and found that the Rab13-JRAB system functions to establish the formation of the tight junctions. We moreover found that another Rab family member Rab8 also interacts with JRAB and that this interaction contributes to the assembly of adherens junctions through regulation of the transport of E-cadherin, an integral adherens junction protein. As to the cell growth, we showed that Rabring7, which we had identified as a novel Rab7 effector protein, has E3 ligase activity and that this protein is involved in the endocytic trafficking of EGF receptor through its E3 ligase activity.

Rab 家族小 G 蛋白由哺乳动物细胞中 60 多个不同的成员组成，是膜运输的关键调节因子。由于每个成员都识别细胞内膜上的不同子集，因此该家族可能有助于各种细胞功能中信号转导的时间和空间调节。在这个项目中，我们分析了 Rab 蛋白在神经传递、细胞间粘附和细胞生长中的功能。在神经传递方面，我们重点关注 Rab3A 及其相关蛋白调节的神经递质释放过程。我们培育了 Rab3 GAP p130 缺陷型小鼠，并通过小鼠证明该蛋白通过调节神经末梢 Rab3A 的活性和易位，在神经递质释放和突触可塑性中发挥重要作用。对于细胞与细胞的粘附，我们重点关注粘附蛋白向上皮细胞的细胞与细胞粘附位点的转运。我们之前发现 Rabl3 调节整合粘附蛋白、claudins 和 occludin 向紧密连接的运输。在这个项目中，我们将 JRAB/MICAL-L2 确定为一种新型 Rabl3 效应蛋白，其定位于紧密连接，并发现 Rab13-JRAB 系统的功能是建立紧密连接的形成。此外，我们发现另一个 Rab 家族成员 Rab8 也与 JRAB 相互作用，并且这种相互作用通过调节 E-钙粘蛋白（一种完整的粘附连接蛋白）的运输有助于粘附连接的组装。至于细胞生长，我们发现Rabring7（我们已鉴定为一种新型Rab7效应蛋白）具有E3连接酶活性，并且该蛋白通过其E3连接酶活性参与EGF受体的内吞运输。