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Gene Review

MAP3K1  -  mitogen-activated protein kinase kinase...

Homo sapiens

Synonyms: MAPK/ERK kinase kinase 1, MAPKKK1, MEK kinase 1, MEKK, MEKK 1, ...
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Disease relevance of MAP3K1


High impact information on MAP3K1

  • In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity [5].
  • Furthermore, recombinant MEKK1 stimulates IKKbeta phosphorylation of IkappaB alpha [4].
  • MEKK1 indirectly suppresses NF-AT4 nuclear import by stabilizing the interaction between NF-AT4 and CKIalpha [6].
  • Eukaryotic cells respond to different extracellular stimuli by recruiting homologous signalling pathways that use members of the MEKK, MEK and ERK families of protein kinases [7].
  • Latest results indicate that caspase-mediated cleavage of the first component of this latter pathway, MEKK-1, may trigger activation of this pathway in anoikis [8].

Chemical compound and disease context of MAP3K1


Biological context of MAP3K1


Anatomical context of MAP3K1


Associations of MAP3K1 with chemical compounds

  • Activation of the AR by dihydrotestosterone (DHT) regulates diverse physiological functions including secondary sexual differentiation in the male and the induction of apoptosis by the JNK kinase, MEKK1 [1].
  • Kinase-inactive MEKK1 inhibits Stat3 phosphorylation on tyrosine and serine, and its transcriptional activity stimulated by epidermal growth factor and platelet-derived growth factor in different cell types [17].
  • The interaction is prevented by mutation of the essential cysteine in the MEKK1 PHD domain [18].
  • These data demonstrate for the first time a novel role of MEKK1 to modulate tyrosine kinases that results in the activation of specific members of STAT family [17].
  • Taken together, these data demonstrate that MLK7 is the MAPKKK required for modulation of the stress-activated MAPKs downstream of anisomycin and UV stimulation and that DHP-2 can be used to block MLK7 pathway activation in cells as well as in vivo [19].

Physical interactions of MAP3K1


Enzymatic interactions of MAP3K1


Regulatory relationships of MAP3K1


Other interactions of MAP3K1

  • MLK3 cooperated with the other two IKKKs, MEKK1 and NF-kappaB-inducing kinase, in the induction of IKK activity [26].
  • In vitro biochemical assays revealed that, when stimulated by MEKK1, four of the five altered MKK4 proteins lacked the ability to phosphorylate stress-activated protein kinase [27].
  • Parthenolide targets a component of the I kappa B kinase complex without directly inhibiting IKK alpha, IKK beta, or MEKK1 [23].
  • Activation of MEKK by formyl-methionyl-leucyl-phenylalanine in human neutrophils. Mapping pathways for mitogen-activated protein kinase activation [16].
  • Western blot analysis of FLS demonstrated that MEKK1, MEKK2, and TAK1 were readily detectable and were subsequently the focus of functional studies [28].

Analytical, diagnostic and therapeutic context of MAP3K1


  1. Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. Fu, M., Wang, C., Wang, J., Zhang, X., Sakamaki, T., Yeung, Y.G., Chang, C., Hopp, T., Fuqua, S.A., Jaffray, E., Hay, R.T., Palvimo, J.J., Jänne, O.A., Pestell, R.G. Mol. Cell. Biol. (2002) [Pubmed]
  2. Lysophosphatidic Acid Stimulates Ovarian Cancer Cell Migration via a Ras-MEK Kinase 1 Pathway. Bian, D., Su, S., Mahanivong, C., Cheng, R.K., Han, Q., Pan, Z.K., Sun, P., Huang, S. Cancer Res. (2004) [Pubmed]
  3. Dominant negative MEKK1 inhibits survival of pancreatic cancer cells. Hirano, T., Shino, Y., Saito, T., Komoda, F., Okutomi, Y., Takeda, A., Ishihara, T., Yamaguchi, T., Saisho, H., Shirasawa, H. Oncogene (2002) [Pubmed]
  4. HTLV-I Tax protein binds to MEKK1 to stimulate IkappaB kinase activity and NF-kappaB activation. Yin, M.J., Christerson, L.B., Yamamoto, Y., Kwak, Y.T., Xu, S., Mercurio, F., Barbosa, M., Cobb, M.H., Gaynor, R.B. Cell (1998) [Pubmed]
  5. The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Waeber, G., Delplanque, J., Bonny, C., Mooser, V., Steinmann, M., Widmann, C., Maillard, A., Miklossy, J., Dina, C., Hani, E.H., Vionnet, N., Nicod, P., Boutin, P., Froguel, P. Nat. Genet. (2000) [Pubmed]
  6. Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1. Zhu, J., Shibasaki, F., Price, R., Guillemot, J.C., Yano, T., Dötsch, V., Wagner, G., Ferrara, P., McKeon, F. Cell (1998) [Pubmed]
  7. Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase. Pombo, C.M., Kehrl, J.H., Sánchez, I., Katz, P., Avruch, J., Zon, L.I., Woodgett, J.R., Force, T., Kyriakis, J.M. Nature (1995) [Pubmed]
  8. Integrins and anoikis. Frisch, S.M., Ruoslahti, E. Curr. Opin. Cell Biol. (1997) [Pubmed]
  9. MEKK1 activation of human estrogen receptor alpha and stimulation of the agonistic activity of 4-hydroxytamoxifen in endometrial and ovarian cancer cells. Lee, H., Jiang, F., Wang, Q., Nicosia, S.V., Yang, J., Su, B., Bai, W. Mol. Endocrinol. (2000) [Pubmed]
  10. Cisplatin-resistance involves the defective processing of MEKK1 in human ovarian adenocarcinoma 2008/C13 cells. Gebauer, G., Mirakhur, B., Nguyen, Q., Shore, S.K., Simpkins, H., Dhanasekaran, N. Int. J. Oncol. (2000) [Pubmed]
  11. Constitutive mutant and putative regulatory serine phosphorylation site of mammalian MAP kinase kinase (MEK1). Pagès, G., Brunet, A., L'Allemain, G., Pouysségur, J. EMBO J. (1994) [Pubmed]
  12. Stress-induced Fas ligand expression in T cells is mediated through a MEK kinase 1-regulated response element in the Fas ligand promoter. Faris, M., Latinis, K.M., Kempiak, S.J., Koretzky, G.A., Nel, A. Mol. Cell. Biol. (1998) [Pubmed]
  13. Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. Wang, X.S., Diener, K., Jannuzzi, D., Trollinger, D., Tan, T.H., Lichenstein, H., Zukowski, M., Yao, Z. J. Biol. Chem. (1996) [Pubmed]
  14. Ubiquitylation of MEKK1 inhibits its phosphorylation of MKK1 and MKK4 and activation of the ERK1/2 and JNK pathways. Witowsky, J.A., Johnson, G.L. J. Biol. Chem. (2003) [Pubmed]
  15. Regulation of interleukin-2 transcription by inducible stable expression of dominant negative and dominant active mitogen-activated protein kinase kinase kinase in jurkat T cells. Evidence for the importance of Ras in a pathway that is controlled by dual receptor stimulation. Faris, M., Kokot, N., Lee, L., Nel, A.E. J. Biol. Chem. (1996) [Pubmed]
  16. Activation of MEKK by formyl-methionyl-leucyl-phenylalanine in human neutrophils. Mapping pathways for mitogen-activated protein kinase activation. Avdi, N.J., Winston, B.W., Russel, M., Young, S.K., Johnson, G.L., Worthen, G.S. J. Biol. Chem. (1996) [Pubmed]
  17. Regulation of Stat3 activation by MEK kinase 1. Lim, C.P., Cao, X. J. Biol. Chem. (2001) [Pubmed]
  18. RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity. Gallagher, E.D., Gutowski, S., Sternweis, P.C., Cobb, M.H. J. Biol. Chem. (2004) [Pubmed]
  19. Complete inhibition of anisomycin and UV radiation but not cytokine induced JNK and p38 activation by an aryl-substituted dihydropyrrolopyrazole quinoline and mixed lineage kinase 7 small interfering RNA. Wang, X., Mader, M.M., Toth, J.E., Yu, X., Jin, N., Campbell, R.M., Smallwood, J.K., Christe, M.E., Chatterjee, A., Goodson, T., Vlahos, C.J., Matter, W.F., Bloem, L.J. J. Biol. Chem. (2005) [Pubmed]
  20. MEKK1 binds raf-1 and the ERK2 cascade components. Karandikar, M., Xu, S., Cobb, M.H. J. Biol. Chem. (2000) [Pubmed]
  21. How does the G protein, Gi2, transduce mitogenic signals? Johnson, G.L., Gardner, A.M., Lange-Carter, C., Qian, N.X., Russell, M., Winitz, S. J. Cell. Biochem. (1994) [Pubmed]
  22. Functional role for protein kinase Cbeta as a regulator of stress-activated protein kinase activation and monocytic differentiation of myeloid leukemia cells. Kaneki, M., Kharbanda, S., Pandey, P., Yoshida, K., Takekawa, M., Liou, J.R., Stone, R., Kufe, D. Mol. Cell. Biol. (1999) [Pubmed]
  23. The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the I kappa B kinase complex. Hehner, S.P., Hofmann, T.G., Dröge, W., Schmitz, M.L. J. Immunol. (1999) [Pubmed]
  24. MEK kinase 1 is essential for Bcr-Abl-induced STAT3 and self-renewal activity in embryonic stem cells. Nakamura, Y., Yujiri, T., Nawata, R., Tagami, K., Tanizawa, Y. Oncogene (2005) [Pubmed]
  25. Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator protein-1- and nuclear factor-kappaB-mediated gene expression in airway epithelial cells. Zhou, L., Tan, A., Iasvovskaia, S., Li, J., Lin, A., Hershenson, M.B. Am. J. Respir. Cell Mol. Biol. (2003) [Pubmed]
  26. Mixed-lineage kinase 3 delivers CD3/CD28-derived signals into the IkappaB kinase complex. Hehner, S.P., Hofmann, T.G., Ushmorov, A., Dienz, O., Wing-Lan Leung, I., Lassam, N., Scheidereit, C., Dröge, W., Schmitz, M.L. Mol. Cell. Biol. (2000) [Pubmed]
  27. Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. Teng, D.H., Perry, W.L., Hogan, J.K., Baumgard, M., Bell, R., Berry, S., Davis, T., Frank, D., Frye, C., Hattier, T., Hu, R., Jammulapati, S., Janecki, T., Leavitt, A., Mitchell, J.T., Pero, R., Sexton, D., Schroeder, M., Su, P.H., Swedlund, B., Kyriakis, J.M., Avruch, J., Bartel, P., Wong, A.K., Tavtigian, S.V. Cancer Res. (1997) [Pubmed]
  28. Regulation of c-Jun N-terminal kinase by MEKK-2 and mitogen-activated protein kinase kinase kinases in rheumatoid arthritis. Hammaker, D.R., Boyle, D.L., Chabaud-Riou, M., Firestein, G.S. J. Immunol. (2004) [Pubmed]
  29. Induced proliferation of human MRC-5 cells by nitrogen oxides via direct and indirect activation of MEKK1, JNK, and p38 signals. Chou, F.P., Tseng, T.H., Chen, J.H., Wang, H.C., Wang, C.J. Toxicol. Appl. Pharmacol. (2002) [Pubmed]
  30. MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42. Fanger, G.R., Johnson, N.L., Johnson, G.L. EMBO J. (1997) [Pubmed]
  31. Prostaglandin E2 stimulates p53 transactivational activity through specific serine 15 phosphorylation in human synovial fibroblasts. Role in suppression of c/EBP/NF-kappaB-mediated MEKK1-induced MMP-1 expression. Faour, W.H., He, Q., Mancini, A., Jovanovic, D., Antoniou, J., Di Battista, J.A. J. Biol. Chem. (2006) [Pubmed]
  32. Specific association of activated MAP kinase kinase kinase (Raf) with the plasma membranes of ras-transformed retinal cells. Traverse, S., Cohen, P., Paterson, H., Marshall, C., Rapp, U., Grand, R.J. Oncogene (1993) [Pubmed]
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