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Atypical MAP Kinase Signal Transduction

非典型 MAP 激酶信号转导

基本信息

批准号：
10577709
负责人：
JEFFREY A HADWIGER
金额：
$ 43.62万
依托单位：
OKLAHOMA STATE UNIVERSITY STILLWATER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-08 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577709
关键词：
Amoeba genus Animal Model Animals Binding Proteins Biological Assay Cell Fate Control Cell Nucleus Cells Chemotaxis Co-Immunoprecipitations Collaborations Cyclic AMP Cytoplasm Development Dictyostelium Dictyostelium discoideum Docking Eukaryota Eukaryotic Cell Folic Acid Funding G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Genetic Immune response Lead Mammals Maps Mass Spectrum Analysis Mediating Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Modification Movement Organism Orthologous Gene Phosphorylation Phosphotransferases Protein Kinase Proteins Receptor Protein-Tyrosine Kinases Regulation Research Role Signal Pathway Signal Transduction Signal Transduction Pathway Site Specificity Testing base biochemical tools cell growth cell motility fungus genetic analysis genetic regulatory protein human disease in vivo insight mutant response transcription factor

项目摘要

Project Summary: MAP kinases (MAPKs) are regulatory components of many signal transduction pathways that impact eukaryotic cell growth, differentiation, and movement. Relatively little is known about the function and regulation of atypical MAPKs (represented by MAPK15/Erk8 in mammals) found only in eukaryotes that have cell motility. Atypical MAPKs are not activated by conventional MAPK kinases and the external signals that trigger activation are not known except in the amoeba Dictyostelium, a model organism for chemotactic movement and development. We have found that the Dictyostelium atypical MAPK, Erk2, is essential for chemotactic movement to multiple signals. In our previously funded research we also discovered that Erk2 phosphorylates specific residues of a GATA transcription factor, GtaC, resulting in the translocation of this factor from the nucleus to the cytoplasm in response to at least two chemotactic signals that promote different cell fates. We have also demonstrated that Erk2 kinase activity is not required for activation in vivo indicating that an unconventional MAPK kinase regulates atypical MAPKs rather than autophosphorylation. The proposed research will investigate if Erk2 promotes different cell fates through the differentially modification of GtaC or through the regulation of other transcription factors. We will use a GFP tagged GtaC to map Erk2 docking sites and compare these to docking sites of other groups of MAPKs. We will also use co-immunoprecipitations, mass spectrometry, and genetic analysis to identify proteins that associate and function with Erk2 in signaling pathways and identify proteins that directly regulate Erk2 activation. The results of this project are expected to identify specific mechanisms of atypical MAPK regulation and function and uncover roles for atypical MAPK signaling in chemotactic movement and cell fate determination that can guide the research of MAPKs in other organisms such as mammals.

项目概要： MAP激酶（MAPKs）是许多信号转导的调节组分影响真核细胞生长、分化和运动的途径。相对关于非典型MAPK的功能和调节知之甚少（由 MAPK 15/Erk 8在哺乳动物中）仅在具有细胞运动性的真核生物中发现。非典型 MAPK不被常规的MAPK激酶激活，触发激活是未知的，除了在阿米巴Dictyosteoba，模式生物用于趋化运动和发育。我们发现网骨藻非典型MAPK，Erk 2，对于多种信号的趋化运动是必需的。在我们之前资助的研究，我们还发现Erk 2磷酸化特异性，加塔转录因子GtaC的残基，导致该因子易位从细胞核到细胞质，以响应至少两种趋化信号，促进不同的细胞命运。我们还证明了Erk 2激酶活性不是这表明非常规MAPK激酶调节非典型MAPK而不是自身磷酸化。拟议的研究将研究Erk 2是否通过差异修饰促进不同的细胞命运 GtaC或通过其他转录因子的调节。我们将使用GFP标记 GtaC绘制Erk 2对接位点，并将其与其他组的对接位点进行比较。 MAPKs我们还将使用免疫共沉淀、质谱和遗传学方法，分析以鉴定在信号传导途径中与Erk 2相关并起作用的蛋白质并鉴定直接调节Erk 2激活的蛋白质。该项目的成果是期望确定非典型MAPK调节和功能的特定机制，揭示非典型MAPK信号在趋化运动和细胞命运中的作用这一确定可以指导其他生物体中MAPK的研究，哺乳动物