![]() The findings linked CCM3 and STK25 with CCM2, which is part of signaling pathways that are essential for vascular development. Further experiments showed that STK25 and CCM2 formed a protein complex. CCM3 was phosphorylated by STK25, whereas the C-terminal domain of FAP1 dephosphorylated CCM3. Yeast 2-hybrid analysis showed that CCM3 directly bound to STK25 ( 602255) and the phosphatase domain of FAP1 ( 600267). (2007) demonstrated that CCM2 coprecipitated and colocalized with CCM3 (PDCD10 609118). (2005) proposed that the genetic heterogeneity observed in familial CCM may reflect mutation of different molecular members of a coordinated signaling complex.īy GST pull-down and coimmunoprecipitation analysis, Voss et al. The authors expanded upon the established involvement of CCM2 in the p38 MAPK signaling module by demonstrating that KRIT1 associated with CCM2 and MEKK3 in a ternary complex. CCM2 and ICAP1, when bound to KRIT1 via their respective PTB domains, differentially influenced KRIT1 subcellular localization. A familial CCM2 L198R mutation ( 607929.0007) abrogated the KRIT1/CCM2 interaction, suggesting that loss of this interaction may be critical in CCM pathogenesis. Analogous to the established interactions of KRIT1/ITGB1 ( 135630) and KRIT1/ICAP1, the KRIT1/CCM2 association was dependent upon phosphotyrosine-binding (PTB) domain of CCM2. (2005) used coimmunoprecipitation, fluorescence resonance energy transfer, and subcellular localization strategies to show that KRIT1 interacted with CCM2. (2003) concluded that the RAC1-OSM-MEKK3-MKK3 complex is required for regulation of p38 activity in response to osmotic shock. Protein interaction assays showed that Osm interacted directly with the Mekk3 substrate Mkk3 (MAP2K3 602315), with actin, and with both GDP- and GTP-loaded Rac1. Mekk3 and Osm colocalized in the cytoplasmic compartment of cotransfected cells, and the Mekk3-Osm complex was recruited to Rac1 ( 602048)- and cytoskeletal actin (see 102560)-containing membrane ruffles in response to sorbitol treatment. (2003) showed that a C-terminal fragment of mouse Osm interacted with Mekk3 (MAP3K3 602539), a p38 (MAPK14 600289) activator that responds to sorbitol-induced hyperosmotic conditions. Northern blot and in situ hybridization of mouse tissues showed highest Osm expression in nervous system and lymphoid tissues.īy yeast 2-hybrid analysis of a mouse T-cell cDNA library, Uhlik et al. (2003) found that CCM2, which they called OSM, was expressed in the majority of mouse and human cell types tested. Using Western blot analysis, Uhlik et al. (2003) found, from Northern blot analysis of human tissues, using the entire cDNA as a probe, that MCG4607 is most highly expressed in skeletal muscle, heart, and liver, with minimal or no expression in the colon and lung. They suggested that it may be part of the complex pathway of integrin signaling that, when perturbed, causes abnormal vascular morphogenesis in the brain, leading to CCM formation. (2003) named the novel protein encoded by the CCM2 gene malcavernin. The same domain had been found in ICAP1-alpha ( 607153), a binding partner of the CCM1 product KRIT1 ( 604214), which is mutant in cerebral cavernous malformations type 1 ( 116860). The gene was chosen because its translation product contains a putative PTP domain. (2003) performed mutational analysis on a positional candidate gene, MGC4607 (CCM2), located in the critical linkage region in the UCSC human genome assembly. In a study of cerebral cavernous malformations type 2 (CCM2 603284), Liquori et al. ![]()
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