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Gene Review

MAP3K11  -  mitogen-activated protein kinase kinase...

Homo sapiens

Synonyms: MEKK11, MLK-3, MLK3, Mitogen-activated protein kinase kinase kinase 11, Mixed lineage kinase 3, ...
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Disease relevance of MAP3K11


High impact information on MAP3K11

  • In addition, TNF-alpha also activates MLK3 and evidently leads to JNK activation in vivo [6].
  • Mixed lineage kinase-3 (MLK3) is a MAP3K that was thought to be a cytokine-activated, and comparatively selective, regulator of the JNK group of MAPKs (refs 1, 4-6) [7].
  • The proliferation of tumour cells containing activating B-raf or raf-1 mutations was unaffected by silencing mlk3 [7].
  • Silencing mlk3 also blocked mitogen-stimulated phosphorylation of B-Raf at Thr 598 and Ser 601, a step required for B-Raf activation [7].
  • Our results define an unexpected role for MLK3 in mitogen regulation of B-Raf, ERK and cell proliferation [7].

Chemical compound and disease context of MAP3K11


Biological context of MAP3K11


Anatomical context of MAP3K11


Associations of MAP3K11 with chemical compounds

  • AKT phosphorylates MLK3 on serine 674 both in vitro and in vivo [9].
  • In this study, we substituted a proposed stabilizing leucine residue in the zipper domain with a helix-disrupting proline to abrogate zipper-mediated SPRK oligomerization [15].
  • Upon treatment of MCF-7 cells with geldanamycin, an ansamycin antibiotic that inhibits Hsp90 function, MLK3 levels decrease dramatically [2].
  • Endogenous JNK, MKK7, and MLK3 kinase activities in HepG2 cells are significantly attenuated by insulin treatment, whereas the phosphatidylinositol 3-kinase inhibitors LY294002 and wortmannin reversed the effect [9].
  • Mutation of this sole proline abrogates SH3 binding and increases MLK3 catalytic activity [16].

Physical interactions of MAP3K11

  • We show that endogenous MLK3 complexes with Hsp90 and p50(cdc37) [2].
  • Thus we propose a model in which GTP-bound Cdc42/Rac binds MLK3 and disrupts SH3-mediated autoinhibition leading to dimerization and activation loop autophosphorylation [14].
  • In addition, we show that Akt activation results in the disassembly of the plenty of SH3s (POSH)-MLK3-Rac1 signaling complex and down-regulation of the activation of MLK3/c-Jun N-terminal kinase (JNK) pathway [17].

Enzymatic interactions of MAP3K11

  • MLK3 directly phosphorylated and thus activated IkappaB kinase alpha (IKKalpha) and IKKbeta, revealing its function as an IkappaB kinase kinase (IKKK) [12].
  • Herein we provide evidence that MLK3 can be phosphorylated by JNK in vitro and in vivo [18].
  • This mechanism involves activation of protein tyrosine kinases (PTK) that phosphorylate IkappaBalpha with peak phosphorylation occurring after 30 min of reoxygenation [19].

Regulatory relationships of MAP3K11


Other interactions of MAP3K11


Analytical, diagnostic and therapeutic context of MAP3K11


  1. Mixed-lineage kinase 3 regulates B-Raf through maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein. Chadee, D.N., Xu, D., Hung, G., Andalibi, A., Lim, D.J., Luo, Z., Gutmann, D.H., Kyriakis, J.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  2. Hsp90/p50cdc37 is required for mixed-lineage kinase (MLK) 3 signaling. Zhang, H., Wu, W., Du, Y., Santos, S.J., Conrad, S.E., Watson, J.T., Grammatikakis, N., Gallo, K.A. J. Biol. Chem. (2004) [Pubmed]
  3. Mixed lineage kinase 3 (MLK3)-activated p38 MAP kinase mediates transforming growth factor-beta-induced apoptosis in hepatoma cells. Kim, K.Y., Kim, B.C., Xu, Z., Kim, S.J. J. Biol. Chem. (2004) [Pubmed]
  4. Inhibition of mixed lineage kinase 3 prevents HIV-1 Tat-mediated neurotoxicity and monocyte activation. Sui, Z., Fan, S., Sniderhan, L., Reisinger, E., Litzburg, A., Schifitto, G., Gelbard, H.A., Dewhurst, S., Maggirwar, S.B. J. Immunol. (2006) [Pubmed]
  5. Genome-wide expression changes induced by HTLV-1 Tax: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-kappaB activation. Ng, P.W., Iha, H., Iwanaga, Y., Bittner, M., Chen, Y., Jiang, Y., Gooden, G., Trent, J.M., Meltzer, P., Jeang, K.T., Zeichner, S.L. Oncogene (2001) [Pubmed]
  6. Activation of the Drosophila MLK by ceramide reveals TNF-alpha and ceramide as agonists of mammalian MLK3. Sathyanarayana, P., Barthwal, M.K., Kundu, C.N., Lane, M.E., Bergmann, A., Tzivion, G., Rana, A. Mol. Cell (2002) [Pubmed]
  7. MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation. Chadee, D.N., Kyriakis, J.M. Nat. Cell Biol. (2004) [Pubmed]
  8. N-Acetylcysteine inhibit the translocation of mixed lineage kinase-3 from cytosol to plasma membrane during transient brain ischemia in rat hippocampus. Pei, D.S., Guan, Q.H., Sun, Y.F., Zhang, Q.X., Xu, T.L., Zhang, G.Y. Neurosci. Lett. (2005) [Pubmed]
  9. Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival. Barthwal, M.K., Sathyanarayana, P., Kundu, C.N., Rana, B., Pradeep, A., Sharma, C., Woodgett, J.R., Rana, A. J. Biol. Chem. (2003) [Pubmed]
  10. Cross-talk between JNK/SAPK and ERK/MAPK pathways: sustained activation of JNK blocks ERK activation by mitogenic factors. Shen, Y.H., Godlewski, J., Zhu, J., Sathyanarayana, P., Leaner, V., Birrer, M.J., Rana, A., Tzivion, G. J. Biol. Chem. (2003) [Pubmed]
  11. Mixed lineage kinase 3 inhibits phorbol myristoyl acetate-induced DNA synthesis but not osteopontin expression in rat mesangial cells. Parameswaran, N., Hall, C.S., Bock, B.C., Sparks, H.V., Gallo, K.A., Spielman, W.S. Mol. Cell. Biochem. (2002) [Pubmed]
  12. 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]
  13. A new identity for MLK3 as an NIMA-related, cell cycle-regulated kinase that is localized near centrosomes and influences microtubule organization. Swenson, K.I., Winkler, K.E., Means, A.R. Mol. Biol. Cell (2003) [Pubmed]
  14. Cdc42 induces activation loop phosphorylation and membrane targeting of mixed lineage kinase 3. Du, Y., Böck, B.C., Schachter, K.A., Chao, M., Gallo, K.A. J. Biol. Chem. (2005) [Pubmed]
  15. Zipper-mediated oligomerization of the mixed lineage kinase SPRK/MLK-3 is not required for its activation by the GTPase cdc 42 but Is necessary for its activation of the JNK pathway. Monomeric SPRK L410P does not catalyze the activating phosphorylation of Thr258 of murine MITOGEN-ACTIVATED protein kinase kinase 4. Vacratsis, P.O., Gallo, K.A. J. Biol. Chem. (2000) [Pubmed]
  16. Autoinhibition of mixed lineage kinase 3 through its Src homology 3 domain. Zhang, H., Gallo, K.A. J. Biol. Chem. (2001) [Pubmed]
  17. Ischemic preconditioning negatively regulates plenty of SH3s-mixed lineage kinase 3-Rac1 complex and c-Jun N-terminal kinase 3 signaling via activation of Akt. Zhang, Q.G., Han, D., Xu, J., Lv, Q., Wang, R., Yin, X.H., Xu, T.L., Zhang, G.Y. Neuroscience (2006) [Pubmed]
  18. Dynamic positive feedback phosphorylation of mixed lineage kinase 3 by JNK reversibly regulates its distribution to Triton-soluble domains. Schachter, K.A., Du, Y., Lin, A., Gallo, K.A. J. Biol. Chem. (2006) [Pubmed]
  19. Atypical mechanism of NF-kappaB activation during reoxygenation stress in microvascular endothelium: a role for tyrosine kinases. Natarajan, R., Fisher, B.J., Jones, D.G., Fowler, A.A. Free Radic. Biol. Med. (2002) [Pubmed]
  20. Inhibition of mixed lineage kinase 3 attenuates MPP+-induced neurotoxicity in SH-SY5Y cells. Mathiasen, J.R., McKenna, B.A., Saporito, M.S., Ghadge, G.D., Roos, R.P., Holskin, B.P., Wu, Z.L., Trusko, S.P., Connors, T.C., Maroney, A.C., Thomas, B.A., Thomas, J.C., Bozyczko-Coyne, D. Brain Res. (2004) [Pubmed]
  21. Dimerization via tandem leucine zippers is essential for the activation of the mitogen-activated protein kinase kinase kinase, MLK-3. Leung, I.W., Lassam, N. J. Biol. Chem. (1998) [Pubmed]
  22. Cdc42-induced activation of the mixed-lineage kinase SPRK in vivo. Requirement of the Cdc42/Rac interactive binding motif and changes in phosphorylation. Böck, B.C., Vacratsis, P.O., Qamirani, E., Gallo, K.A. J. Biol. Chem. (2000) [Pubmed]
  23. MLK-3: identification of a widely-expressed protein kinase bearing an SH3 domain and a leucine zipper-basic region domain. Ing, Y.L., Leung, I.W., Heng, H.H., Tsui, L.C., Lassam, N.J. Oncogene (1994) [Pubmed]
  24. Identification of in vivo phosphorylation sites of MLK3 by mass spectrometry and phosphopeptide mapping. Vacratsis, P.O., Phinney, B.S., Gage, D.A., Gallo, K.A. Biochemistry (2002) [Pubmed]
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