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.
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.
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