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Gene Review

Map3k1  -  mitogen activated protein kinase kinase...

Rattus norvegicus

Synonyms: MAPK/ERK kinase kinase 1, MEK kinase 1, MEKK 1, Mekk, Mekk1, ...
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Disease relevance of Map3k1


High impact information on Map3k1

  • MEK kinase (MEKK) is part of a family of serine-threonine protein kinases that phosphorylate and activate MEKs independently of Raf [6].
  • Ras-dependent growth factor regulation of MEK kinase in PC12 cells [6].
  • Stimulation of synthesis of cyclic adenosine 3',5'-monophosphate abolished activation of MEKK and B-Raf by EGF, NGF, and TPA [6].
  • However, neurite outgrowth is triggered when c-Jun is co-expressed with activated MEKK1 or SEK1 [7].
  • Endogenous and recombinant rat MEKK1 are enriched in membranes; little of either is found in soluble fractions [8].

Biological context of Map3k1

  • Several PKCs are activated, and PKCbeta regulates phosphorylation of serine in MEKK1 [9].
  • Insulin activates a novel adipocyte mitogen-activated protein kinase kinase kinase that shows rapid phasic kinetics and is distinct from c-Raf [10].
  • Furthermore, transfection of ventricular myocytes with activated protein kinases (MEKK1 and SEK1) that may be involved in the upstream activation of JNK/ SAPKs induces increases in myocyte size and transcriptional changes typical of the hypertrophic response [11].
  • The open reading frame is 4.5 kb and predicts a protein with molecular mass of 161,225 Da, which is twice the size of the previously published MEKK1 sequence and reveals 801 amino acids of novel coding sequence [8].
  • Our results indicate that the NFkappaB/rel sites are not only responsible for the modulation of HCMV-IE enhancer activity by MEKK1 but also control the basic transcription activity of the HCMV-IE promoter [1].

Anatomical context of Map3k1


Associations of Map3k1 with chemical compounds


Enzymatic interactions of Map3k1

  • Moreover, site-directed mutation of the residues on MEK that are phosphorylated by raf does not completely abrogate phosphorylation by the MEK kinase, suggesting that this enzyme may share some phosphorylation sites with raf, but also phosphorylates MEK on other sites [19].

Other interactions of Map3k1

  • We have identified a novel insulin-stimulated MEK kinase (I-MEKK) in the 100,000 x g infranatant that shows rapid phasic kinetics that temporally precede that of MEK [10].
  • Incubation of RGMEC with PD 98059 (MEK kinase inhibitor) significantly reduced PGE(2)-induced ERK2 activity, VEGF mRNA and protein expression [20].
  • A similar result was observed in cells treated with the MEKK inhibitor PD98059 and IFN-gamma [21].
  • These data indicate that this interaction was not dependent upon the activation state of these enzymes; however, MEK kinase activity was found to be associated with p21ras following incubation with NGF-treated samples at levels higher than those obtained from unstimulated cells [22].
  • In contrast, no binding to c-Raf or the MEKK1 activator p65-PAK could be detected [14].

Analytical, diagnostic and therapeutic context of Map3k1


  1. Modulation of human cytomegalovirus immediate-early gene enhancer by mitogen-activated protein kinase kinase kinase-1. Sun, B., Harrowe, G., Reinhard, C., Yoshihara, C., Chu, K., Zhuo, S. J. Cell. Biochem. (2001) [Pubmed]
  2. Hypoxia and hypoxia/reoxygenation activate Raf-1, mitogen-activated protein kinase kinase, mitogen-activated protein kinases, and S6 kinase in cultured rat cardiac myocytes. Seko, Y., Tobe, K., Ueki, K., Kadowaki, T., Yazaki, Y. Circ. Res. (1996) [Pubmed]
  3. MEKK4 mediates differentiation in response to retinoic acid via activation of c-Jun N-terminal kinase in rat embryonal carcinoma P19 cells. Kanungo, J., Potapova, I., Malbon, C.C., Wang, H. J. Biol. Chem. (2000) [Pubmed]
  4. Differential regulation of Raf isozymes by growth versus differentiation inducing factors in PC12 pheochromocytoma cells. Wixler, V., Smola, U., Schuler, M., Rapp, U. FEBS Lett. (1996) [Pubmed]
  5. Activation of TGF-beta1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats. Matsumoto-Ida, M., Takimoto, Y., Aoyama, T., Akao, M., Takeda, T., Kita, T. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  6. Ras-dependent growth factor regulation of MEK kinase in PC12 cells. Lange-Carter, C.A., Johnson, G.L. Science (1994) [Pubmed]
  7. Differential regulation of c-Jun by ERK and JNK during PC12 cell differentiation. Leppä, S., Saffrich, R., Ansorge, W., Bohmann, D. EMBO J. (1998) [Pubmed]
  8. Cloning of rat MEK kinase 1 cDNA reveals an endogenous membrane-associated 195-kDa protein with a large regulatory domain. Xu, S., Robbins, D.J., Christerson, L.B., English, J.M., Vanderbilt, C.A., Cobb, M.H. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  9. Ca2+- and Protein Kinase C-dependent Signaling Pathway for Nuclear Factor-{kappa}B Activation, Inducible Nitric-oxide Synthase Expression, and Tumor Necrosis Factor-{alpha} Production in Lipopolysaccharide-stimulated Rat Peritoneal Macrophages. Zhou, X., Yang, W., Li, J. J. Biol. Chem. (2006) [Pubmed]
  10. Insulin activates a novel adipocyte mitogen-activated protein kinase kinase kinase that shows rapid phasic kinetics and is distinct from c-Raf. Haystead, C.M., Gregory, P., Shirazi, A., Fadden, P., Mosse, C., Dent, P., Haystead, T.A. J. Biol. Chem. (1994) [Pubmed]
  11. Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. Bogoyevitch, M.A., Gillespie-Brown, J., Ketterman, A.J., Fuller, S.J., Ben-Levy, R., Ashworth, A., Marshall, C.J., Sugden, P.H. Circ. Res. (1996) [Pubmed]
  12. MEKK1 controls neurite regrowth after experimental injury by balancing ERK1/2 and JNK2 signaling. Waetzig, V., Herdegen, T. Mol. Cell. Neurosci. (2005) [Pubmed]
  13. Disruption of Raf-1/heat shock protein 90 complex and Raf signaling by dexamethasone in mast cells. Cissel, D.S., Beaven, M.A. J. Biol. Chem. (2000) [Pubmed]
  14. Differential binding of ceramide to MEKK1 in glomerular endothelial and mesangial cells. Huwiler, A., Xin, C., Brust, A.K., Briner, V.A., Pfeilschifter, J. Biochim. Biophys. Acta (2004) [Pubmed]
  15. G alpha 13-mediated transformation and apoptosis are permissively dependent on basal ERK activity. Adarichev, V.A., Vaiskunaite, R., Niu, J., Balyasnikova, I.V., Voyno-Yasenetskaya, T.A. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  16. Presence and regulation of Raf-1-K (Kinase), MAPK-K, MAP-K, and S6-K in rat nephron segments. Terada, Y., Yamada, T., Takayama, M., Nonoguchi, H., Sasaki, S., Tomita, K., Marumo, F. J. Am. Soc. Nephrol. (1995) [Pubmed]
  17. A novel lipopolysaccharide-modulated Jun binding repressor in intron 2 of CYP2E1. Tindberg, N., Bengtsson, I., Hu, Y. J. Neurochem. (2004) [Pubmed]
  18. Retrograde axonal transport of signal transduction proteins in rat sciatic nerve. Johanson, S.O., Crouch, M.F., Hendry, I.A. Brain Res. (1995) [Pubmed]
  19. Nerve growth factor stimulates a novel protein kinase in PC-12 cells that phosphorylates and activates mitogen-activated protein kinase kinase (MEK). Pang, L., Zheng, C.F., Guan, K.L., Saltiel, A.R. Biochem. J. (1995) [Pubmed]
  20. PGE(2) stimulates VEGF expression in endothelial cells via ERK2/JNK1 signaling pathways. Pai, R., Szabo, I.L., Soreghan, B.A., Atay, S., Kawanaka, H., Tarnawski, A.S. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  21. Statin inhibits interferon-gamma-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells. Chung, H.K., Lee, I.K., Kang, H., Suh, J.M., Kim, H., Park, K.C., Kim, D.W., Kim, Y.K., Ro, H.K., Shong, M. Exp. Mol. Med. (2002) [Pubmed]
  22. The mitogen-activated protein kinase cascade is activated by B-Raf in response to nerve growth factor through interaction with p21ras. Jaiswal, R.K., Moodie, S.A., Wolfman, A., Landreth, G.E. Mol. Cell. Biol. (1994) [Pubmed]
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