Dual specificity mitogen-activated protein kinase kinase 6

Details

Name
Dual specificity mitogen-activated protein kinase kinase 6
Synonyms
  • 2.7.12.2
  • MAP kinase kinase 6
  • MAPK/ERK kinase 6
  • MEK 6
  • MEK6
  • MKK6
  • PRKMK6
  • SAPK kinase 3
  • SAPKK-3
  • SAPKK3
  • SKK3
  • Stress-activated protein kinase kinase 3
Gene Name
MAP2K6
Organism
Humans
Amino acid sequence
>lcl|BSEQ0051800|Dual specificity mitogen-activated protein kinase kinase 6
MSQSKGKKRNPGLKIPKEAFEQPQTSSTPPRDLDSKACISIGNQNFEVKADDLEPIMELG
RGAYGVVEKMRHVPSGQIMAVKRIRATVNSQEQKRLLMDLDISMRTVDCPFTVTFYGALF
REGDVWICMELMDTSLDKFYKQVIDKGQTIPEDILGKIAVSIVKALEHLHSKLSVIHRDV
KPSNVLINALGQVKMCDFGISGYLVDSVAKTIDAGCKPYMAPERINPELNQKGYSVKSDI
WSLGITMIELAILRFPYDSWGTPFQQLKQVVEEPSPQLPADKFSAEFVDFTSQCLKKNSK
ERPTYPELMQHPFFTLHESKGTDVASFVKLILGD
Number of residues
334
Molecular Weight
37492.055
Theoretical pI
Not Available
GO Classification
Functions
ATP binding / identical protein binding / MAP kinase kinase activity / protein kinase binding / protein serine/threonine kinase activity / protein tyrosine kinase activity
Processes
activation of MAPK activity / activation of protein kinase activity / apoptotic process / cardiac muscle contraction / cell cycle arrest / cellular response to sorbitol / DNA damage induced protein phosphorylation / interleukin-1-mediated signaling pathway / nucleotide-binding oligomerization domain containing signaling pathway / ovulation cycle process / positive regulation of apoptotic process / positive regulation of nitric-oxide synthase biosynthetic process / positive regulation of prostaglandin secretion / proteolysis in other organism / regulation of apoptotic process / regulation of mitotic cell cycle / regulation of transcription, DNA-templated / response to drug / response to ischemia / signal transduction / signal transduction by protein phosphorylation / stress-activated protein kinase signaling cascade / transcription, DNA-templated
Components
cytoplasm / cytoskeleton / cytosol / nucleoplasm / nucleus
General Function
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.
Specific Function
Atp binding
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Nucleus
Gene sequence
>lcl|BSEQ0051801|Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6)
ATGTCTCAGTCGAAAGGCAAGAAGCGAAACCCTGGCCTTAAAATTCCAAAAGAAGCATTT
GAACAACCTCAGACCAGTTCCACACCACCTCGAGATTTAGACTCCAAGGCTTGCATTTCT
ATTGGAAATCAGAACTTTGAGGTGAAGGCAGATGACCTGGAGCCTATAATGGAACTGGGA
CGAGGTGCGTACGGGGTGGTGGAGAAGATGCGGCACGTGCCCAGCGGGCAGATCATGGCA
GTGAAGCGGATCCGAGCCACAGTAAATAGCCAGGAACAGAAACGGCTACTGATGGATTTG
GATATTTCCATGAGGACGGTGGACTGTCCATTCACTGTCACCTTTTATGGCGCACTGTTT
CGGGAGGGTGATGTGTGGATCTGCATGGAGCTCATGGATACATCACTAGATAAATTCTAC
AAACAAGTTATTGATAAAGGCCAGACAATTCCAGAGGACATCTTAGGGAAAATAGCAGTT
TCTATTGTAAAAGCATTAGAACATTTACATAGTAAGCTGTCTGTCATTCACAGAGACGTC
AAGCCTTCTAATGTACTCATCAATGCTCTCGGTCAAGTGAAGATGTGCGATTTTGGAATC
AGTGGCTACTTGGTGGACTCTGTTGCTAAAACAATTGATGCAGGTTGCAAACCATACATG
GCCCCTGAAAGAATAAACCCAGAGCTCAACCAGAAGGGATACAGTGTGAAGTCTGACATT
TGGAGTCTGGGCATCACGATGATTGAGTTGGCCATCCTTCGATTTCCCTATGATTCATGG
GGAACTCCATTTCAGCAGCTCAAACAGGTGGTAGAGGAGCCATCGCCACAACTCCCAGCA
GACAAGTTCTCTGCAGAGTTTGTTGACTTTACCTCACAGTGCTTAAAGAAGAATTCCAAA
GAACGGCCTACATACCCAGAGCTAATGCAACATCCATTTTTCACCCTACATGAATCCAAA
GGAACAGATGTGGCATCTTTTGTAAAACTGATTCTTGGAGACTAA
Chromosome Location
17
Locus
17q24.3
External Identifiers
ResourceLink
UniProtKB IDP52564
UniProtKB Entry NameMP2K6_HUMAN
HGNC IDHGNC:6846
General References
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  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. [Article]
  3. Han J, Lee JD, Jiang Y, Li Z, Feng L, Ulevitch RJ: Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J Biol Chem. 1996 Feb 9;271(6):2886-91. [Article]
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  5. Cuenda A, Alonso G, Morrice N, Jones M, Meier R, Cohen P, Nebreda AR: Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells. EMBO J. 1996 Aug 15;15(16):4156-64. [Article]
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  7. 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. [Article]
  8. Ben-Levy R, Hooper S, Wilson R, Paterson HF, Marshall CJ: Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr Biol. 1998 Sep 24;8(19):1049-57. [Article]
  9. Chan-Hui PY, Weaver R: Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades. Biochem J. 1998 Dec 15;336 ( Pt 3):599-609. [Article]
  10. Deacon K, Blank JL: MEK kinase 3 directly activates MKK6 and MKK7, specific activators of the p38 and c-Jun NH2-terminal kinases. J Biol Chem. 1999 Jun 4;274(23):16604-10. [Article]
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  12. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K: The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature. 1999 Mar 18;398(6724):252-6. [Article]
  13. Vitale G, Bernardi L, Napolitani G, Mock M, Montecucco C: Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem J. 2000 Dec 15;352 Pt 3:739-45. [Article]
  14. 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. [Article]
  15. 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. [Article]
  16. Morita K, Saitoh M, Tobiume K, Matsuura H, Enomoto S, Nishitoh H, Ichijo H: Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress. EMBO J. 2001 Nov 1;20(21):6028-36. [Article]
  17. Chen Z, Cobb MH: Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2. J Biol Chem. 2001 May 11;276(19):16070-5. Epub 2001 Mar 8. [Article]
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  19. Silva AM, Whitmore M, Xu Z, Jiang Z, Li X, Williams BR: Protein kinase R (PKR) interacts with and activates mitogen-activated protein kinase kinase 6 (MKK6) in response to double-stranded RNA stimulation. J Biol Chem. 2004 Sep 3;279(36):37670-6. Epub 2004 Jun 30. [Article]
  20. Cheung PY, Zhang Y, Long J, Lin S, Zhang M, Jiang Y, Wu Z: p150(Glued), Dynein, and microtubules are specifically required for activation of MKK3/6 and p38 MAPKs. J Biol Chem. 2004 Oct 29;279(44):45308-11. Epub 2004 Sep 16. [Article]
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  24. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP: A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. doi: 10.1073/pnas.0805139105. Epub 2008 Jul 31. [Article]
  25. Sturchler E, Feurstein D, McDonald P, Duckett D: Mechanism of oxidative stress-induced ASK1-catalyzed MKK6 phosphorylation. Biochemistry. 2010 May 18;49(19):4094-102. doi: 10.1021/bi100010j. [Article]
  26. 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. [Article]
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  29. Zhou H, Di Palma S, Preisinger C, Peng M, Polat AN, Heck AJ, Mohammed S: Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res. 2013 Jan 4;12(1):260-71. doi: 10.1021/pr300630k. Epub 2012 Dec 18. [Article]
  30. 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. doi: 10.1016/j.str.2008.11.007. [Article]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB12010Fostamatinibapproved, investigationalunknowninhibitorDetails