Gene Symbol: Map2k3
Description: mitogen activated protein kinase kinase 3
Alias: Mek3, Mkk3, dual specificity mitogen-activated protein kinase kinase 3, dual specificity mitogen-activated protein kinase kinase 3-like
Species: rat
Products:     Map2k3

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. MacNeil A, Jiao S, McEachern L, Yang Y, Dennis A, Yu H, et al. MAPK kinase 3 is a tumor suppressor with reduced copy number in breast cancer. Cancer Res. 2014;74:162-72 pubmed publisher
    ..Here, we show that the mitogen-activated protein kinase (MAPK) MKK3 suppresses the growth of breast cancer, in which it varies in copy number...
  3. 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 ..
  4. 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
    ..Acute pain behaviors were not altered in MKK3 or MKK6 deficient mice...
  5. Jung H, Seong H, Ha H. Murine protein serine/threonine kinase 38 activates apoptosis signal-regulating kinase 1 via Thr 838 phosphorylation. J Biol Chem. 2008;283:34541-53 pubmed publisher
    ..MPK38-mediated ASK1 activation was induced through the increased interaction between ASK1 and its substrate MKK3. MPK38 also stimulated H(2)O(2)-mediated apoptosis by enhancing the ASK1 activity through Thr(838) phosphorylation...
  6. Demuth T, Reavie L, Rennert J, Nakada M, Nakada S, Hoelzinger D, et al. MAP-ing glioma invasion: mitogen-activated protein kinase kinase 3 and p38 drive glioma invasion and progression and predict patient survival. Mol Cancer Ther. 2007;6:1212-22 pubmed
    ..We identify mitogen-activated protein kinase (MAPK) kinase 3 (MKK3) as a key activator of p38 MAPK in glioma; MKK3 activation is strongly correlated with p38 activation in vitro and ..
  7. Thirone A, Jebailey L, Bilan P, Klip A. Opposite effect of JAK2 on insulin-dependent activation of mitogen-activated protein kinases and Akt in muscle cells: possible target to ameliorate insulin resistance. Diabetes. 2006;55:942-51 pubmed
    ..extracellular signal-related kinase, p38, and Jun NH2-terminal kinase and their respective upstream kinases MKK1/2, MKK3/6, and MKK4/7 was significantly lowered when JAK2 was depleted, correlating with a significant drop in insulin-..
  8. Bassi R, Burgoyne J, DeNicola G, Rudyk O, DeSantis V, Charles R, et al. Redox-dependent dimerization of p38α mitogen-activated protein kinase with mitogen-activated protein kinase kinase 3. J Biol Chem. 2017;292:16161-16173 pubmed publisher
    ..p38α was activated and formed a disulfide-bound heterodimer with MAP2K3 (MKK3) in rat cardiomyocytes and isolated hearts exposed to H2O2 This disulfide heterodimer ..
  9. Kim S, Irwin P, Katz S, Pelech S. Expression of mitogen-activated protein kinase pathways during postnatal development of rat heart. J Cell Biochem. 1998;71:286-301 pubmed
    ..Erk2, and Rsk1 were significantly down-regulated, whereas the stress signaling kinases, such as Mlk3, Mekkl, Sekl, Mkk3, and Mapkapk2 were up-regulated in expression during postnatal development...

More Information


  1. 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...
  2. Chen Z, Cobb M. Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2. J Biol Chem. 2001;276:16070-5 pubmed
    ..Cotransfection experiments suggested that TAO2 selectively activates MEK3 and MEK6 but not MEKs 1, 4, or 7...
  3. Li L, Ginet V, Liu X, Vergun O, Tuittila M, Mathieu M, et al. The nNOS-p38MAPK pathway is mediated by NOS1AP during neuronal death. J Neurosci. 2013;33:8185-201 pubmed publisher
    ..2008; Brzustowicz, 2008; Lehtinen et al., 2008). Here we find it interacts with p38MAPK-activating kinase MKK3. Excitotoxic stimulus induces recruitment of NOS1AP to nNOS in rat cortical neuron culture...
  4. Moriguchi T, Toyoshima F, Gotoh Y, Iwamatsu A, Irie K, Mori E, et al. 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;271:26981-8 pubmed
    ..raised against recombinant MAPKK6 recognized specifically the 36-kDa MAPKK6 protein but did not cross-react with MKK3 proteins...
  5. Wang H, Cheng Z, Malbon C. Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer. Cancer Lett. 2003;191:229-37 pubmed
    ..The expression of mitogen and extracellularly-activated protein kinase kinase (MEK)2 and MEK3, upstream protein kinases of Erkl,2 and p38, respectively, was elevated 4- to 5-fold...
  6. Lu H, Yang D, Wysk M, Gatti E, Mellman I, Davis R, et al. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J. 1999;18:1845-57 pubmed
    ..To study the role of the p38 MAPK pathway in vivo, we have used homologous recombination in mice to inactivate the Mkk3 gene, one of the two specific MAPK kinases (MAPKKs) that activate p38 MAPK...
  7. 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
    ..Phosphorylation of MAPKK 3/6 (MKK3/6) and p38 MAPK, the downstream targets of TAK1, was also increased in the noninfarcted region...
  8. Kelicen P, Tindberg N. Lipopolysaccharide induces CYP2E1 in astrocytes through MAP kinase kinase-3 and C/EBPbeta and -delta. J Biol Chem. 2004;279:15734-42 pubmed
    ..MAP kinase kinase-3 (MKK3) was phosphorylated in response to LPS, and expression of constitutively active MKK3, but not the MAP kinase ..
  9. Wang R, Wan Q, Zhang Y, Huang F, Yu K, Xu D, et al. Emodin suppresses interleukin-1beta induced mesangial cells proliferation and extracellular matrix production via inhibiting P38 MAPK. Life Sci. 2007;80:2481-8 pubmed
    ..P38 mRNA, protein levels of P-P38, P-MKK3/6 and P-MKK4 were quantified...
  10. Uesugi M, Nakajima K, Tohyama Y, Kohsaka S, Kurihara T. Nonparticipation of nuclear factor kappa B (NFkappaB) in the signaling cascade of c-Jun N-terminal kinase (JNK)- and p38 mitogen-activated protein kinase (p38MAPK)-dependent tumor necrosis factor alpha (TNFalpha) induction in lipopolysaccharide (LPS). Brain Res. 2006;1073-1074:48-59 pubmed
    ..However, SN50 was found to prevent the activation of MKK3/6-p38MAPK and MKK4-JNK pathways...
  11. Inomata Y, Nakamura H, Tanito M, Teratani A, Kawaji T, Kondo N, et al. Thioredoxin inhibits NMDA-induced neurotoxicity in the rat retina. J Neurochem. 2006;98:372-85 pubmed
    ..activation of the MAPKs, p38 kinase and c-Jun N-terminal kinase after 6 h and of the MAPK kinases (MKKs) MKK3/6 and MKK4 after 3 h was markedly suppressed in retinal ganglion cells by TRX but not by the mutant form...
  12. 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
    ..We examined the activity and expression of the p38 MAPK pathway members, p38 MAPK, MKK3/6, cAMP-responsive element binding protein (CREB), and MAPK phosphatase-1 (MKP-1), in experimental DN in rats over ..
  13. 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. ..
  14. Lu G, Kang Y, Han J, Herschman H, Stefani E, Wang Y. TAB-1 modulates intracellular localization of p38 MAP kinase and downstream signaling. J Biol Chem. 2006;281:6087-95 pubmed
    ..In contrast to MKK3-induced p38 kinase downstream effects, TAB-1-induced p38 kinase activation does not induce expression of pro-..
  15. 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 ..
  16. Pin A, Houle F, Guillonneau M, Paquet E, Simard M, Huot J. miR-20a represses endothelial cell migration by targeting MKK3 and inhibiting p38 MAP kinase activation in response to VEGF. Angiogenesis. 2012;15:593-608 pubmed publisher
    ..miR-20a does not affect either the expression of other known actors of the p38 MAP kinase pathway except MKK3. Indeed, by using quantitative PCR and Western Blot analysis, we found that pmiR-20a decreases the expression of ..
  17. Lim S, Jin K, Friedman E. Mirk protein kinase is activated by MKK3 and functions as a transcriptional activator of HNF1alpha. J Biol Chem. 2002;277:25040-6 pubmed
    ..Mirk co-immunoprecipitated with the MAPK kinase MKK3, an upstream activator of p38...
  18. Yoshino Y, Yamamoto S, Kohsaka S, Oshiro S, Nakajima K. Superoxide anion contributes to the induction of tumor necrosis factor alpha (TNF?) through activation of the MKK3/6-p38 MAPK cascade in rat microglia. Brain Res. 2011;1422:1-12 pubmed publisher
    ..Moreover, the addition of SIN-1 to microglia resulted in activation of p38 MAPK and its upstream kinase MKK3/6...
  19. 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
    ..OPN induces CD44-mediated MKK3/6 phosphorylation which in turn phosphorylates p38 in these cells...
  20. 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
    ..Intracerebroventricular injection of Abeta1-40 induced an increase in phosphorylated MKK3/MKK6 and p38 MAPK expressions in hippocampal tissue...
  21. 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
    ..DHPG) activates p38 MAPK through G protein betagamma-subunit, small GTPase Rap1, and MAPK kinase 3/6 (MKK3/6), thus resulting in mGluR5-dependent LTD...