3enm

Structural highlights

Function

[MP2K6_HUMAN] Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases.^{[1] [2] [3] [4] [5] [6] [7] [8]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Mitogen-activated protein kinase kinase

References

1. ↑ Raingeaud J, Whitmarsh AJ, Barrett T, Derijard B, Davis RJ. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996 Mar;16(3):1247-55. PMID:8622669
2. ↑ Stein B, Brady H, Yang MX, Young DB, Barbosa MS. Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. J Biol Chem. 1996 May 10;271(19):11427-33. PMID:8626699
3. ↑ Moriguchi T, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kano T, Shirakabe K, Muro Y, Shibuya H, Matsumoto K, Nishida E, Hagiwara M. A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem. 1996 Jun 7;271(23):13675-9. PMID:8663074
4. ↑ Goedert M, Cuenda A, Craxton M, Jakes R, Cohen P. Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO J. 1997 Jun 16;16(12):3563-71. PMID:9218798 doi:http://dx.doi.org/10.1093/emboj/16.12.3563
5. ↑ Visconti R, Gadina M, Chiariello M, Chen EH, Stancato LF, Gutkind JS, O'Shea JJ. Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood. 2000 Sep 1;96(5):1844-52. PMID:10961885
6. ↑ Bode JG, Ludwig S, Freitas CA, Schaper F, Ruhl M, Melmed S, Heinrich PC, Haussinger D. The MKK6/p38 mitogen-activated protein kinase pathway is capable of inducing SOCS3 gene expression and inhibits IL-6-induced transcription. Biol Chem. 2001 Oct;382(10):1447-53. PMID:11727828 doi:http://dx.doi.org/10.1515/BC.2001.178
7. ↑ Kaur R, Liu X, Gjoerup O, Zhang A, Yuan X, Balk SP, Schneider MC, Lu ML. Activation of p21-activated kinase 6 by MAP kinase kinase 6 and p38 MAP kinase. J Biol Chem. 2005 Feb 4;280(5):3323-30. Epub 2004 Nov 18. PMID:15550393 doi:http://dx.doi.org/10.1074/jbc.M406701200
8. ↑ Kim MY, Choi TY, Kim JH, Lee JH, Kim JG, Sohn KC, Yoon KS, Kim CD, Lee JH, Yoon TJ. MKK6 increases the melanocyte dendricity through the regulation of Rho family GTPases. J Dermatol Sci. 2010 Nov;60(2):114-9. doi: 10.1016/j.jdermsci.2010.08.006. Epub, 2010 Sep 24. PMID:20869211 doi:http://dx.doi.org/10.1016/j.jdermsci.2010.08.006
9. ↑ Min X, Akella R, He H, Humphreys JM, Tsutakawa SE, Lee SJ, Tainer JA, Cobb MH, Goldsmith EJ. The structure of the MAP2K MEK6 reveals an autoinhibitory dimer. Structure. 2009 Jan 14;17(1):96-104. PMID:19141286 doi:10.1016/j.str.2008.11.007