Modes of activation and action of Small G proteins

小G蛋白存在于从酵母到人类的真核生物中，构成了一个由100多个成员组成的超家族。这个超家族在结构上至少分为五个家族：RAS、RHO、RAB、SARL/ARF和RAN家族。它们调节多种细胞功能：Ras家族调节基因表达；Rho家族调节细胞骨架的重组和基因表达；Rab和Sarl/Arf家族调节囊泡运输；RAN家族调节核质运输。许多小G蛋白的上游调控因子和下游效应因子已经被分离出来。在本研究项目中，我们研究了小G蛋白的激活和作用方式，特别是Rab和Rho家族。Rab家族的调节机制：Rab3A是Rab家族的成员，尤其与神经末梢的神经递质释放有关。我们分离了它的调控蛋白，命名为Rab GDI，Rab3…更多GEP和Rab3 Gap。在这个研究项目中，我们已经证明了这些蛋白质通过调节Rab3A2来调节神经递质的释放过程。Rab家族的下游途径：我们已经分离到了Rab3A的一个效应子，命名为RabPhilin-3A。在这个研究项目中，我们已经证明了RabPhilin-3A实际上在利用鱿鱼巨大轴突系统释放神经递质方面发挥了关键作用。此外，我们还鉴定了Rab11的一个效应子，命名为RabPhilin-11，并发现Rab11-RabPhilin-11系统通过调节囊泡的循环参与细胞的迁移。Rho家族的调控机制：我们发现了一种新的CDC42的GDP/GTP交换蛋白，命名为Frabin，并表明Frabin-CDc42途径是细胞迁移最上游的调节因子。Rho家族的下游途径：在酿酒酵母中，我们分离了Rho的两个下游效应子BNI1和BNR1，并证明Rho通过这些靶点调节肌动蛋白细胞骨架和微管，导致萌芽或细胞质分裂。在哺乳动物细胞中，丝氨酸/苏氨酸蛋白激酶ROCK和哺乳动物BNI1的对应物MDIA协同调节肌动蛋白细胞骨架的重组。我们还发现RAC和CDC42调节基于钙粘附素的细胞-细胞黏附。较少

Small G proteins exist in eukaryotes from yeast to human and constitute a superfamily consisting of more than one hundred members. This superfamily is structurally classified into at least five families : the Ras, Rho, Rab, Sarl/Arf, and Ran families. They regulate a wide variety of cell functions : The Ras family regulates gene expression; the Rho family regulates reorganization of cytoskeleton and gene expression; the Rab and Sarl/Arf families regulate vesicle trafficking; and the Ran family regulates nucleocytoplasmic transport. Many upstream regulators and downstream effectors of small G proteins have been isolated. In the present research project, we have studied the modes of activation and action of small G proteins, especially the Rab and Rho families.1. The regulatory mechanism of the Rab family : Rab3A is a member of the Rab family which is particularly implicated in neurotransmitter release from the nerve terminal. We had isolated its regulatory proteins, named Rab GDI, Rab3 … More GEP, and Rab3 GAP. In this research project, we have shown that these proteins modulate the neurotransmitter release process through regulation of Rab3A.2. The downstream pathway of the Rab family : We had isolated an effector of Rab3A, named Rabphilin-3A. In this research project, we have shown that Rabphilin-3A actually plays a crucial role in neurotransmitter release using the squid giant axon system. Moreover, we have identified an effector of Rab11, named Rabphilin-11, and found that the Rab11-Rabphilin-11 system is involved in cell migration through regulation of the vesicle recycling.3. The regulatory mechanism of the Rho family : We have discovered a novel GDP/GTP exchange protein of Cdc42, named Frabin, and shown that the Frabin-Cdc42 pathway functions as the most upstream regulator for cell migration.4. The downstream pathway of the Rho family : In S. cerevisiae, we have isolated two downstream effectors of Rho, BNI1 and BNR1, and demonstrated that Rho regulates actin cytoskeleton and microtubules through these targets, leading to budding or cytokinesis. In mammalian cells, ROCK, a serine/threonine protein kinase, and mDia, a mammalian counterpart of BNI1, cooperatively regulate reorganization of the actin cytoskeleton. We have also shown that Rac and Cdc42 regulate cadherin-based cell-cell adhesion. Less