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MKK6

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Encyclopedia of Signaling Molecules

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Synonyms

Mitogen activated protein kinase kinase 6; MAP2K6; MAPKK6; MEK6; PRKMK6; SAPKK3

Historical Background

MKK6 is a dual specificity mitogen-activated protein kinase that was first cloned by PCR using degenerate primers for the conserved kinase domain of MKKs (Han et al. 1996). MKK6 amino-acid sequence shares about 80% of similarity with MKK3 and 40% with MKK4 (Stein et al. 1996). Two MKK6 isoforms have been described in mouse and human (Cuenda et al. 1996; Han et al. 1996). The bigger isoform contains 334 amino acids and is highly expressed in heart, skeletal muscle, pancreas, and liver, while the smaller isoform of 278 amino acids has been detected only in skeletal muscle (Han et al. 1996).

Regulation of MKK6 Activity

Several extracellular stimuli initiate a signaling cascade of kinases that activate MKK6 by phosphorylating it at two residues (serine 207 and threonine 211) located in the activation loop domain (Fig. 1). The interaction of activation kinases with MKK6 is...

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References

  • Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21(3):383–421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ambrosino C, Mace G, Galban S, Fritsch C, Vintersten K, Black E, Gorospe M, Nebreda AR. Negative feedback regulation of MKK6 mRNA stability by p38alpha mitogen-activated protein kinase. Mol Cell Biol. 2003;23(1):370–81. PubMed PMID: 12482988; PubMed Central PMCID: PMC140674.

    Google Scholar 

  • Bhatnagar S, Kumar A, Makonchuk DY, Li H, Kumar A. Transforming growth factor-beta-activated kinase 1 is an essential regulator of myogenic differentiation. J Biol Chem. 2010;285(9):6401–11.

    Article  CAS  PubMed  Google Scholar 

  • Brancho D, Tanaka N, Jaeschke A, Ventura JJ, Kelkar N, Tanaka Y, Kyuuma M, Takeshita T, Flavell RA, Davis RJ. Mechanism of p38 MAP kinase activation in vivo. Genes Dev. 2003;17(16):1969–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.

    Google Scholar 

  • Chabaud-Riou M, Firestein GS. Expression and activation of mitogen-activated protein kinase kinases-3 and -6 in rheumatoid arthritis. Am J Pathol. 2004;164(1):177–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Z, Cobb MH. Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2. J Biol Chem. 2001;276(19):16070–5.

    Article  CAS  PubMed  Google Scholar 

  • 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;279(44):45308–11.

    Article  CAS  PubMed  Google Scholar 

  • 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;15(16):4156–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Derijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ, Davis RJ. Independent human MAP- kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995;267(5198):682–5.

    Article  CAS  PubMed  Google Scholar 

  • Enslen H, Brancho DM, Davis RJ. Molecular determinants that mediate selective activation of p38 MAP kinase isoforms. EMBO J. 2000;19(6):1301–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Forcales SV, Albini S, Giordani L, Malecova B, Cignolo L, Chernov A, Coutinho P, Saccone V, Consalvi S, Williams R, Wang K, Wu Z, Baranovskaya S, Miller A, Dilworth FJ, Puri PL. Signal-dependent incorporation of MyoD-BAF60c into Brg1-based SWI/SNF chromatin-remodelling complex. EMBO J. 2012;31(2):301–16. doi:10.1038/emboj.2011.391.

    Article  CAS  PubMed  Google Scholar 

  • Gillespie MA, Le Grand F, Scimè A, Kuang S, von Maltzahn J, Seale V, Cuenda A, Ranish JA, Rudnicki MA. p38-{gamma}-dependent gene silencing restricts entry into the myogenic differentiation program. J Cell Biol. 2009;187(7):991–1005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta J, del Barco Barrantes I, Igea A, Sakellariou S, Pateras IS, Gorgoulis VG, Nebreda AR. Dual function of p38α MAPK in colon cancer: suppression of colitis-associated tumor initiation but requirement for cancer cell survival. Cancer Cell. 2014;25(4):484–500. doi: 10.1016/j.ccr.2014.02.019. Epub 2014 Mar 27. PubMed

    Google Scholar 

  • 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;271(6):2886–91.

    Article  CAS  PubMed  Google Scholar 

  • Hickson JA, Huo D, Vander Griend DJ, Lin A, Rinker-Schaeffer CW, Yamada SD. The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. Cancer Res. 2006;66(4):2264–70.

    Article  CAS  PubMed  Google Scholar 

  • Humphreys JM, Piala AT, Akella R, He H, Goldsmith EJ. Precisely ordered phosphorylation reactions in the p38 mitogen-activated protein (MAP) kinase cascade. J Biol Chem. 2013;288(32):23322–30. doi: 10.1074/jbc.M113.462101. Epub 2013 Jun 6. PubMed PMID: 23744074; PubMed Central PMCID: PMC3743502.

    Google Scholar 

  • Huth HW, Albarnaz JD, Torres AA, Bonjardim CA, Ropert C. MEK2 controls the activation of MKK3/MKK6-p38 axis involved in the MDA-MB-231 breast cancer cell survival: correlation with cyclin D1 expression. Cell Signal. 2016;28(9):1283–91. doi: 10.1016/j.cellsig.2016.05.009. Epub 2016 May 13. PubMed PMID: 27181679

    Google Scholar 

  • Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997;275(5296):90–4.

    Article  CAS  PubMed  Google Scholar 

  • Igea A, Nebreda AR. The stress kinase p38a as a target for cancer therapy. Cancer Res. 2015;75(19):3997–4002. doi: 10.1158/0008-5472.CAN-15-0173. Epub 2015 Sep 16. Review. PubMed PMID: 26377941

    Google Scholar 

  • Inoue T, Hammaker D, Boyle DL, Firestein GS. Regulation of p38 MAPK by MAPK kinases 3 and 6 in fibroblast-like synoviocytes. J Immunol. 2005;174(7):4301–6.

    Article  CAS  PubMed  Google Scholar 

  • Iyoda K, Sasaki Y, Horimoto M, Toyama T, Yakushijin T, Sakakibara M, Takehara T, Fujimoto J, Hori M, Wands JR, Hayashi N. Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma. Cancer. 2003;97(12):3017–26.

    Article  CAS  PubMed  Google Scholar 

  • Köfel R, Meshcheryakova A, Warszawska J, Hennig A, Wagner K, Jörgl A, Gubi D, Moser D, Hladik A, Hoffmann U, Fischer MB, van den Berg W, Koenders M, Scheinecker C, Gesslbauer B, Knapp S, Strobl H. Monocytic cell differentiation from band-stage neutrophils under inflammatory conditions via MKK6 activation. Blood. 2014;124(17):2713–24.

    Article  Google Scholar 

  • Lluís F, Ballestar E, Suelves M, Esteller M, Muñoz-Cànoves P. E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription. EMBO J. 2005;24(5):974–84.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ma FY, Tesch GH, Flavell RA, Davis RJ, Nikolic-Paterson DJ. MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney. Am J Physiol Renal Physiol. 2007;293(5):F1556–63. Epub 2007 Aug 8. PubMed PMID: 17686961

    Google Scholar 

  • Mao Z, Bonni A, Xia F, Nadal-Vicens M, Greenber ME. Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science. 1999;286(5440):785–90.

    Article  CAS  PubMed  Google Scholar 

  • Martindale JJ, Wall JA, Martinez-Longoria DM, Aryal P, Rockman HA, Guo Y, Bolli R, Glembotski CC. Overexpression of mitogen-activated protein kinase kinase 6 in the heart improves functional recovery from ischemia in vitro and protects against myocardial infarction in vivo. J Biol Chem. 2005;280(1):669–76.

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto T, Kinoshita T, Matsuzaka H, Nakai R, Kirii Y, Yokota K, Tada T. Crystal structure of non-phosphorylated MAP2K6 in a putative auto-inhibition state. J Biochem. 2012;151(5):541–9. doi: 10.1093/jb/mvs023. Epub 2012 Mar 1. PubMed PMID: 22383536

    Google Scholar 

  • 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 dimmer. Structure. 2009;17:96–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moriguchi T, Toyoshima F, Gotoh Y, Iwamatsu A, Irie K, Mori E, Kuroyanagi N, Hagiwara M, Matsumoto K, Nishida E. Purification and identification of a major activator for p38 from osmotically shocked cells. Activation of mitogen-activated protein kinase kinase 6 by osmotic shock, tumor necrosis factor-alpha, and H2O2. J Biol Chem. 1996;271(43):26981–8.

    Article  CAS  PubMed  Google Scholar 

  • Mukherjee S, Keitany G, Li Y, Wang Y, Ball HL, Goldsmith EJ, Orth K. Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation. Science. 2006;312(5777):1211–4.

    Article  CAS  PubMed  Google Scholar 

  • Olson JM, Hallahan AR. p38 MAP kinase: a convergence point in cancer therapy. Trends Mol Med. 2004;10(3):125–9. Review. PubMed PMID: 15102355

    Google Scholar 

  • Parray AA, Baba RA, Bhat HF, Wani L, Mokhdomi TA, Mushtaq U, Bhat SS, Kirmani D, Kuchay S, Wani MM, Khanday FA. MKK6 is upregulated in human esophageal, stomach, and colon cancers. Cancer Invest. 2014;32(8):416–22. doi: 10.3109/07357907.2014.933236. Epub 2014 Jul 14. PubMed PMID: 25019214

    Google Scholar 

  • Perdiguero E, Ruiz-Bonilla V, Serrano AL, Muñoz-Cánoves P. Genetic deficiency of p38alpha reveals its critical role in myoblast cell cycle exit: the p38alpha-JNK connection. Cell Cycle. 2007;6(11):1298–303.

    Article  CAS  PubMed  Google Scholar 

  • Puri PL, Wu Z, Zhang P, Wood LD, Bhakta KS, Han J, Feramisco JR, Karin M, Wang JY. Induction of terminal differentiation by constitutive activation of p38 MAP kinase in human rhabdomyosarcoma cells. Genes Dev. 2000;14(5):574–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995;270(13):7420–6.

    Article  CAS  PubMed  Google Scholar 

  • 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. Mol Cell Biol. 1996;16(3):1247–55. PubMed PMID: 8622669; PubMed Central PMCID: PMC231107.

    Google Scholar 

  • Rampalli S, Li L, Mak E, Ge K, Brand M, Tapscott SJ, Dilworth FJ. p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation. Nat Struct Mol Biol. 2007;12:1150–6.

    Article  Google Scholar 

  • Remy G, Risco AM, Iñesta-Vaquera FA, González-Terán B, Sabio G, Davis RJ, Cuenda A. Differential activation of p38MAPK isoforms by MKK6 and MKK3. Cell Signal. 2010;22(4):660–7.

    Article  CAS  PubMed  Google Scholar 

  • Simone C, Forcales SV, Hill DA, Imbalzano AN, Latella L, Puri PL. p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci. Nat Genet. 2004;36(7):738–43.

    Article  CAS  PubMed  Google Scholar 

  • Sorci G, Riuzzi F, Arcuri C, Giambanco I, Donato R. Amphoterin stimulates myogenesis and counteracts the antimyogenic factors basic fibroblast growth factor and S100B via RAGE binding. Mol Cell Biol. 2004;24(11):4880–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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;271(19):11427–33.

    Article  CAS  PubMed  Google Scholar 

  • Takaesu G, Kang JS, Bae GU, Yi MJ, Lee CM, Reddy EP, Krauss RS. Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP to the cell surface protein Cdo. J Cell Biol. 2006;175(3):383–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takahashi M, Gotoh Y, Isagawa T, Nishimura T, Goyama E, Kim HS, Mukai H, Ono Y. Regulation of a mitogen-activated protein kinase kinase kinase MLTK by PKN. J Biochem. 2003;133(2):181–7.

    Article  CAS  PubMed  Google Scholar 

  • Takekawa M, Posas F, Saito H. A human homolog of the yeast Ssk2/Ssk22 MAPkinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways. EMBO J. 1997;16(16):4973–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takekawa M, Maeda T, Saito H. Protein phosphatase 2Calpha inhibits the human stress-responsive p38 and JNK MAPK pathways. EMBO J. 1998;17(16):4744–52. PubMed PMID: 9707433; PubMed Central PMCID: PMC1170803.

    Google Scholar 

  • Takekawa M, Tatebayashi K, Saito H. Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases. Mol Cell. 2005;18(3):295–306. PMID 15866172

    Article  CAS  PubMed  Google Scholar 

  • Tanaka N, Kamanaka M, Enslen H, Dong C, Wysk M, Davis RJ, Flavell RA. Differential involvement of p38 mitogen-activated protein kinases MKK3 and MKK6 in T-cell apoptosis. EMBO Rep. 2002;3(8):785–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Timofeev O, Lee TY, Bulavin DV. A subtle change in p38 MAPK activity is sufficient to suppress in vivo tumorigenesis. Cell Cycle. 2005;4(1):118–20.

    Article  CAS  PubMed  Google Scholar 

  • Wan Y, Xiao H, Affolter J, Kim TW, Bulek K, Chaudhuri S, Carlson D, Hamilton T, Mazumder B, Stark GR, Thomas J, Li X. Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control. J Biol Chem. 2009;284(16):10367–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang H, Xu Q, Xiao F, Jiang Y, Wu Z. Involvement of the p38 mitogen-activated protein kinase alpha, beta, and gamma isoforms in myogenic differentiation. Mol Biol Cell. 2008;19(4):1519–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshizawa T, Hammaker D, Boyle DL, Corr M, Flavell R, Davis R, Schett G, Firestein GS. Role of MAPK kinase 6 in arthritis: distinct mechanism of action inflammation and cytokine expression. J Immunol. 2009;183(2):1360–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zetser A, Gredinger E, Bengal E. p38 mitogen-activated protein kinase pathway promotes skeletal muscle differentiation. Participation of the Mef2c transcription factor. J Biol Chem. 1999;274(8):5193–200.

    Article  CAS  PubMed  Google Scholar 

  • Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F, Olson EN, Ulevitch RJ, Han J. Regulation of the MEF2 family of transcription factors by p38. Mol Cell Biol. 1999;1:21–30.

    Article  Google Scholar 

  • Zhu X, Rottkamp CA, Hartzler A, Sun Z, Takeda A, Boux H, Shimohama S, Perry G, Smith MA. Activation of MKK6, an upstream activator of p38, in Alzheimer’s disease. J Neurochem. 2001;79(2):311–8.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Germans Trias i Pujol Health Sciences Research Institute (IGTP), Program of Predictive and Personalized Medicine of Cancer (PMPPC), Ctra. de Can Ruti, Camí de les escoles s/n,, 08916, Badalona, Barcelona, Spain

    Sonia-Vanina Forcales

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  1. Sonia-Vanina Forcales
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Correspondence to Sonia-Vanina Forcales .

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  1. Dept. Biological Science, Department of Molecular Science and Tech College of Natural Science, Suwon, Korea (Republic of)

    Sangdun Choi

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Forcales, SV. (2016). MKK6. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6438-9_622-1

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