Molecular mechanisms of signal transduction regulating cell proliferation, cell differentiation and cell cycle

信号转导调控细胞增殖、细胞分化和细胞周期的分子机制

基本信息

批准号：
12219208
负责人：
NISHIDA Eisuke
金额：
$ 284.1万
依托单位：
Kyoto University
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

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12219208/
关键词：
MAP kinase cell cycle signal transduction growth factor cell transformation 細胞癌化ドッキング相互作用 Tob シグナル伝達インヒビター Sprouty Plk1 Cdc25C 核内移行サイクリンB1

项目摘要

MAP kinase is shown to play an important role in regulation of cell proliferation, cell differentiation, and cell transformation. We have analyzed the MAP kinase-mediated docking interaction that could regulate the specificity and efficiency of the MAP kinase signal transduction, and identified a docking groove on the surface of MAP kinase that includes the CD domain and the ED site. ERK MAP kinase functions downstream of receptor tyrosine kinase, and spatiotemporal control of ERK MAP kinase signaling is crucial for cell fate decision. We have shown that Sprouty is a novel type of negative feedback inhibitor that regulates the duration and/or magnitude of ERK activity, and demonstrated that Sef is a spatial regulator that specifically inhibits ERK nuclear translocation without inhibiting ERK activity in the cytoplasm. We have then analyzed that temporal program of ERK-mediated gene expression, and revealed a molecular basis underlying the mechanism by which sustained ERK activation promotes G1 phase progression. Polo-like kinase 1 (Plk1) is an evolutionarily conserved M phase protein kinase that is involved in a wide variety of M phase events. We have demonstrated that Plk1 regulates nuclear import of both cdc2/cyclinB complex, the master engine of M phase entry, and cdc25C, the activator of cdc2/cyclinB complex. In addition, our results have identified the consensus phosphorylation motif by Plk1, and shown that the protein kinase Myt1 is a substrate of Plk1.

显示MAP激酶在调节细胞增殖，细胞分化和细胞转化中起着重要作用。我们已经分析了MAP激酶介导的对接相互作用，该相互作用可以调节MAP激酶信号转导的特异性和效率，并在MAP激酶表面上鉴定了包括CD域和ED位点的MAP激酶表面上的对接凹槽。 ERK MAP激酶功能在受体酪氨酸激酶的下游，ERK MAP MAP激酶信号的时空控制对于细胞命运决策至关重要。我们已经表明，发芽是一种新型的负反馈抑制剂，可调节ERK活性的持续时间和/或幅度，并证明SEF是一种空间调节剂，该空间调节因子专门抑制ERK核转运而不抑制细胞质中ERK活性。然后，我们分析了ERK介导的基因表达的时间程序，并揭示了持续ERK激活促进G1相位进程的机制的分子基础。 polo样激酶1（PLK1）是一种进化保守的M相蛋白激酶，与多种M相事件有关。我们已经证明，PLK1调节M相进入的主发动机Cdc2/Cyclinb复合物和Cdc2/cyclinb复合物的激活剂Cdc25c的核进口。此外，我们的结果已经确定了PLK1共有的磷酸化基序，并表明蛋白激酶MyT1是PLK1的底物。