权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Functional analysis of scaffold proteins for mammalian stress-responsive MAP kinase signaling pathways

哺乳动物应激反应 MAP 激酶信号通路支架蛋白的功能分析

基本信息

批准号：
14086205
负责人：
YOSHIOKA Katsuji
金额：
$ 76.99万
依托单位：
Kanazawa 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：
2002
资助国家：
日本
起止时间：
2002 至 2006
项目状态：
已结题

项目摘要

Scaffold proteins of the mammalian MAP kinase (MAPK) cascades are considered having critical roles in spatio-temporal regulation of MAPK pathways by organizing their signaling components into functional modules. We are particularly interested in the functions of these scaffold proteins, mainly c-Jun NH_2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1); a scaffold protein that participates in JNK MAPK cascades, both in vitro and in vivo. Our findings are summarized as follows :1) We first investigated the JSAP1-null ES cells. We found that the cardiomyogenesis and neurogenesis process in JSAP1-null mutants were seriously impaired, which strongly indicated that JSAP1 plays an important role in cardiomyocyte and neural development (JBC, 2002 ; BBRC, 2005).2) We also demonstrated that JSAP1 regulates cell movement in cooperation with the focal adhesion kinase (Oncogene, 2002 ; JBC 2005).3) We further showed that JSAP1 scaffold regulates cell-cell interact … More ions in PC12h cells specifically in the NGF-induced signaling pathway, and does so by modulating N-cadherin (BBRC, 2007) through the knock down experiments in PC12h cells.4) We also studied JSAP1 and JNK expression in mouse brains. Our results obtained by in situ hybridization and immunohistochemical analyses strongly suggested that JSAP1-JNK signaling plays important roles in developing and adult mouse brains (JNC, 2006).5) During the development of the cerebellum, massive clonal expansion of granule cell precursors (GCPs) occurs in the outer part of the external granular layer (EGL). We have provided evidence that JSAP1 and active JNK were expressed preferentially in the post-mitotic inner EGL progenitors in the developing cerebellum. Moreover, jsapl deficiency resulted in increasing numbers of proliferating GCPs in mouse embryos. Besides, overexpression of JSAP1 in cultured GCPs led to increased numbers of NeuN-positive cells together with the activation of JNK. Together, these data strongly indicated that JSAP1 promotes the cell-cycle exit and differentiation of GCPs by modulating JNK activity in cerebellar development (in preparation). Less

哺乳动物MAPK(MAPK)级联的支架蛋白通过将其信号组件组织成功能模块，在MAPK通路的时空调控中发挥关键作用。我们对这些支架蛋白的功能特别感兴趣，主要是c-Jun氨基末端激酶(JNK)/应激激活蛋白激酶相关蛋白1(JSAP1)，这是一种在体外和体内参与JNK MAPK级联反应的支架蛋白。我们的研究结果总结如下：1)我们首先研究了JSAP1缺失的ES细胞。我们发现JSAP1缺失突变体的心肌发生和神经发生过程严重受损，这有力地表明JSAP1在心肌细胞和神经发育中发挥着重要作用(JBC，2002；BBRC，2005)2)我们还证明了JSAP1与粘着斑激酶协同调节细胞运动(Oncogene，2002；JBC 2005)。3)我们进一步证明了JSAP1支架调节细胞-细胞相互作用…更多的离子在PC12h细胞中特异性地参与NGF诱导的信号通路，并通过在PC12h细胞中的击倒实验调节N-钙粘蛋白(BBRC，2007)来实现这一点。4)我们还研究了JSAP1和JNK在小鼠脑中的表达。我们通过原位杂交和免疫组织化学分析的结果有力地表明JSAP1-JNK信号在发育和成年小鼠脑中发挥着重要作用(JNC，2006)。5)在小脑发育过程中，颗粒细胞前体(GCP)大量克隆性扩张发生在外部颗粒层(EGL)的外部。我们提供的证据表明，JSAP1和激活的JNK在发育中的小脑中优先表达于有丝分裂后的内EGL前体细胞。此外，JSAP1缺乏导致小鼠胚胎中增殖的GCP数量增加。此外，在培养的GCP中过表达JSAP1导致NeuN阳性细胞数量增加，同时JNK被激活。总之，这些数据有力地表明，JSAP1通过调节小脑发育中的JNK活性来促进GCP的细胞周期退出和分化(准备中)。较少