Alternative titles; symbols
HGNC Approved Gene Symbol: MAP2K6
Cytogenetic location: 17q24.3 Genomic coordinates (GRCh38): 17:69,414,697-69,553,865 (from NCBI)
Mitogen-activated protein kinases (MAPKs) are key components in various cellular signal transduction pathways that affect growth factor-induced proliferation, gene expression, and compensation for environmental changes (for a review, see Seger and Krebs (1995)). To become activated, MAPKs require dual phosphorylation on threonine and tyrosine residues, an activation step carried out by MAPK kinases (MAP2Ks, also called MKKs or MEKs). At least 4 MAPK pathways exist in higher eukaryotes and are composed of signaling cascades that lead to activation of at least 4 specific MAP2Ks. MKK1 (MAP2K1; 176872) phosphorylates and activates ERK, an extracellular signal-regulated kinase (see 176948). MKK3 (MAP2K3; 602315), MKK4 (MAP2K4; 601335), and MKK6 activate p38 MAPK (600289), but not ERK (Han et al., 1996).
Han et al. (1996) used degenerate oligonucleotide primers from the conserved kinase domains of MKK3 and MKK4 and cloned 2 human cDNAs and 1 murine cDNA encoding closely related proteins of the MKK family. The 2 human clones appear to be different isoforms of the same gene generated by differential splicing: the shorter clone, which they designated MKK6, encodes a 278-amino acid protein, while the longer clone, designated MKK6b, encodes a 334-amino acid protein. MKK6 is about 80% identical to MKK3 and 40% identical to MKK4. Northern blot analysis showed that the 1.7-kb human MKK6 transcript was highly expressed in skeletal muscle, while an MKK6b-specific probe detected mRNA bands of 1.8, 2.4, and 4.5 kb that were enriched in heart, skeletal muscle, pancreas, and liver. The authors suggested that tissue-specific splicing occurs and may play a role in the control of MKK6 expression.
Han et al. (1996) described experiments addressing the function of MKK6 in intracellular signaling pathways leading toward activation of p38 MAPK.
During mammalian development, electrical activity promotes the calcium-dependent survival of neurons that have made appropriate synaptic connections. Mao et al. (1999) showed that calcium influx into cerebellar neurons triggers activation of the MKK6-p38 MAP kinase cascade and that p38 MAP kinase then phosphorylates and activates MEF2s. Once activated by this calcium-dependent p38 MAP kinase signaling pathway, MEF2 can regulate expression of genes critical for survival of newly differentiated neurons.
Mukherjee et al. (2006) found that the Yersinia YopJ virulence factor acted as an acetyltransferase, using coenzyme A to modify critical ser and thr residues in the MAP2K6 activation loop, thereby blocking phosphorylation and kinase activation. They proposed that ser and/or thr acetylation by a bacterial effector may be a mechanism that occurs in other signaling pathways.
Han, J., Lee, J.-D., Jiang, Y., Li, Z., Feng, L., Ulevitch, R. J. Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J. Biol. Chem. 271: 2886-2891, 1996. [PubMed: 8621675] [Full Text: https://doi.org/10.1074/jbc.271.6.2886]
Mao, Z., Bonni, A., Xia, F., Nadal-Vicans, M., Greenberg, M. E. Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science 286: 785-790, 1999. [PubMed: 10531066] [Full Text: https://doi.org/10.1126/science.286.5440.785]
Mukherjee, S., Keitany, G., Li, Y., Wang, Y., Ball, H. L., Goldsmith, E. J., Orth, K. Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation. Science 312: 1211-1214, 2006. [PubMed: 16728640] [Full Text: https://doi.org/10.1126/science.1126867]
Seger, R., Krebs, E. G. The MAPK signaling cascade. FASEB J. 9: 726-735, 1995. [PubMed: 7601337]