Control of MAPK Signaling by Cell Polarity Proteins

细胞极性蛋白对 MAPK 信号传导的控制

基本信息

批准号：
10378066
负责人：
PAUL James CULLEN
金额：
$ 34.48万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10378066
关键词：
Address Binding Cancer Etiology Cell Differentiation process Cell Polarity Cell Shape Cell membrane Cells Cyclic GMP-Dependent Protein Kinases Disease Family GTP Binding GTP-Binding Proteins Glycoproteins Goals Growth Guanosine Triphosphate Health Human Link Lysine MAP Kinase Gene MAPK Signaling Pathway Pathway MAPK3 gene Malignant Neoplasms Maps Mitogen-Activated Protein Kinases Modification Monomeric GTP-Binding Proteins Mucins Output Pathway interactions Phosphotransferases Post-Translational Protein Processing Process Protein Kinase Proteins Regulation Reporting Role Signal Pathway Signal Transduction Signal Transduction Pathway Site Specificity System Testing Ubiquitin Virulence Work Yeasts cell type experimental study insight microbial pathogenic fungus protein degradation protein function ral Guanine Nucleotide Exchange Factor response rho GTP-Binding Proteins scaffold sensor ubiquitin ligase

项目摘要

Signal transduction pathways function in interconnected networks comprising common or shared proteins. How specific signals are directed through a common protein module to induce a highly specific response is not clear. Some diseases like cancer can arise because a signal that is meant to follow one path is misdirected into another. One MAPK pathway in yeast regulates a microbial differentiation response called filamentous growth. In fungal pathogens, filamentous growth is required for virulence. The MAPK pathway is composed of G proteins and protein kinases that function in multiple pathways. A major regulator of the pathway is the Rho GTPase, Cdc42, which is widely considered a master regulator of cell polarity and signaling. In this proposal is reported the discovery that Cdc42 is degraded by a mechanism that involves ubiquitin modification of the protein. This discovery is important because it provides a new way to regulate signaling pathways that require Cdc42 for function. Thus, one objective of the proposal is to determine the functional consequences of Cdc42 turnover on MAP kinase signaling (Aim 1). In addition to Cdc42, several protein kinases are shared among MAPK pathways. In Aim 2, a newly identified scaffold of the Ral GDS type will be examined that binds to kinases to direct them to the MAPK pathway. The filamentous growth pathway is regulated by a sensor protein of the mucin family. Mucins are large glycoproteins that regulate signaling pathways through mechanisms that remain uclear. In Aim 3 of the proposal, how the mucin connects to and regulates Cdc42 will be determined. One candidate is the cell's main polairty scaffold, which has recently been found to also regulate the MAPK pathway. Experiments are proposed to determine how the mucin directs the polarity scaffold to the Cdc42 module. Collectively, this proposal will define new mechanisms of G protein regulation, as well as how commom proteins are directed to specific pathways. Given that the proteins in this pathway are highly conserved from yeast to humans, insights gained from this proposal will likely extend to signaling pathways in general, including those that are relevant to human health.

信号转导途径在包含的互连网络中的功能常见或共享蛋白质。特定信号是如何通过共同的诱导高度特异性反应的蛋白质模块尚不清楚。一些疾病喜欢癌症可能会出现，因为旨在遵循一条路径的信号被误导到其他。酵母中的一个MAPK途径调节微生物分化反应称为丝状生长。在真菌病原体中，需要丝状生长毒力。 MAPK途径由G蛋白和蛋白激酶组成在多个途径中功能。途径的主要调节因子是Rho GTPase， Cdc42，被广泛认为是细胞极性和信号传导的主要调节剂。在此提案中，发现Cdc42被机制降解的发现这涉及蛋白质的泛素修饰。这个发现很重要因为它提供了一种新方法来调节需要CDC42的信号通路功能。因此，该提案的一个目的是确定功能 MAP激酶信号传导上CDC42营业额的后果（AIM 1）。此外 CDC42，在MAPK途径之间共享几种蛋白激酶。在AIM 2中将检查与激酶结合的新发现的RAL GDS类型的支架将它们引导到MAPK路径。丝状生长途径受到调节通过粘蛋白家族的传感器蛋白。粘蛋白是调节的大糖蛋白信号通路通过仍然是Uclear的机制。在目标3中建议，将确定粘蛋白如何与CDC42连接并调节。一候选人是该细胞的主要圆锥形脚手架，最近也发现调节MAPK途径。提出了实验以确定粘蛋白的方式将极性支架引导到CDC42模块。总的来说，该提议将定义G蛋白调节的新机制，以及孔蛋白如何针对特定途径。鉴于该途径中的蛋白质高度高从酵母到人类的保守，从该提议中获得的见解可能会扩展一般而言，信号通路，包括与人类健康相关的途径。