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Signal Transduction and Cellular Functions of the Small GTPase Rho and its Effectors

小 GTPase Rho 及其效应器的信号转导和细胞功能

基本信息

批准号：
08102007
负责人：
NARUMIYA Shuh
金额：
$ 195.2万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Specially Promoted Research
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 2000
项目状态：
已结题

项目摘要

Effectors for the small GTPase Rho were determined, and signal tranuction pathways from Rho to the reorganization of the actin cytoskeleton were identified. (1) We identified that ROCK-kinase, that is activated downstream of Rho, moblizes at least three pathways to regulate the actin cytoskeleton, one being phsporylaiton and inacitvation of myosin phosphatas to increase the myosin-based contractility, the second phosphorylaiton and acivaton of LIM-linase leading to inactivation of actin depolymerizing activity of cofilin, and the third phosphorylation of type I NaH exchanger. We further showed that these Rho-ROCK pathways are impliated in elicitation of hypertension and invasion and metastasis of tumor cells. (2) We identified p140mDia as a novel Rho effector protein. This protein binds profiin through its FH1 region and regulate alignment of microtubules through its FH2 region, and thereby integrate the organization of the actin cytoskeleton and microtubules. We showed that this action of mDia is essential in Rho-induced inducion and alignment of stress fibers. (3) We identified Citron-kinase, and showed that it works as a Rho effector in cytokinesis. We heve also developed a pull-down assay for GTP-Rho, and showed that ECT2 is a Rho exchanger working in cytokinesis. (4) We identified ropporin as a binding protein of rhophilin, and showed that the two proteins together localize in the sperm tail. We also showed that ropporin makes a homo dimer and binds to another sperm protein, AKAP-110.

确定了小 GTP 酶 Rho 的效应子，并鉴定了从 Rho 到肌动蛋白细胞骨架重组的信号转导途径。 (1) 我们发现，在 Rho 下游被激活的 ROCK 激酶动员至少三种途径来调节肌动蛋白细胞骨架，一种是肌球蛋白磷酸化和失活，以增加基于肌球蛋白的收缩力，第二种是 LIM 激酶的磷酸化和激活，导致肌动蛋白丝切蛋白的肌动蛋白解聚活性失活，第三种是 LIM 激酶的磷酸化和失活，导致肌动蛋白丝切蛋白的肌动蛋白解聚活性失活 I型NaH交换体的磷酸化。我们进一步表明，这些 Rho-ROCK 通路与高血压的诱发以及肿瘤细胞的侵袭和转移有关。 (2) 我们鉴定出 p140mDia 是一种新型 Rho 效应蛋白。该蛋白通过其 FH1 区域结合 Profiin，并通过其 FH2 区域调节微管的排列，从而整合肌动蛋白细胞骨架和微管的组织。我们证明 mDia 的这种作用对于 Rho 诱导的应力纤维的诱导和排列至关重要。 (3) 我们鉴定了香橼激酶，并证明它在胞质分裂中作为 Rho 效应子发挥作用。我们还开发了 GTP-Rho 的 Pull-down 测定，并表明 ECT2 是在胞质分裂中起作用的 Rho 交换器。 (4)我们鉴定出ropporin是rhophilin的结合蛋白，并表明这两种蛋白一起定位于精子尾部。我们还表明，ropporin 会形成同源二聚体并与另一种精子蛋白 AKAP-110 结合。