MAP2K6 explained

See main article: Mitogen-activated protein kinase kinase.

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^{[3] [6] [7] [8]} and MAP3K7.^{[9] [10] [11] [12]}

Further reading

• 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 . Current Biology . 8 . 19 . 1049–57 . Sep 1998 . 9768359 . 10.1016/S0960-9822(98)70442-7 . 15627349 . free . 1998CBio....8.1049B .
• Tanaka S, Nakamura K, Takahasi N, Suda T . Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system . Immunological Reviews . 208 . 30–49 . Dec 2005 . 16313339 . 10.1111/j.0105-2896.2005.00327.x . 13811917 .
• Doza YN, Cuenda A, Thomas GM, Cohen P, Nebreda AR . 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 Letters . 364 . 2 . 223–8 . May 1995 . 7750576 . 10.1016/0014-5793(95)00346-B . 25025858 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Raingeaud J, Whitmarsh AJ, Barrett T, Dérijard B, Davis RJ . MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway . Molecular and Cellular Biology . 16 . 3 . 1247–55 . Mar 1996 . 8622669 . 231107 . 10.1128/mcb.16.3.1247.
• 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 . The Journal of Biological Chemistry . 271 . 19 . 11427–33 . May 1996 . 8626699 . 10.1074/jbc.271.19.11427 . free .
• 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 . The Journal of Biological Chemistry . 271 . 23 . 13675–9 . Jun 1996 . 8663074 . 10.1074/jbc.271.23.13675 . free .
• 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 . The EMBO Journal . 15 . 16 . 4156–64 . Aug 1996 . 8861944 . 452138 . 10.1002/j.1460-2075.1996.tb00790.x.
• 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 . The EMBO Journal . 16 . 12 . 3563–71 . Jun 1997 . 9218798 . 1169981 . 10.1093/emboj/16.12.3563 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Enslen H, Raingeaud J, Davis RJ . Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6 . The Journal of Biological Chemistry . 273 . 3 . 1741–8 . Jan 1998 . 9430721 . 10.1074/jbc.273.3.1741 . free .
• Chan-Hui PY, Weaver R . Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades . The Biochemical Journal . 336 . Pt 3 . 599–609 . Dec 1998 . 9841871 . 1219910 . 10.1042/bj3360599.
• Chen Z, Hutchison M, Cobb MH . Isolation of the protein kinase TAO2 and identification of its mitogen-activated protein kinase/extracellular signal-regulated kinase kinase binding domain . The Journal of Biological Chemistry . 274 . 40 . 28803–7 . Oct 1999 . 10497253 . 10.1074/jbc.274.40.28803 . free .
• Cong F, Goff SP . c-Abl-induced apoptosis, but not cell cycle arrest, requires mitogen-activated protein kinase kinase 6 activation . Proceedings of the National Academy of Sciences of the United States of America . 96 . 24 . 13819–24 . Nov 1999 . 10570156 . 24148 . 10.1073/pnas.96.24.13819 . 1999PNAS...9613819C . free .
• Wang X, McGowan CH, Zhao M, He L, Downey JS, Fearns C, Wang Y, Huang S, Han J . Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest . Molecular and Cellular Biology . 20 . 13 . 4543–52 . Jul 2000 . 10848581 . 85840 . 10.1128/MCB.20.13.4543-4552.2000 .
• 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 . 96 . 5 . 1844–52 . Sep 2000 . 10961885 . 10.1182/blood.V96.5.1844.
• Fleming Y, Armstrong CG, Morrice N, Paterson A, Goedert M, Cohen P . 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 . The Biochemical Journal . 352 Pt 1 . Pt 1 . 145–54 . Nov 2000 . 11062067 . 1221441 . 10.1042/0264-6021:3520145 .
• 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 . The Biochemical Journal . 352 Pt 3 . Pt 3 . 739–45 . Dec 2000 . 11104681 . 1221512 . 10.1042/0264-6021:3520739 .

Notes and References

1. 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) . The Journal of Biological Chemistry . 271 . 6 . 2886–91 . Feb 1996 . 8621675 . 10.1074/jbc.271.6.2886 . free .
2. Web site: Entrez Gene: MAP2K6 mitogen-activated protein kinase kinase 6.
3. Chen Z, Cobb MH . Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2 . The Journal of Biological Chemistry . 276 . 19 . 16070–5 . May 2001 . 11279118 . 10.1074/jbc.M100681200 . free .
4. Huang S, Shu L, Dilling MB, Easton J, Harwood FC, Ichijo H, Houghton PJ . Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1) . Molecular Cell . 11 . 6 . 1491–501 . Jun 2003 . 12820963 . 10.1016/S1097-2765(03)00180-1 . free .
5. 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 . The EMBO Journal . 20 . 21 . 6028–36 . Nov 2001 . 11689443 . 125685 . 10.1093/emboj/20.21.6028 .
6. Sanz-Moreno V, Casar B, Crespo P . p38alpha 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 . Molecular and Cellular Biology . 23 . 9 . 3079–90 . May 2003 . 12697810 . 153192 . 10.1128/MCB.23.9.3079-3090.2003 .
7. Raingeaud J, Whitmarsh AJ, Barrett T, Dérijard B, Davis RJ . MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway . Molecular and Cellular Biology . 16 . 3 . 1247–55 . Mar 1996 . 8622669 . 231107 . 10.1128/mcb.16.3.1247.
8. 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 . The Journal of Biological Chemistry . 271 . 19 . 11427–33 . May 1996 . 8626699 . 10.1074/jbc.271.19.11427 . free .
9. Ishitani T, Takaesu G, Ninomiya-Tsuji J, Shibuya H, Gaynor RB, Matsumoto K. Richard Gaynor . Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling . The EMBO Journal . 22 . 23 . 6277–88 . Dec 2003 . 14633987 . 291846 . 10.1093/emboj/cdg605 .
10. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ . TAK1 is a ubiquitin-dependent kinase of MKK and IKK . Nature . 412 . 6844 . 346–51 . Jul 2001 . 11460167 . 10.1038/35085597 . 2001Natur.412..346W . 9641806 .
11. 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 . 398 . 6724 . 252–6 . Mar 1999 . 10094049 . 10.1038/18465 . 1999Natur.398..252N . 4421236 .
12. Sakurai H, Miyoshi H, Mizukami J, Sugita T . Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1 . FEBS Letters . 474 . 2–3 . 141–5 . Jun 2000 . 10838074 . 10.1016/S0014-5793(00)01588-X . 30831863 .