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Role of MAP kinase cascades in the regulation of diverse cellular functions

MAP 激酶级联在调节多种细胞功能中的作用

基本信息

批准号：
17390020
负责人：
KOHNO Michiaki
金额：
$ 9.6万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390020/
关键词：
ERK-MAP Kinase Intracellular Localization GEF-H1 Cell Motility c-Jun N-terminal Kinase Intermediate Filaments Cell Cycle Spindle Checkpoint スピンドルチェックポイント p90^<RSK>RhoA 細胞内局在性ケラチン8 細胞質分裂

项目摘要

1. We have examined a possible molecular mechanism through which nuclear translocation and retention of ERK-MAP kinases is regulated. A novel 26-kD protein (p26) which contains a SH3 domain at the N-terminus and three ankyrin repeat sequences at the C-terminus has been identified as a candidate molecule which is involved in the regulation of nuclear translocation/retention of ERK-MAP kinases. Overexpression of p26 suppresses the HGF-induced nuclear localization/retention of ERK-MAP kinases in MDCK cells, while siRNA-mediated knockdown of p26 enhances it. p26 interact specifically with a novel 120-kDa protein (p120), and this interaction is suppressed by the phosphorylation of p26 by p90^<rsk>, an effector molecule downstream of the ERK-MAP kinases. These results suggest that nuclear translocation/retention of ERK-MAP kinases is regulated by the ERK-MAP kinase signaling pathway by itself.2. A novel GDP/GTP exchanger of RhoA, GEF-H1, has been shown to be a physiological substrate of ERK- … More MAP kinases. Expression of GEF-H1 is up-regulated by the ERK MAP kinase pathway. Phosphorylation of Thr^<678> by ERK-MAP kinases induces the activation of GEF-H1 thereby activates RhoA, whereas it induces the inhibition of Rac1. Furthermore, siRNA-mediated knock down of GEF-H1 enhances the cell motility response. These results suggest that GEF-H1 is involved in the ERK-MAF kinase pathway-mediated cell motility response.3. c-Jun N-Terminal Kinase (JNK) has been shown to be involved in the regulation of cytokinesis. JNK phosphorylates keratin 8 to induce the relaxation of keratin filaments, which appear to be one of the prerequisites for cells to undergo cytokinesis.4. Combination of 50 μM PD98059 and a low concentration (3 nM) of vincristin induces marked apoptotic cell death response in G_2/M-phase-arrested T24 cells, but not in G_1-/S-phase-arrested cells. Under such conditions, accumulation of cyclinB, Plk1and Aurora-B has been observed. These results suggest that ERK-MAP Kinase pathway is involved in the regulation of spindle check point. Less

1.我们已经研究了一种可能的分子机制，通过这种机制调节ERK-MAP激酶的核转位和保留。一种新的26 kD蛋白（p26），其N端含有一个SH 3结构域，C端含有三个锚蛋白重复序列，已被鉴定为参与调节ERK-MAP激酶核转位/滞留的候选分子。在MDCK细胞中，p26的过表达抑制HGF诱导的ERK-MAP激酶的核定位/保留，而siRNA介导的p26敲低增强了它。p26与一种新的120-kDa蛋白（p120）特异性相互作用，并且这种相互作用被p90-β<rsk>（ERK-MAP激酶下游的效应分子）磷酸化p26所抑制。这些结果表明，ERK-MAP激酶的核转位/滞留受ERK-MAP激酶信号通路自身的调节.一种新的RhoA的GDP/GTP交换剂GEF-H1已被证明是ERK的生理底物。 ...更多信息 MAP激酶。GEF-H1的表达通过ERK MAP激酶途径上调。通过ERK-MAP激酶磷酸化Thr 1<678>诱导GEF-H1的活化，从而活化RhoA，而它诱导Rac 1的抑制。此外，siRNA介导的GEF-H1敲低增强了细胞运动性反应。这些结果表明GEF-H1参与了ERK-MAF激酶途径介导的细胞运动反应. c-Jun N-末端激酶（JNK）已被证明参与胞质分裂的调节。JNK使角蛋白8磷酸化，诱导角蛋白丝松弛，这似乎是细胞发生凋亡的先决条件之一. 50 μM PD 98059和低浓度长春新碱（3 nM）联合应用可诱导G_2/M期阻滞的T24细胞发生明显的凋亡反应，但对G_1/S期阻滞的细胞无明显作用。在此条件下，已观察到cyclinB、Plk 1和Aurora-B的积累。这些结果表明，ERK-MAP激酶通路参与了纺锤体检查点的调控。少