Function of MEKK3 and its osmosensing scaffold protein

MEKK3及其渗透感应支架蛋白的功能

基本信息

批准号：
7889368
负责人：
GARY L. JOHNSON
金额：
$ 10.38万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-13 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7889368
关键词：
Adaptor Signaling Protein Affect Age Alanine Angiopoietin-1 Back Behavior Binding Binding Proteins Blood capillaries Brain CCM1 gene Catalytic Domain Cavernous Malformation Cell Nucleus Cell physiology Cells Cerebrum Complex Cytoplasm Cytosol Disease Dominant-Negative Mutation Employee Strikes Endothelial Cells Fluorescence Fluorescence Recovery After Photobleaching Fluorescence Resonance Energy Transfer Genes Goals Grant Immunoblotting Individual Inherited Lead Life Lipopolysaccharides Location MAP Kinase Gene MAPK14 gene MAPK7 gene Maintenance Maps Measures Membrane Methodology Migraine Multiprotein Complexes Mus Mutate Mutation Names Nature Neuraxis Neurologic Nuclear PTB Domain Pathology Pathway interactions Patients Peptide Hydrolases Permeability Phosphorylation Phosphotransferases Photobleaching Population Prevention Proteins Publishing Recommendation Regulation Relative (related person)Repression Research Research Personnel Role Scaffolding Protein Seizures Serine Signal Transduction Small Interfering RNA Sorbitol Stimulus Stress Stroke Symptoms Testing Thrombin Tight Junctions Time Tube Ubiquitin Ubiquitination United States Vascular Endothelial Cell Vascular Endothelial Growth Factors Work base capillary cellular imaging cytokine disease-causing mutation human disease immunocytochemistry member migration mutant novel therapeutics nucleocytoplasmic transport overexpression protein complex protein degradation protein function public health relevance receptor research study response scaffold small hairpin RNA ubiquitin ligase ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): MEKK3 is a MAP3kinase that regulates the p38 and ERK5 MAPK pathways. A scaffolding protein was identified that binds MEKK3, named osmosensing scaffold for MEKK3 or OSM. OSM has been defined as a gene mutated in the human disease cerebral cavernous malformations (CCM). Familial CCM is a hereditary microvascular disorder that results in the formation of dilated, leaky capillaries in the central nervous system of affected individuals. Loci for CCM were mapped to three genes, Krit (ccm1), OSM (ccm2) and PDCD10 (ccm3). We have shown that OSM (CCM2), KRIT (CCM1) and PDCD10 (CCM3) are genetically in the same pathway and biochemically form a complex, indicating that they work in concert. CCM1, 2 and 3 appear to have no identifiable catalytic domains. CCM1 and CCM2 are scaffold-like proteins organizing a larger protein complex while CCM3 is predicted to have protein adaptor-like function. Our studies will define at a mechanistic level the function and spatio-temporal regulation of the CCM protein complex for the control of endothelial cell physiology. The hypothesis for this proposal is that the CCM protein complex is dynamic with spatio-temporal changes in composition and subcellular location. CCM1-CCM2-CCM3 complexes are localized both in the cytoplasm and in lamellipodia-like membrane protrusions. In addition, CCM2 rapidly transients in and out of the nucleus and functions as a nucleocytoplasmic shuttling protein. CCM1 can also be found in the nucleus and CCM2 overexpression redistributes CCM1 to the cytoplasm, indicating the CCM1-CCM2 interaction alters the localization of CCM1 in the cell (nuclear versus cytoplasmic), suggesting CCM2 may shuttle CCM1 out of the nucleus. CCM1 (KRIT) can target to endothelial cell tight junctions and regulate tight junction integrity. Thus, the dynamic regulation of CCM1 as part of the CCM1-CCM2-CCM3 complex appears required for the maintenance of microvascular integrity in the CNS. PUBLIC HEALTH RELEVANCE: CCM is a disease caused by mutation of genes encoding proteins that regulate the function of vascular endothelial cells. CCM affects approximately 0.5% of the population in the United States and is a major underlying pathology for hemorrhagic strike. The goal of this proposal is to understand the regulation and function of the CCM protein complex in vascular endothelial cells, which will lead to an understanding of the underlying pathology of CCM and provide potential new therapeutic strategies for cure and prevention.

描述（由申请人提供）：MEKK3是一种MAP3KINASE，可调节p38和ERK5 MAPK途径。鉴定出脚手架蛋白可以结合Mekk3，该蛋白质为MEKK3或OSM命名为osmosensing脚手架。 OSM已被定义为在人类疾病脑海绵状畸形（CCM）中突变的基因。家族性CCM是一种遗传性微血管疾病，导致在受影响个体的中枢神经系统中形成扩张，漏水的毛细血管。 CCM的基因座映射到三个基因KRIT（CCM1），OSM（CCM2）和PDCD10（CCM3）。我们已经表明，OSM（CCM2），KRIT（CCM1）和PDCD10（CCM3）在遗传上处于相同的途径中，并且在生物化学上形成复合物，表明它们在协同中起作用。 CCM1、2和3似乎没有可识别的催化域。 CCM1和CCM2是类似支架的蛋白质，组织较大的蛋白质复合物，而CCM3预计具有蛋白质适应器样功能。我们的研究将在机械水平上定义CCM蛋白复合物的功能和时空调节，以控制内皮细胞生理。该提议的假设是CCM蛋白复合物具有动态性，并且在组成和亚细胞位置的时空变化。 CCM1-CCM2-CCM3复合物均位于细胞质和层状膜状膜突起中。此外，CCM2迅速瞬时瞬时瞬时，并用作核质式穿梭蛋白。 CCM1 can also be found in the nucleus and CCM2 overexpression redistributes CCM1 to the cytoplasm, indicating the CCM1-CCM2 interaction alters the localization of CCM1 in the cell (nuclear versus cytoplasmic), suggesting CCM2 may shuttle CCM1 out of the nucleus. CCM1（KRIT）可以靶向内皮细胞紧密连接并调节紧密连接完整性。因此，CCM1作为CCM1-CCM2-CCM3复合物的一部分的动态调节似乎是维持CNS中微血管完整性所必需的。公共卫生相关性：CCM是一种由编码调节血管内皮细胞功能的蛋白质突变引起的疾病。 CCM影响美国大约0.5％的人口，是出血罢工的主要基础病理。该建议的目的是了解血管内皮细胞中CCM蛋白复合物的调节和功能，这将导致对CCM的潜在病理的理解，并为治愈和预防提供潜在的新治疗策略。