Signal Transduction and Biological Significance of the Small GTPase Rho

小 GTP 酶 Rho 的信号转导和生物学意义

• 批准号: 13002007
• 负责人: NARUMIYA Shuh
• 金额: $ 417.66万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13002007/
• 关键词: Rho; Actin; microtubules; Cell motility; Cell cycle; Cdc42; mDia; ROCK; ミオシン; 細胞分裂; KOマウス; ROCK(Rho kinase); 神経突起形成; ROCK-II欠損マウス; 染色体分離; Rac; 神経突起; 細胞接着; アクチン細胞骨格; citron-kinase; 細胞移動; 細胞質分裂

1.The property and function of mDial were studied. It was shown: (1) mDial produces long straight actin filament in the cell by exerting its actin nucleation and polymerization activity, (2) mDial links Rho to Rac ac)tivation through c-Src-Cas-DOCK180 pathway, and antagonizes contractile action of the Rho-ROCK pathway, (3) the balance of the mDial and ROCK determines the cell morphology, a typical example being neurite extension in which the Rho-mDial pathwa extends and the Rho-ROCK pathway retracts neurites dependent on the level of GTP-Rho, and (4) mDial regulates polarity and adhesion turnover in migrating cells and functions in directed cell migration.2.The regulation and function of Rho GTPases in cell division were studied. It was shown: (1) Cdc42 is specifically activated in metaphase and this activation is regulated by a Rho-GEF, ECT2, and a Rho-GAP, MgcRacGAP, (2) Cdc42 acts on a mDia isoform, mDia3, present at the kinetochore, and this pathway contribute biorient binding of the spndle microtubules to the knetochore, thereby regulating chromosome congression in metaphase.3.Mice deficient in either one of the two ROCK isoforms, ROCK-I or ROCK-II, individually, were generated and their phenotypes were studied. This study has elucidated the importance of ROCK-II in homeostatic regulation of placental circulation and that of both isoforms in tissue closure during development. The absence of ROCK-II induces throm4.5.bosis in the placenta and causes intrauterine growth retardation, and the loss of either isoform results in open eye at birth and omphalocele due to impaied closure of the eyelids and ventral body wall.

1.研究了mDial的特性和功能。结果表明：(1)mDial通过发挥其肌动蛋白的成核和聚合活性在细胞内产生长而直的肌动蛋白细丝；(2)mDial通过c-Src-Cas-DOCK180途径将Rho与Rac连接起来，并拮抗Rho-Rock途径的收缩作用；(3)mDial和Rock的平衡决定了细胞的形态，典型的例子是Rho-mDial途径延伸，Rho-Rock途径收缩，这取决于GTP-Rho的水平。以及(4)mDial调节迁移细胞的极性和黏附周转，以及在定向细胞迁移中的作用。2.研究了Rho GTP酶在细胞分裂中的调控和作用。结果表明：(1)Cdc42是在中期特异激活的，这种激活受Rho-gef、ECT2和Rho-Gap的调节；(2)Cdc42作用于存在于着丝点的mdia异构体mDia3，这一途径有助于纺锤体微管与knetochore的生物定向结合，从而调节中期的染色体聚集。这项研究阐明了ROCK-II在胎盘循环的动态平衡调节中的重要性，以及这两种异构体在发育过程中组织关闭的重要性。ROCK-II的缺失会导致胎盘血栓4.5，并导致宫内发育迟缓，其中任何一种亚型的缺失都会导致出生时睁开眼睛和脐膨出，这是由于眼皮和体壁腹侧关闭的障碍。

项目成果

Ishizaki, T. et al.: "Coordination of microtubules and actin cytoskeleton by a Rho effector, mDia1"Nature Cell Biology. 3. 8-14 (2001)

Ishizaki, T. 等人：“Rho 效应子 mDia1 协调微管和肌动蛋白细胞骨架”《自然细胞生物学》。

Dean, T., et al.: "Targeted disrupton of the mouse Rho-associated kinase 2 (mROCK-II) gene results in intrauterine growth retardation and fetal death."Molecular and Cellular Biology. 23. 5043-5055 (2003)

Dean, T. 等人：“小鼠 Rho 相关激酶 2 (mROCK-II) 基因的靶向破坏会导致子宫内生长迟缓和胎儿死亡。” 分子和细胞生物学。

Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis.

ECT2和MGCRACGAP调节Cdc42在有丝分裂中的激活和功能。

• DOI: 10.1083/jcb.200408085
• 发表时间: 2005-01-17
• 期刊: JOURNAL OF CELL BIOLOGY
• 影响因子: 7.8
• 作者: Oceguera-Yanez, F;Kimura, K;Yasuda, S;Higashida, C;Kitamura, T;Hiraoka, Y;Haraguchi, T;Narumiya, S
• 通讯作者: Narumiya, S

Thromboxane A_2 and prostaglandin F_<2a> mediate inflammatory tachycardia.

血栓素A_2和前列腺素F_2a介导炎症性心动过速。

• 发表时间: 2005
• 期刊: Nature Medicine 11・5
• 作者: Takayama;K. et al.
• 通讯作者: K. et al.

Riveline, D. et al.: "Focal contacts as mechanosensors : Externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism"Journal of Cell Biology. 153. 1175-1186 (2001)

Riveline, D. 等人：“作为机械传感器的焦点接触：外部施加的局部机械力通过 mDia1 依赖性和 ROCK 独立机制诱导焦点接触的生长”《细胞生物学杂志》。