Scientific background: |
MAP3K3(Mitogen-activated protein kinase kinase kinase 3), also known as MAP/ERK KINASE KINASE 3, MEKK3 or MAPKKK3, is an enzyme that in humans is encoded by the MAP3K3 gene. MAP3K3 is contiguously distal to LYK5 on chromosome 17 (Puffenberger et al., 2007). By yeast 2-hybrid analysis of a mouse T-cell cDNA library, Uhlik et al. (2003) showed that a C-terminal fragment of mouse Osm (CCM2) interacted with Mekk3, which activates p38 in response to sorbitol-induced hyperosmotic conditions. Mekk3 and Osm colocalized in the cytoplasmic compartment of cotransfected cells, and the Mekk3-Osm complex was recruited to Rac1 and cytoskeletal actin-containing membrane ruffles in response to sorbitol treatment. Protein interaction assays showed that Osm interacted directly with the Mekk3 substrate Mkk3 (MAP2K3), with actin, and with both GDP- and GTP-loaded Rac1. Uhlik et al. (2003) concluded that the RAC1-OSM-MEKK3-MKK3 complex is required for regulation of p38 activity in response to osmotic shock. |
References: |
1. Channavajhala, P. L., Rao, V. R., Spaulding, V., Lin, L. L., Zhang, Y. G. hKSR-2 inhibits MEKK3-activated MAP kinase and NF-kappa-B pathways in inflammation. Biochem. Biophys. Res. Commun. 334: 1214-1218, 2005.
2. Puffenberger, E. G., Strauss, K. A., Ramsey, K. E., Craig, D. W., Stephan, D. A., Robinson, D. L., Hendrickson, C. L., Gottlieb, S., Ramsay, D. A., Siu, V. M., Heuer, G. G., Crino, P. B., Morton, D. H. Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5. Brain 130: 1929-1941, 2007.
3. Uhlik, M. T., Abell, A. N., Johnson, N. L., Sun, W., Cuevas, B. D., Lobel-Rice, K. E., Horne, E. A., Dell'Acqua, M. L., Johnson, G. L. Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. Nature Cell Biol. 5: 1104-1110, 2003.
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