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G protein-dependent vectorial transportation of receptors, ion channels, and transporters

受体、离子通道和转运蛋白的 G 蛋白依赖性载体运输

基本信息

批准号：
12144202
负责人：
KATADA Toshiaki
金额：
$ 32.77万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

G protein-coupled or tyrosine kinase-linked receptors are involved in the regulations of many signal transductions. After the stimulation of these membrane receptors, not only the receptor molecules themselves but also ion channels or transporters are internalized into the cells through endocytic pathways. Thus, there is vectorial transportation in the membrane trafficking. In this study, we investigated the molecular mechanisms whereby these receptors regulate the vectorial transportation.The major findings obtained in this study are summarized as follows.1) The lipid kinase phosphatidylinositol (PI) 3-OH kinase is synergistically stimulated by different types of membrane receptors, such as G protein-coupled and tyrosine kinase-linked receptors. We have found that the class I (p110beta subtype) PI 3-OH kinase is responsible for the synergistic stimulation and that its adaptor, Gab2, is involved in the signaling through its dual phosphorylation by Src tyrosine kinase and ERK. 2) The small GTPase Rab family are involved in membrane trafficking pathways. We have identified novel members of the RIN family as guanine nucleotide-exchange factors (GEFs) for Rab5. The RIN family, which contains many functional domains, such as SH2, Pro-rich region (binding to SH3), Vps9 (GEF), and RA (Ras-association), appear to act as adaptors or scaffold proteins in early steps of the endocytic pathway. 3) We have also identified novel family of Ras-like small GTPases, Di-Ras, Rheb, which might be involved in membrane trafficking pathways. Rheb expression in culture cells induced formation of the cytoplasmic large vacuoles, which are characterized as late endocytic (late endosome-and lysosome-like) components. Rheb appears to regulate the internalization of glutamate transporter in glial cells.

G蛋白偶联或酪氨酸激酶相关受体参与许多信号转导的调节。在这些膜受体的刺激后，不仅受体分子本身，而且离子通道或转运蛋白通过内吞途径内化到细胞中。因此，在膜运输中存在矢量运输。本研究主要研究了这些受体调节载体转运的分子机制，主要结果如下：1）磷脂酰肌醇（PI）3-OH激酶可被不同类型的膜受体（如G蛋白偶联受体和酪氨酸激酶连接受体）协同激活。我们已经发现I类（p110 β亚型）PI 3-OH激酶负责协同刺激，并且其接头Gab 2通过Src酪氨酸激酶和ERK的双重磷酸化参与信号传导。2)小的GTTRab家族参与膜运输途径。我们已经确定了RIN家族的新成员作为Rab 5的鸟嘌呤核苷酸交换因子（GEF）。RIN家族包含许多功能结构域，如SH 2、Pro富集区（结合SH 3）、Vps 9（GEF）和RA（Ras缔合），似乎在内吞途径的早期步骤中充当衔接子或支架蛋白。3)我们还鉴定了一个新的Ras样小GTP酶家族，Di-Ras，Rheb，它们可能参与膜转运途径。Rheb在培养细胞中的表达诱导细胞质大空泡的形成，其特征在于晚期内吞（晚期内体和溶酶体样）组分。Rheb似乎调节神经胶质细胞中谷氨酸转运体的内化。