Gene Symbol: Map2k6
Description: mitogen-activated protein kinase kinase 6
Alias: Mkk6, dual specificity mitogen-activated protein kinase kinase 6
Species: rat
Products:     Map2k6

Top Publications

  1. Liao P, Georgakopoulos D, Kovacs A, Zheng M, Lerner D, Pu H, et al. The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. Proc Natl Acad Sci U S A. 2001;98:12283-8 pubmed
  2. Kaiser R, Bueno O, Lips D, Doevendans P, Jones F, Kimball T, et al. Targeted inhibition of p38 mitogen-activated protein kinase antagonizes cardiac injury and cell death following ischemia-reperfusion in vivo. J Biol Chem. 2004;279:15524-30 pubmed
    ..In vivo, transgenic mice expressing a dominant-negative MKK6 mutant or a dominant-negative p38alpha mutant were each significantly protected from ischemia-reperfusion injury, ..
  3. Hartzler A, Zhu X, Siedlak S, Castellani R, Avila J, Perry G, et al. The p38 pathway is activated in Pick disease and progressive supranuclear palsy: a mechanistic link between mitogenic pathways, oxidative stress, and tau. Neurobiol Aging. 2002;23:855-9 pubmed that the lesions of both Pick disease and PSP are associated with the activation of the p38 pathway (phospho-MKK6 and phospho-p38), one of the best characterized of the mitogen-activated protein kinase pathways...
  4. Kumar V, Behera R, Lohite K, Karnik S, Kundu G. p38 kinase is crucial for osteopontin-induced furin expression that supports cervical cancer progression. Cancer Res. 2010;70:10381-91 pubmed publisher
    ..In summary, our findings offer a proof of concept for targeting OPN and its downstream p38 signaling as a novel therapeutic strategy to manage cervical cancer. ..
  5. Chen Z, Cobb M. Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2. J Biol Chem. 2001;276:16070-5 pubmed
    ..Activation of endogenous TAO2 during differentiation of C2C12 myoblasts paralleled activation of p38 but not JNK/SAPK, consistent with the idea that TAO2 is a physiological regulator of p38 under certain circumstances. ..
  6. Jin Y, Fan Y, Yan E, Liu Z, Zong Z, Qi Z. Effects of sodium ferulate on amyloid-beta-induced MKK3/MKK6-p38 MAPK-Hsp27 signal pathway and apoptosis in rat hippocampus. Acta Pharmacol Sin. 2006;27:1309-16 pubmed
    ..blotting was used to determine the expressions of phosphorylated mitogen-activated protein kinase kinase (MKK) 3/MKK6, phospho-p38 MAPK, interleukin (IL)-1beta, phospho-MAPK activating protein kinase 2 (MAPKAPK-2), the 27 kDa heat ..
  7. Kang S, Adler S, LaPage J, Natarajan R. p38 MAPK and MAPK kinase 3/6 mRNA and activities are increased in early diabetic glomeruli. Kidney Int. 2001;60:543-52 pubmed
    ..This activated p38 MAPK pathway in diabetic glomeruli may, in part, play a role in the pathogenesis of early hypertrophy and extracellular matrix accumulation. ..
  8. Chang A. Pro-life role for c-Jun N-terminal kinase and p38 mitogen-activated protein kinase at rostral ventrolateral medulla in experimental brain stem death. J Biomed Sci. 2012;19:96 pubmed publisher
    ..originally identified as stress-activated protein kinases, are activated specifically by MAPK kinase 4 (MAP2K4) or MAP2K6 and play a pro-life role in RVLM during experimental brain stem death...
  9. Hickson J, Huo D, Vander Griend D, Lin A, Rinker Schaeffer C, Yamada S. The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. Cancer Res. 2006;66:2264-70 pubmed
    ..Because MKK4 can activate either of two MAPKs, p38 or JNK, we expressed MKK6 or MKK7, specific activators of these MAPKs, respectively, to delineate which MAPK signaling module was involved in ..

More Information


  1. Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 2007;1773:1358-75 pubmed
    ..Here we focus on these emergent roles of p38MAPKs and their implication in different pathologies. ..
  2. Fan M, Rhee J, St Pierre J, Handschin C, Puigserver P, Lin J, et al. Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1alpha: modulation by p38 MAPK. Genes Dev. 2004;18:278-89 pubmed
    ..The discovery of p160MBP as a PGC-1alpha regulator has important implications for the understanding of energy balance and diabetes. ..
  3. Huang C, You J, Wu M, Hsu K. Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. J Biol Chem. 2004;279:12286-92 pubmed
    ..These results suggest an important role for Rap1-MKK3/6-p38 MAPK pathway in the induction of mGluR-dependent LTD by directly coupling to receptor trafficking machineries to facilitate the loss of synaptic AMPA receptors. ..
  4. Maizels E, Mukherjee A, Sithanandam G, Peters C, Cottom J, Mayo K, et al. Developmental regulation of mitogen-activated protein kinase-activated kinases-2 and -3 (MAPKAPK-2/-3) in vivo during corpus luteum formation in the rat. Mol Endocrinol. 2001;15:716-33 pubmed
    ..Both p38 MAPK and its upstream activator MAPK kinase-6 (MKK6) were found to be chronically activated during the luteal maturation phase, with activation detected by 24 h post ..
  5. Andrews C, Ho P, Dillmann W, Glembotski C, McDonough P. The MKK6-p38 MAPK pathway prolongs the cardiac contractile calcium transient, downregulates SERCA2, and activates NF-AT. Cardiovasc Res. 2003;59:46-56 pubmed
    Our goal was to determine if the MKK6-p38 MAPK pathway regulates cardiac intracellular calcium ([Ca(2+)](i))...
  6. Degousee N, Martindale J, Stefanski E, Cieslak M, Lindsay T, Fish J, et al. MAP kinase kinase 6-p38 MAP kinase signaling cascade regulates cyclooxygenase-2 expression in cardiac myocytes in vitro and in vivo. Circ Res. 2003;92:757-64 pubmed
    ..The purpose of this study was to evaluate the role of the MAP kinase kinase 6 (MKK6)-p38 MAPK signaling cascade in the regulation of myocardial COX-2 gene expression, in vitro and in vivo...
  7. Li M, Katsura K, Nomiyama H, Komaki K, Ninomiya Tsuji J, Matsumoto K, et al. Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2Cepsilon). J Biol Chem. 2003;278:12013-21 pubmed
    ..experiments indicated that PP2Cepsilon associates stably with TAK1 and attenuates the binding of TAK1 to MKK4 or MKK6. Ectopic expression of a phosphatase-negative mutant of PP2Cepsilon, PP2Cepsilon(D/A), which acted as a dominant ..
  8. Min X, Akella R, He H, Humphreys J, Tsutakawa S, Lee S, et al. The structure of the MAP2K MEK6 reveals an autoinhibitory dimer. Structure. 2009;17:96-104 pubmed publisher
    ..The autoinhibited structure likely confers specificity on active MAP2Ks. The dimer may also serve the function in unphosphorylated MEK6 of preventing activation loop phosphorylation by inappropriate kinases. ..
  9. Guan Z, Buckman S, Springer L, Morrison A. Both p38alpha(MAPK) and JNK/SAPK pathways are important for induction of nitric-oxide synthase by interleukin-1beta in rat glomerular mesangial cells. J Biol Chem. 1999;274:36200-6 pubmed
    ..In previous studies we demonstrated that IL-1beta can activate MKK4/SEK1, MKK3, and MKK6 in renal mesangial cells; therefore, we examined the role of these MAPK kinases in the modulation of iNOS induced ..
  10. Bashir M, Parray A, Baba R, Bhat H, Bhat S, Mushtaq U, et al. ?-Amyloid-evoked apoptotic cell death is mediated through MKK6-p66shc pathway. Neuromolecular Med. 2014;16:137-49 pubmed publisher
    ..Amyloid leads to the phosphorylation of p66shc at the serine 36 residue and activates MKK6, by mediating the phosphorylation at serine 207 residue...
  11. Matsumoto Ida M, Takimoto Y, Aoyama T, Akao M, Takeda T, Kita T. Activation of TGF-beta1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats. Am J Physiol Heart Circ Physiol. 2006;290:H709-15 pubmed
    ..Thus the TGF-beta1-TAK1-MKK3/6-p38 MAPK pathway in the cardiomyocytes of noninfarcted spared myocardium is activated after acute MI and may play an important role in ventricular hypertrophy and post-MI remodeling in rats. ..
  12. Lotan T, Lyon M, Huo D, Taxy J, Brendler C, Foster B, et al. Up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression: an important role for SAPK signalling in prostatic neoplasia. J Pathol. 2007;212:386-94 pubmed
    ..This study evaluates MKK4, MKK6 and MKK7 expression during prostate cancer progression in humans and in the transgenic adenocarcinoma of a mouse ..
  13. Martindale J, Wall J, Martinez Longoria D, Aryal P, Rockman H, Guo Y, et al. 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;280:669-76 pubmed
    ..promotes cell survival or death depending on whether it is activated by mitogen-activated protein kinase kinase 6 (MKK6) or MKK3, respectively...
  14. Umemoto S, Kawahara S, Hashimoto R, Umeji K, Matsuda S, Tanaka M, et al. Different effects of amlodipine and enalapril on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase pathway for induction of vascular smooth muscle cell differentiation in vivo. Hypertens Res. 2006;29:179-86 pubmed
    ..The levels of MKK6, p38 MAPK, MEK1 and p-42/44 ERK were significantly higher in the vehicle-treated SHRSP than in the WKY...
  15. Vander Griend D, Kocherginsky M, Hickson J, Stadler W, Lin A, Rinker Schaeffer C. Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7. Cancer Res. 2005;65:10984-91 pubmed
    ..of the JNK-specific kinase MKK7 suppresses the formation of overt metastases, whereas the p38-specific kinase MKK6 has no effect...
  16. Demidov O, Kek C, Shreeram S, Timofeev O, Fornace A, Appella E, et al. The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis. Oncogene. 2007;26:2502-6 pubmed
    ..This tumor-prone phenotype of Wip1 is fully eliminated through attenuation of proliferation by activating the MKK6/p38 mitogen-activated protein kinases (MAPK) cascade in mice bearing a constitutively active form of MKK6...
  17. Harding S, Browne G, Miller B, Prigent S, Dickens M. Activation of ASK1, downstream MAPKK and MAPK isoforms during cardiac ischaemia. Biochim Biophys Acta. 2010;1802:733-40 pubmed publisher
    ..Ischaemia strongly activated p38alpha but not the JNK pathway. The MAPKKs, MKK3, MKK4 and MKK6 have previously been identified as potential upstream activators of p38; however, in the ischaemic perfused heart, ..
  18. Morinobu A, Gadina M, Strober W, Visconti R, Fornace A, Montagna C, et al. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc Natl Acad Sci U S A. 2002;99:12281-6 pubmed
    ..We show here that GADD45-beta and GADD45-gamma can induce STAT4 S721 phosphorylation via the MKK6/p38 pathway...
  19. Fernando P, Deng W, Pekalska B, DeRepentigny Y, Kothary R, Kelly J, et al. Active kinase proteome screening reveals novel signal complexity in cardiomyopathy. Mol Cell Proteomics. 2005;4:673-82 pubmed
    ..that were associated with activation of a myopathic cascade as mediated by the mitogen-activated protein kinase MKK6 and established the novel observation that MKK6 promotes the development of cardiomyopathy through multiple ..
  20. Humphreys J, Piala A, Akella R, He H, Goldsmith E. Precisely ordered phosphorylation reactions in the p38 mitogen-activated protein (MAP) kinase cascade. J Biol Chem. 2013;288:23322-30 pubmed publisher
    ..The models confirmed the reaction order, revealed processivity in the phosphorylation of MEK6 by ASK1, and suggested that the order of phosphorylation is dictated by both binding and catalysis rates. ..
  21. Park H, Kim B, Kim S, Choi K. Role of MAP kinases and their cross-talk in TGF-beta1-induced apoptosis in FaO rat hepatoma cell line. Hepatology. 2002;35:1360-71 pubmed
    ..In contrast, both interfering with p38 activity by overexpression of the dominant negative (DN) MKK6 mutant and inhibition of the JNK pathway by overexpression of the DN SEK1 mutant resulted in suppression of ..