Gene Symbol: Map2k6
Description: mitogen-activated protein kinase kinase 6
Alias: MAPKK 6, MAPKK6, MEK6, MKK6, Prkmk6, SAPKK3, dual specificity mitogen-activated protein kinase kinase 6, MAP kinase kinase 6, MAPK/ERK kinase 6, protein kinase, mitogen activated, kinase 6
Species: mouse
Products:     Map2k6

Top Publications

  1. Huang H, Ryu J, Ha J, Chang E, Kim H, Kim H, et al. Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-kappaB transactivation by RANKL. Cell Death Differ. 2006;13:1879-91 pubmed
    ..we found that p38 MAPK upstream components transforming growth factor-beta-activated kinase 1 (TAK1), MKK3, and MKK6 increased by RANKL in an early stage of osteoclastogenesis from primary bone marrow cells, which led to enhanced ..
  2. Yoshizawa T, Hammaker D, Boyle D, Corr M, Flavell R, Davis R, et al. Role of MAPK kinase 6 in arthritis: distinct mechanism of action in inflammation and cytokine expression. J Immunol. 2009;183:1360-7 pubmed publisher
    ..Therefore, we evaluated whether MKK6, an upstream kinase that regulates multiple p38 isoforms, might be an alternative therapeutic target in ..
  3. Yamashita T, Kobayashi Y, Mizoguchi T, Yamaki M, Miura T, Tanaka S, et al. MKK6-p38 MAPK signaling pathway enhances survival but not bone-resorbing activity of osteoclasts. Biochem Biophys Res Commun. 2008;365:252-7 pubmed
    ..In this study, a constitutively active form of MKK6 (MKK6CA) was expressed in osteoclasts using adenoviral gene transfer in vitro...
  4. Han J, Lee J, Jiang Y, Li Z, Feng L, Ulevitch R. Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J Biol Chem. 1996;271:2886-91 pubmed
    ..Here we describe the characteristics of a new MKK termed MKK6. The clones we isolated encode two splice isoforms of human MKK6 comprised of 278 and 334 amino acids, respectively,..
  5. Schonhoff C, Park S, Webster C, Anwer M. p38 MAPK ? and ? isoforms differentially regulate plasma membrane localization of MRP2. Am J Physiol Gastrointest Liver Physiol. 2016;310:G999-G1005 pubmed publisher
    ..via different p38 MAPK isoforms (? and ?) that are activated differentially by upstream kinases (MKK3, MKK4, and MKK6)...
  6. Nagaleekar V, Sabio G, Aktan I, Chant A, Howe I, Thornton T, et al. Translational control of NKT cell cytokine production by p38 MAPK. J Immunol. 2011;186:4140-6 pubmed publisher
    ..Thus, in addition to gene expression, translational regulation by p38 MAPK could be a novel mechanism that contributes to the overall production of cytokine by NKT cells. ..
  7. Wall J, Wei J, Ly M, Belmont P, Martindale J, Tran D, et al. Alterations in oxidative phosphorylation complex proteins in the hearts of transgenic mice that overexpress the p38 MAP kinase activator, MAP kinase kinase 6. Am J Physiol Heart Circ Physiol. 2006;291:H2462-72 pubmed
    ..that I/R injury is reduced in the hearts of transgenic mice that overexpress the p38 MAPK activator MAPK kinase 6 (MKK6)...
  8. Tanaka N, Kamanaka M, Enslen H, Dong C, Wysk M, Davis R, et al. Differential involvement of p38 mitogen-activated protein kinase kinases MKK3 and MKK6 in T-cell apoptosis. EMBO Rep. 2002;3:785-91 pubmed
    ..The activation of p38MAPK is predominantly mediated by the two upstream MAPK kinases MKK3 and MKK6. To study the role of the p38MAPK pathway in vivo, we generated Mkk6-/- mice...
  9. 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...

More Information


  1. 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. ..
  2. Matesanz N, Bernardo E, Acin Perez R, Manieri E, Pérez Sieira S, Hernández Cosido L, et al. MKK6 controls T3-mediated browning of white adipose tissue. Nat Commun. 2017;8:856 pubmed publisher
    ..Here, we report that expression of the p38 MAPK activator MKK6 is elevated in white adipose tissue of obese individuals...
  3. Escolano A, Martínez Martínez S, Alfranca A, Urso K, Izquierdo H, Delgado M, et al. Specific calcineurin targeting in macrophages confers resistance to inflammation via MKP-1 and p38. EMBO J. 2014;33:1117-33 pubmed publisher
    ..Our results identify a key role for CN and p38 in the modulation of macrophage phenotype and suggest an alternative treatment for inflammation based on redirecting macrophages toward an anti-inflammatory status. ..
  4. Fong B, Watson P, Watson A. Mouse preimplantation embryo responses to culture medium osmolarity include increased expression of CCM2 and p38 MAPK activation. BMC Dev Biol. 2007;7:2 pubmed
    ..Our results indicate that Ccm2 along with upstream p38 MAPK pathway constituents (Map3k3, Map2k3, Map2k6, and Map2k4) are expressed throughout mouse preimplantation development...
  5. Abell A, Rivera Perez J, Cuevas B, Uhlik M, Sather S, Johnson N, et al. Ablation of MEKK4 kinase activity causes neurulation and skeletal patterning defects in the mouse embryo. Mol Cell Biol. 2005;25:8948-59 pubmed
    ..Together, these data demonstrate MEKK4 regulation of p38 and that substrates downstream of p38 control cellular homeostasis. The findings are the first demonstration that MEKK4-regulated p38 activity is critical for neurulation. ..
  6. Li Y, Batra S, Sassano A, Majchrzak B, Levy D, Gaestel M, et al. Activation of mitogen-activated protein kinase kinase (MKK) 3 and MKK6 by type I interferons. J Biol Chem. 2005;280:10001-10 pubmed
    ..of sensitive cell lines with IFNalpha results in activation of both MAP kinase kinase 3 (MKK3) and MAP kinase kinase 6 (MKK6)...
  7. Ambrosino C, Mace G, Galban S, Fritsch C, Vintersten K, Black E, et al. Negative feedback regulation of MKK6 mRNA stability by p38alpha mitogen-activated protein kinase. Mol Cell Biol. 2003;23:370-81 pubmed
    ..the absence of p38alpha correlates with the up-regulation of one of its upstream activators, the MAP kinase kinase MKK6, in p38alpha(-/-) knockout mice and in cultured cells derived from them...
  8. Boyle D, Hammaker D, Edgar M, Zaiss M, Teufel S, David J, et al. Differential roles of MAPK kinases MKK3 and MKK6 in osteoclastogenesis and bone loss. PLoS ONE. 2014;9:e84818 pubmed publisher
    ..p38 function is regulated by two upstream MAPK kinases, namely MKK3 and MKK6. The goal of this study was to assess the effect of MKK3- or MKK6-deficiency on osteoclastogenesis in vitro and on ..
  9. Wen H, Avivar Valderas A, Sosa M, Girnius N, Farias E, Davis R, et al. p38? Signaling Induces Anoikis and Lumen Formation During Mammary Morphogenesis. Sci Signal. 2011;4:ra34 pubmed publisher
    ..The mammary glands of MKK3/6 knockout mice (MKK3(-/-)/MKK6(+/- )) showed accelerated branching morphogenesis relative to those of wild-type mice, as well as ductal lumen ..
  10. Bulat N, Waeber G, Widmann C. LDLs stimulate p38 MAPKs and wound healing through SR-BI independently of Ras and PI3 kinase. J Lipid Res. 2009;50:81-9 pubmed publisher
    ..Here we show that MAPK kinases MKK3 and MKK6, but not MKK4, are the upstream kinases responsible for the activation of the p38 MAPKs and stimulation of wound ..
  11. Hernández Porras I, Fabbiano S, Schuhmacher A, Aicher A, Cañamero M, Cámara J, et al. K-RasV14I recapitulates Noonan syndrome in mice. Proc Natl Acad Sci U S A. 2014;111:16395-400 pubmed publisher
    ..Perhaps more importantly, they should be useful as a preclinical model to test new therapies aimed at preventing or ameliorating those deficits associated with this syndrome. ..
  12. Remy G, Risco A, Iñesta Vaquera F, González Terán B, Sabio G, Davis R, et al. Differential activation of p38MAPK isoforms by MKK6 and MKK3. Cell Signal. 2010;22:660-7 pubmed publisher
    ..This phosphorylation is mediated by three kinases, MKK3, MKK6 and MKK4, at least in vitro...
  13. Greenblatt M, Kim J, Oh H, Park K, Choo M, Sano Y, et al. p38α MAPK is required for tooth morphogenesis and enamel secretion. J Biol Chem. 2015;290:284-95 pubmed publisher
    ..Mice lacking the MAP2K MKK6, but not mice lacking MAP2K MKK3, also show the enamel defects, implying that MKK6 functions as an upstream kinase ..
  14. Serra C, Palacios D, Mozzetta C, Forcales S, Morantte I, Ripani M, et al. Functional interdependence at the chromatin level between the MKK6/p38 and IGF1/PI3K/AKT pathways during muscle differentiation. Mol Cell. 2007;28:200-13 pubmed
    ..We show that inflammation-activated MKK6-p38 and insulin growth factor 1 (IGF1)-induced PI3K/AKT pathways converge on the chromatin of muscle genes to ..
  15. Zhang R, Murakami S, Coustry F, Wang Y, de Crombrugghe B. Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation. Proc Natl Acad Sci U S A. 2006;103:365-70 pubmed
    ..ossification, we generated transgenic mice with expression in chondrocytes of a constitutively active mutant of MKK6, a MAPK kinase that specifically activates p38...
  16. Warr N, Siggers P, Carré G, Wells S, Greenfield A. Genetic Analyses Reveal Functions for MAP2K3 and MAP2K6 in Mouse Testis Determination. Biol Reprod. 2016;94:103 pubmed publisher
    ..Here, we report roles for the kinases MAP2K3 and MAP2K6 in testis determination...
  17. Yang Y, Xia F, Hermance N, Mabb A, Simonson S, Morrissey S, et al. A cytosolic ATM/NEMO/RIP1 complex recruits TAK1 to mediate the NF-kappaB and p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 responses to DNA damage. Mol Cell Biol. 2011;31:2774-86 pubmed publisher
    ..These findings have translational implications and reveal RIP1 and TAK1 as potential therapeutic targets in chemoresistance. ..
  18. Brancho D, Tanaka N, Jaeschke A, Ventura J, Kelkar N, Tanaka Y, et al. Mechanism of p38 MAP kinase activation in vivo. Genes Dev. 2003;17:1969-78 pubmed
    ..mitogen-activated protein kinase (MAPK) is activated in vitro by three different protein kinases: MKK3, MKK4, and MKK6. To examine the relative roles of these protein kinases in the mechanism of p38 MAP kinase activation in vivo, we ..
  19. Sours K, Kwok S, Rachidi T, Lee T, Ring A, Hoofnagle A, et al. Hydrogen-exchange mass spectrometry reveals activation-induced changes in the conformational mobility of p38alpha MAP kinase. J Mol Biol. 2008;379:1075-93 pubmed publisher
  20. Kelkar N, Standen C, Davis R. Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways. Mol Cell Biol. 2005;25:2733-43 pubmed
    ..of the p38 mitogen-activated protein (MAP) kinase pathway by a mechanism that requires the MAP kinase kinases MKK3 and MKK6. The JIP4 scaffold protein therefore appears to be a new component of the p38 MAP kinase signaling pathway.
  21. 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 ..
  22. 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
  23. Takahashi N, Nagamine M, Tanno S, Motomura W, Kohgo Y, Okumura T. A diacylglycerol kinase inhibitor, R59022, stimulates glucose transport through a MKK3/6-p38 signaling pathway in skeletal muscle cells. Biochem Biophys Res Commun. 2007;360:244-50 pubmed
    ..All these results suggest that DGK may play a role in glucose transport in the skeletal muscle cells through modulating a MKK3/6-p38 signaling pathway. ..
  24. Adams R, Porras A, Alonso G, Jones M, Vintersten K, Panelli S, et al. Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol Cell. 2000;6:109-16 pubmed
    ..Our results indicate that p38alpha is required for placental organogenesis but is not essential for other aspects of mammalian embryonic development. ..
  25. Harraz M, Park A, Abbott D, Zhou W, Zhang Y, Engelhardt J. MKK6 phosphorylation regulates production of superoxide by enhancing Rac GTPase activity. Antioxid Redox Signal. 2007;9:1803-13 pubmed
    ..To this end, we searched for binding partners of Rac1 and identified a tyrosine-phosphorylated fragment of MKK6 that bound to Rac1 under redox-stress conditions...
  26. González Terán B, Cortes J, Manieri E, Matesanz N, Verdugo Á, Rodriguez M, et al. Eukaryotic elongation factor 2 controls TNF-? translation in LPS-induced hepatitis. J Clin Invest. 2013;123:164-78 pubmed publisher
    ..These results identify a new signaling pathway that regulates TNF-? production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-? production is involved. ..
  27. Suzuki H, Wu J, Hossain K, Ohhata T, Du J, Akhand A, et al. Involvement of MKK6 in TCRalphabeta(int)CD69lo: a target population for apoptotic cell death in thymocytes. FASEB J. 2003;17:1538-40 pubmed
    ..The number of caspase-active cells and DNA-fragmented cells in MKK6-deficient mice, which were originally generated in our laboratory by gene targeting, was decreased in the ..
  28. Diao Y, Liu W, Wong C, Wang X, Lee K, Cheung P, et al. Oxidation-induced intramolecular disulfide bond inactivates mitogen-activated protein kinase kinase 6 by inhibiting ATP binding. Proc Natl Acad Sci U S A. 2010;107:20974-9 pubmed publisher
    Mitogen-activated protein kinase kinase 6 (MKK6) is a member of the mitogen-activated protein kinase (MAPK) kinase (MAP2K) subfamily that specifically phosphorylates and activates the p38 MAPKs...
  29. Sorkin L, Boyle D, Hammaker D, Herman D, Vail E, Firestein G. MKK3, an upstream activator of p38, contributes to formalin phase 2 and late allodynia in mice. Neuroscience. 2009;162:462-71 pubmed publisher
    ..of p38 regulation, we determined if known upstream activators of p38 (mitogen activated kinase kinase [MKK] 3 and MKK6), are involved in development and maintenance of pain and spinal p38 phosphorylation...
  30. Wysk M, Yang D, Lu H, Flavell R, Davis R. Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression. Proc Natl Acad Sci U S A. 1999;96:3763-8 pubmed
    ..The effects of these stimuli on p38 MAP kinase are mediated by the MAP kinase kinases (MKKs) MKK3, MKK4, and MKK6. We have examined the function of the p38 MAP kinase signaling pathway by investigating the effect of targeted ..
  31. Boucherat O, Landry Truchon K, Aoidi R, Houde N, Nadeau V, Charron J, et al. Lung development requires an active ERK/MAPK pathway in the lung mesenchyme. Dev Dyn. 2017;246:72-82 pubmed publisher
    ..Lung development necessitates a functional ERK/MAPK pathway in the lung mesenchymal layer in order to coordinate efficient epithelial-mesenchymal interactions. Developmental Dynamics 246:72-82, 2017. © 2016 Wiley Periodicals, Inc. ..
  32. Cuenda A, Alonso G, Morrice N, Jones M, Meier R, Cohen P, et al. Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells. EMBO J. 1996;15:4156-64 pubmed
    ..protein kinase kinases (SAPKKs) have been identified in several mammalian cells, termed SAPKK2 and SAPKK3, which activate the MAP kinase family member RK/p38 but not JNK/SAPK in vitro...