MAP2K6

Main article: Mitogen-activated protein kinase kinase

Mitogen-activated protein kinase kinase 6
Rendering based on PDB 3ENM.
Available structures PDB 3ENM, 3FME
Identifiers
Symbols	MAP2K6; MAPKK6; MEK6; MKK6; PRKMK6; SAPKK3
External IDs	OMIM: 601254 MGI: 1346870 HomoloGene: 55686 GeneCards: MAP2K6 Gene
EC number	2.7.12.2
Gene Ontology Molecular function • nucleotide binding • protein serine/threonine kinase activity • MAP kinase kinase activity • protein tyrosine kinase activity • protein binding • ATP binding Cellular component • nucleoplasm • cytosol • cytosol Biological process • activation of MAPK activity • toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • DNA damage induced protein phosphorylation • cell cycle arrest • signal transduction • Toll signaling pathway • toll-like receptor 1 signaling pathway • toll-like receptor 2 signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • response to drug • muscle cell differentiation • positive regulation of apoptosis • innate immune response • positive regulation of muscle cell differentiation • stress-activated MAPK cascade • cardiac muscle contraction Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5608	26399
Ensembl	ENSG00000108984	ENSMUSG00000020623
UniProt	P52564	P70273
RefSeq (mRNA)	NM_002758.3	NM_011943.2
RefSeq (protein)	NP_002749.2	NP_036073.1
Location (UCSC)	Chr 17: 67.41 – 67.54 Mb	Chr 11: 110.26 – 110.39 Mb
PubMed search	[1]	[2]

Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 (MAPKK 6) or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the MAP2K6 gene, on chromosome 17.^[1]

Function

MAPKK 6 is a member of the dual specificity protein kinase family, which functions as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein phosphorylates and activates p38 MAP kinase in response to inflammatory cytokines or environmental stress. As an essential component of p38 MAP kinase mediated signal transduction pathway, this gene is involved in many cellular processes such as stress-induced cell cycle arrest, transcription activation and apoptosis.^[2]

Interactions

MAP2K6 has been shown to interact with TAOK2,^[3] ASK1,^[4][5] MAPK14^[6][7][8][3] and MAP3K7.^{[9][10][11][12]}

References

1. ^ Han J, Lee JD, Jiang Y, Li Z, Feng L, Ulevitch RJ (Jun 1996). "Characterization of the structure and function of a novel MAP kinase kinase (MKK6)". J Biol Chem 271 (6): 2886–91. doi:10.1074/jbc.271.6.2886. PMID 8621675. 
2. ^ "Entrez Gene: MAP2K6 mitogen-activated protein kinase kinase 6". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5608. 
3. ^ ^{a b} Chen, Z; Cobb M H (May. 2001). "Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2". J. Biol. Chem. (United States) 276 (19): 16070–5. doi:10.1074/jbc.M100681200. ISSN 0021-9258. PMID 11279118. 
4. ^ Huang, Shile; Shu Lili, Dilling Michael B, Easton John, Harwood Franklin C, Ichijo Hidenori, Houghton Peter J (Jun. 2003). "Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1)". Mol. Cell (United States) 11 (6): 1491–501. doi:10.1016/S1097-2765(03)00180-1. ISSN 1097-2765. PMID 12820963. 
5. ^ Morita, K; Saitoh M, Tobiume K, Matsuura H, Enomoto S, Nishitoh H, Ichijo H (Nov. 2001). "Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress". EMBO J. (England) 20 (21): 6028–36. doi:10.1093/emboj/20.21.6028. ISSN 0261-4189. PMC 125685. PMID 11689443. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=125685. 
6. ^ Sanz-Moreno, Victoria; Casar Berta, Crespo Piero (May. 2003). "p38α Isoform Mxi2 Binds to Extracellular Signal-Regulated Kinase 1 and 2 Mitogen-Activated Protein Kinase and Regulates Its Nuclear Activity by Sustaining Its Phosphorylation Levels". Mol. Cell. Biol. (United States) 23 (9): 3079–90. doi:10.1128/MCB.23.9.3079-3090.2003. ISSN 0270-7306. PMC 153192. PMID 12697810. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=153192. 
7. ^ Raingeaud, J; Whitmarsh A J, Barrett T, Dérijard B, Davis R J (Mar. 1996). "MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway". Mol. Cell. Biol. (UNITED STATES) 16 (3): 1247–55. ISSN 0270-7306. PMC 231107. PMID 8622669. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=231107. 
8. ^ Stein, B; Brady H, Yang M X, Young D B, Barbosa M S (May. 1996). "Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade". J. Biol. Chem. (UNITED STATES) 271 (19): 11427–33. doi:10.1074/jbc.271.19.11427. ISSN 0021-9258. PMID 8626699. 
9. ^ Ishitani, Tohru; Takaesu Giichi, Ninomiya-Tsuji Jun, Shibuya Hiroshi, Gaynor Richard B, Matsumoto Kunihiro (Dec. 2003). "Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling". EMBO J. (England) 22 (23): 6277–88. doi:10.1093/emboj/cdg605. ISSN 0261-4189. PMC 291846. PMID 14633987. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=291846. 
10. ^ Wang, C; Deng L, Hong M, Akkaraju G R, Inoue J, Chen Z J (Jul. 2001). "TAK1 is a ubiquitin-dependent kinase of MKK and IKK". Nature (England) 412 (6844): 346–51. doi:10.1038/35085597. ISSN 0028-0836. PMID 11460167. 
11. ^ Ninomiya-Tsuji, J; Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K (Mar. 1999). "The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway". Nature (ENGLAND) 398 (6724): 252–6. doi:10.1038/18465. ISSN 0028-0836. PMID 10094049. 
12. ^ Sakurai, H; Miyoshi H, Mizukami J, Sugita T (Jun. 2000). "Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1". FEBS Lett. (NETHERLANDS) 474 (2–3): 141–5. doi:10.1016/S0014-5793(00)01588-X. ISSN 0014-5793. PMID 10838074. 

Further reading

• Ben-Levy R, Hooper S, Wilson R et al. (1999). "Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2". Curr. Biol. 8 (19): 1049–57. doi:10.1016/S0960-9822(98)70442-7. PMID 9768359. 
• Tanaka S, Nakamura K, Takahasi N, Suda T (2006). "Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system". Immunol. Rev. 208: 30–49. doi:10.1111/j.0105-2896.2005.00327.x. PMID 16313339. 
• Doza YN, Cuenda A, Thomas GM et al. (1995). "Activation of the MAP kinase homologue RK requires the phosphorylation of Thr-180 and Tyr-182 and both residues are phosphorylated in chemically stressed KB cells". FEBS Lett. 364 (2): 223–8. doi:10.1016/0014-5793(95)00346-B. PMID 7750576. 
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298. 
• Raingeaud J, Whitmarsh AJ, Barrett T et al. (1996). "MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway". Mol. Cell. Biol. 16 (3): 1247–55. PMC 231107. PMID 8622669. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=231107. 
• Stein B, Brady H, Yang MX et al. (1996). "Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade". J. Biol. Chem. 271 (19): 11427–33. doi:10.1074/jbc.271.19.11427. PMID 8626699. 
• Moriguchi T, Kuroyanagi N, Yamaguchi K et al. (1996). "A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3". J. Biol. Chem. 271 (23): 13675–9. doi:10.1074/jbc.271.23.13675. PMID 8663074. 
• Cuenda A, Alonso G, Morrice N et al. (1996). "Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells". EMBO J. 15 (16): 4156–64. PMC 452138. PMID 8861944. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=452138. 
• Goedert M, Cuenda A, Craxton M et al. (1997). "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. 16 (12): 3563–71. doi:10.1093/emboj/16.12.3563. PMC 1169981. PMID 9218798. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1169981. 
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. 
• Enslen H, Raingeaud J, Davis RJ (1998). "Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6". J. Biol. Chem. 273 (3): 1741–8. doi:10.1074/jbc.273.3.1741. PMID 9430721. 
• Chan-Hui PY, Weaver R (1999). "Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades". Biochem. J. 336 ( Pt 3) (Pt 3): 599–609. PMC 1219910. PMID 9841871. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1219910. 
• Chen Z, Hutchison M, Cobb MH (1999). "Isolation of the protein kinase TAO2 and identification of its mitogen-activated protein kinase/extracellular signal-regulated kinase kinase binding domain". J. Biol. Chem. 274 (40): 28803–7. doi:10.1074/jbc.274.40.28803. PMID 10497253. 
• Cong F, Goff SP (2000). "c-Abl-induced apoptosis, but not cell cycle arrest, requires mitogen-activated protein kinase kinase 6 activation". Proc. Natl. Acad. Sci. U.S.A. 96 (24): 13819–24. doi:10.1073/pnas.96.24.13819. PMC 24148. PMID 10570156. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=24148. 
• Wang X, McGowan CH, Zhao M et al. (2000). "Involvement of the MKK6-p38γ Cascade in γ-Radiation-Induced Cell Cycle Arrest". Mol. Cell. Biol. 20 (13): 4543–52. doi:10.1128/MCB.20.13.4543-4552.2000. PMC 85840. PMID 10848581. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=85840. 
• Visconti R, Gadina M, Chiariello M et al. (2000). "Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity". Blood 96 (5): 1844–52. PMID 10961885. 
• Fleming Y, Armstrong CG, Morrice N et al. (2001). "Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7". Biochem. J. 352 Pt 1 (Pt 1): 145–54. PMC 1221441. PMID 11062067. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1221441. 
• Vitale G, Bernardi L, Napolitani G et al. (2001). "Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor". Biochem. J. 352 Pt 3 (Pt 3): 739–45. PMC 1221512. PMID 11104681. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1221512.