Alternative titles; symbols
HGNC Approved Gene Symbol: MAP2K3
Cytogenetic location: 17p11.2 Genomic coordinates (GRCh38): 17:21,284,711-21,315,240 (from NCBI)
Mitogen-activated protein kinases (MAPKs) act in cellular signal transduction pathways in response to many extracellular signals. Activation of specific classes of MAPKs requires phosphorylation by specific MAPK kinases (MAP2Ks), also called MKKs or MEKs (see 601254), such as MAP2K3.
PBS2, a yeast MKK, activates stress-activated protein kinases (SAPKs). Derijard et al. (1995) cloned 2 human homologs of PBS2 (MKK3 and MKK4), using primers based on distinct regions of the yeast gene to amplify cDNA clones from brain by PCR. The predicted 322-amino acid MKK3 protein is 40 to 42% identical to PBS2 and human MEK1 (176872) and MEK2 (601263), and 52% identical to MKK4 within the conserved region. Northern blot analysis showed that MKK3 is widely expressed, with highest expression in skeletal muscle.
Han et al. (1997) cloned another form of MKK3, termed MKK3b, which has an additional 29 N-terminal amino acids. Northern blot analysis showed that MKK3b mRNA is much more abundant than MKK3, but has a similar expression pattern.
In vitro kinase assays and in vivo overexpression studies by Derijard et al. (1995) suggested that the SAPK p38 (MAPK14; 600289) is the substrate for MKK3.
A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD protein that perturbs a multiplicity of signaling pathways. These include inhibition of the extracellular signal-regulated kinase ERK, c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways and inhibition of the nuclear factor kappa B (NF-kappa-B) pathway. The expression of YopJ has been correlated with the induction of apoptosis by Yersinia. Using a yeast 2-hybrid screen based on a LexA-YopJ fusion protein and a HeLa cDNA library, Orth et al. (1999) identified mammalian binding partners of YopJ. These included the fusion proteins of the GAL4 activation domain with MAPK kinases MKK1 (176872), MKK2 (601263), and MKK4/SEK1 (601335). YopJ was found to bind directly to MKKs in vitro, including MKK1, MKK3, MKK4, and MKK5 (602448). Binding of YopJ to the MKK blocked both phosphorylation and subsequent activation of the MKKs. These results explain the diverse activities of YopJ in inhibiting the ERK, JNK, p38, and NF-kappa-B signaling pathways, preventing cytokine synthesis and promoting apoptosis. YopJ-related proteins that are found in a number of bacterial pathogens of animals and plants may function to block MKKs so that host signaling responses can be modulated upon infection.
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; 607929) interacted with Mekk3 (MAP3K3; 602539), a p38 activator that responds 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 (602048)- and cytoskeletal actin (see 102560)-containing membrane ruffles in response to sorbitol treatment. Protein interaction assays showed that Osm interacted directly with the Mekk3 substrate Mkk3, 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.
Using radiation hybrid mapping, Rampoldi et al. (1997) localized the MAP2K3 gene to 17q11.2.
Lu et al. (1999) used homologous recombination in mice to inactivate the Mkk3 gene, 1 of 2 specific MAPK kinases that activate p38 MAPK. Mkk3-null mice were viable and fertile, but their macrophages and dendritic cells were defective in IL12 (see 161560) production. Interferon-gamma (147570) production following immunization with protein antigens and in vitro differentiation of naive T cells were also greatly reduced, suggesting an impaired type I cytokine immune response. Lu et al. (1999) concluded that p38 MAP kinase, activated through MKK3, was required to produce inflammatory cytokines by both antigen presenting cells and CD4 (186940)-positive T cells.
Derijard, B., Raingeaud, J., Barrett, T., Wu, I.-H., Han, J., Ulevitch, R. J., Davis, R. J. Independent human MAP kinase signal transduction pathways defined by MEK AND MKK isoforms. Science 267: 682-685, 1995. Note: Erratum: Science 269: 17 only, 1995. [PubMed: 7839144] [Full Text: https://doi.org/10.1126/science.7839144]
Han, J., Wang, X., Jiang, Y., Ulevitch, R. J., Lin, S. Identification and characterization of a predominant isoform of human MKK3. FEBS Lett. 403: 19-22, 1997. [PubMed: 9038352] [Full Text: https://doi.org/10.1016/s0014-5793(97)00021-5]
Lu, H.-T., Yang, D. D., Wysk, M., Gatti, E., Mellman, I., Davis, R. J., Flavell, R. A. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J. 18: 1845-1857, 1999. [PubMed: 10202148] [Full Text: https://doi.org/10.1093/emboj/18.7.1845]
Orth, K., Palmer, L. E., Bao, Z. Q., Stewart, S., Rudolph, A. E., Bliska, J. B., Dixon, J. E. Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Science 285: 1920-1923, 1999. [PubMed: 10489373] [Full Text: https://doi.org/10.1126/science.285.5435.1920]
Rampoldi, L., Zimbello, R., Bortoluzzi, S., Tiso, N., Valle, G., Lanfranchi, G., Danieli, G. A. Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5. Cytogenet. Cell Genet. 78: 301-303, 1997. [PubMed: 9465908] [Full Text: https://doi.org/10.1159/000134677]
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. [PubMed: 14634666] [Full Text: https://doi.org/10.1038/ncb1071]