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ONCOGENESIS/CONTROL--PHOSPHOINOSITIDE CYCLE/KINASE C

致癌/控制--磷酸肌醇循环/激酶 C

基本信息

批准号：
6350046
负责人：
IAN G MACARA
金额：
$ 29.95万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-06-01 至 2003-01-31
项目状态：
已结题

项目摘要

DESCRIPTION: (adapted from the investigator's abstract) The Ras GTPase has been implicated in about 20% of all human cancers. The regulation of signal transduction through Ras is complex and is not fully understood. Multiple nucleotide exchange factors can activate Ras, and other factors called GTPase activating proteins (GAPs) can inactivate it. One such GAP, p120, can associate with another protein called p190, which is a GAP for the Rac/Rho GTPase family, and can thereby link these two signaling pathways. The activation of the Rac and Rho GTPases is required for transformation by Ras, and mediates changes in the actin cytoskeleton. The goals of this project are: (1) to understand the mechanisms that regulate the Ras exchange factor, p140 Ras-GRF; and (2) to determine the function of the GTP-binding domain in the p190 RhoGAP. GRF is expressed predominantly in neurons, and may be the key regulator of Ras activity in the brain. GRF can be controlled by phosphorylation of Ser residues in response to muscarinic receptor activation. The first specific aims include: (a) identification of the phosphorylated Ser residues; (b) identification of the protein kinase responsible for agonist-dependent GRF phosphorylation; (c) the function of the pleckstrin homology, coiled-coil, IQ and Dbl domains of GRF in regulating phosphorylation; and (d) the role of GRF in neuronal signal transduction. The GTP-binding domain of p190 RhoGAP is required for morphological and protein kinase responses of cells to p190 expression. Specific aims in this section include identification of: (e) the mechanism by which the GTP-binding domain exerts these effects and the role of the interaction of p190 with p120 RasGAP; and (f) factors that regulate p190 GTP binding and hydrolysis, using the isolated p190 GTP-binding domain as a substrate. Overall these studies should lead to significant new insights into signaling through the Ras pathway, and may lead to new therapeutic targets for certain types of cancer.

描述：（改编自研究者摘要）Ras GTvalve具有与大约20%的人类癌症有关。信号调节通过Ras的转导是复杂的并且尚未完全理解。多核苷酸交换因子可以激活Ras，而其他称为 GTP酶激活蛋白（GAP）可以使其失活。其中一种GAP，p120，可以与另一种称为p190的蛋白质结合，这是一种GAP， Rac/Rho GTdR家族，从而可以连接这两个信号通路。 Rac和Rho GTPases的激活是转化所需的 Ras，并介导肌动蛋白细胞骨架的变化。本项目的目标是：（1）了解调节Ras交换因子，p140 Ras-GRF;和（2）确定 p190 RhoGAP中GTP结合结构域的功能。 GRF主要在神经元中表达，并且可能是GRF的关键调节因子。大脑中的Ras活动。 GRF可以通过Ser的磷酸化来控制反应于毒蕈碱受体活化的残基。第一特定目的包括：（a）鉴定磷酸化的Ser残基;（B）确定负责激动剂依赖性GRF的蛋白激酶磷酸化;（c）普列克底物蛋白同源性，卷曲螺旋， GRF的IQ和Db 1结构域在调节磷酸化中的作用;和（d） GRF在神经元信号转导中的作用 p190 RhoGAP的GTP结合结构域是形态学和生物学功能所必需的。细胞对p190表达的蛋白激酶反应。其中的具体目标（e）通过何种机制， GTP结合结构域发挥这些作用，并相互作用， p190与p120 RasGAP;和（f）调节p190 GTP结合的因子，水解，使用分离的p190 GTP结合结构域作为底物。总的来说，这些研究应该会对信号传导产生重要的新见解通过Ras途径，并可能导致某些新的治疗靶点，癌症的类型。