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：
8725195
负责人：
PAUL James CULLEN
金额：
$ 29.75万
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8725195
关键词：
Accounting Address Biochemical Biological Cancer Etiology Cell Cycle Progression Cell Differentiation process Cell Polarity Cell Proliferation Cell Surface Proteins Cell surface Cells Cellular biology Co-Immunoprecipitations Decision Making Disease Eukaryota G Protein-Coupled Receptor Genes Gene Expression Genetic Genetic Models Genomics Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Health Human In Vitro Internet Light Link Lipids MAP Kinase Gene Malignant Neoplasms Maps Modeling Modification Molecular Monomeric GTP-Binding Proteins Mucins Neoplasm Metastasis Output Partner in relationship Pathway interactions Phosphorylation Play Process Proteins Recruitment Activity Regulation Regulatory Pathway Role Saccharomyces cerevisiae Saccharomycetales Signal Pathway Signal Transduction Signal Transduction Pathway Site Specific qualifier value Specificity Stimulus System Testing Work Yeasts cell cortex in vitro testing in vivo inhibitor/antagonist mutant novel response rho GTP-Binding Proteins scaffold trafficking

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand how intracellular signals are directed along specific pathways to induce a defined output. Signal transduction pathways typically function in interconnected web-like networks composed of common or "shared" signaling modules. An important question is how does a signal follow a particular path through a common module to induce a specific response? Some diseases like cancer can arise because a signal that meant to follow one path is misdirected to another. The proposal focuses on the Rho GTPase Cdc42 in the model eukaryote, Saccharomyces cerevisiae. In S. cerevisiae, Cdc42 is a major regulator of multiple signaling pathways, but it is not clear how Cdc42 induces a specific response in one setting and a completely different response in another. Importantly, Cdc42 also functions in determining the axis of cell polarity, and this provides a clue to its specificity. A recent discovery from our lab showed that proteins required for establishing polarity also direct Cdc42 function to a specific MAPK pathway. This discovery is important because it links positional information with the cell's decision-making process. This proposal will attempt to uncover the molecular mechanisms for how positional information is used to direct pathway specificity. Aim1 will test how recruitment of the Cdc42 activating protein (GEF) by polar landmarks controls MAPK activation. This will be done by using a combination of genetic and cell biological approaches. Aim 2 will use molecular and biochemical approaches to investigate the role of a Cdc42-interacting protein (Bem4) as a pathway-specific scaffold for the MAPK pathway. The potential mechanism(s) by which Bem4 regulates Cdc42 will be tested. Aim3 focuses on a newly- identified cell-surface protein (Opy2) that acts with a signaling mucin to stimulate Cdc42. Mucins are important but poorly understood proteins whose function is mechanistically distinct from the well-studied GPCR class of MAPK regulators. How the Opy2 mucin adaptor activates Cdc42 will be determined.

描述（由申请人提供）：该提案的长期目标是了解如何沿特定途径指向细胞内信号以诱导定义的输出。信号转导途径通常在由通用或“共享”信号模块组成的互连网络状网络中起作用。一个重要的问题是，信号如何遵循通用模块的特定路径来诱导特定响应？可能会出现一些像癌症这样的疾病，因为旨在遵循一条路径的信号被误导到另一种路径。该提案重点介绍了真核生物酿酒酵母模型中的Rho GTPase CDC42。在酿酒酵母中，cdc42是多个信号通路的主要调节剂，但尚不清楚cdc42如何在一种环境中诱导特定响应，而在另一种设置中却是完全不同的响应。重要的是，CDC42还起作用，可在确定细胞极性轴上，这为其特异性提供了线索。我们实验室的最新发现表明，建立极性所需的蛋白质也将CDC42功能直接直接为特定的MAPK途径。该发现很重要，因为它将位置信息与单元的决策过程联系起来。该建议将试图揭示如何使用位置信息来指导途径特异性的分子机制。 AIM1将测试如何通过极地地标控制MAPK激活CDC42激活蛋白（GEF）。这将通过结合遗传和细胞生物学方法来完成。 AIM 2将使用分子和生化方法研究Cdc42相互作用蛋白（BEM4）作为MAPK途径的途径特异性支架的作用。将测试BEM4调节CDC42的潜在机制。 AIM3专注于新近鉴定的细胞表面蛋白（OPY2），该蛋白（OPY2）用信号粘蛋白作用以刺激Cdc42。粘蛋白是重要但知之甚少的蛋白质，其功能在机械上与良好的MAPK调节剂的GPCR类别不同。 OPY2粘蛋白适配器如何激活CDC42。