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Gene Review

MAP3K12  -  mitogen-activated protein kinase kinase...

Homo sapiens

Synonyms: DLK, Dual leucine zipper bearing kinase, Leucine-zipper protein kinase, MAPK-upstream kinase, MEKK12, ...
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Disease relevance of MAP3K12


High impact information on MAP3K12

  • The small molecule inhibitor of the mixed-lineage kinase (MLK) family of kinases, CEP-1347, inhibits the activation of the JNK pathway and, consequently, the cell death in many cell culture and animal models of neuronal death [6].
  • In addition, NGF deprivation or UV irradiation leads to an increase in both level and phosphorylation of endogenous DLK [7].
  • CEP-1347 (KT7515), which blocks neuronal death caused by NGF deprivation and a variety of additional apoptotic stimuli and which selectively inhibits the activities of MLKs, effectively protects neuronal PC12 cells from death induced by overexpression of MLK family members [7].
  • Together, these results reveal that peroxynitrite-induced activation of the intrinsic apoptotic pathway involves interactions with the MLK/MAPK and Akt signaling pathways [8].
  • The mitogen-activated protein kinase kinase kinase dual leucine zipper-bearing kinase (DLK) acts as a key regulator of keratinocyte terminal differentiation [2].

Biological context of MAP3K12

  • Differences in primary protein structure place these MLK (mixed lineage kinase) enzymes in separate subfamilies and suggest that they perform distinct functional roles [9].
  • The dissimilar cellular specificity of DLK and MLK3 and the specific substrate utilization and subcellular compartmentation of DLK suggest that specific mixed lineage kinases participate in unique signal transduction events [9].
  • Adenoviral dominant negative constructs of two other MLK family members (MLK 2 and DLK) did not protect against MPP(+)-induced cell death [10].
  • MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest [11].
  • Our results suggest that, for the selective expression of ZPK gene, cell-specific negative regulatory element(s) which locate outside of the core promoter region repress the potent basic promoter activity [12].

Anatomical context of MAP3K12

  • Subcellular fractionation experiments of cerebral cortex identified DLK and MKK7 in similar nuclear and extranuclear subcellular compartments [9].
  • However, the core promoter activity was still potent even in HeLa cells which barely express ZPK [12].
  • Together these results identify DLK as a signaling molecule implicated in the regulation of keratinocyte terminal differentiation and cornification [2].
  • Similarly, DLK transiently expressed in COS 7 cells autophosphorylated in vivo and migrated at approximately 260 kDa when separated by nonreducing SDS-polyacrylamide gel electrophoresis [13].
  • In aggregating neuronal-glial cultures, depolarization of plasma membrane lead to dephosphorylation of DLK [13].

Associations of MAP3K12 with chemical compounds

  • The amino acid sequence of the kinase catalytic domain was a hybrid between those in serine/threonine and tyrosine protein kinases, indicating that LZK belongs to the subfamily of the mixed lineage kinase (MLK) family [14].
  • However, cyclosporin A completely inhibited DLK dephosphorylation upon membrane depolarization [13].
  • DLK/MUK/ZPK is a serine/threonine kinase that belongs to the mixed-lineage (MLK) subfamily of protein kinases [15].
  • Consistent with localization studies, biochemical analyses revealed that DLK/MUK/ZPK was predominantly associated with Golgi membranes on fractionation of cellular extracts and was entirely partitioned into the aqueous phase when membranes were subjected to Triton X-114 extraction [15].
  • DLK was also effective in response to glucose, the most potent physiological stimulus and known to cause membrane depolarisation of beta cells [16].

Regulatory relationships of MAP3K12

  • Moreover the expression of wild-type DLK in keratinocytes stimulated transglutaminase activity and the consequent formation of the cornified cell envelope, while a kinase-inactive variant of DLK did not [2].

Other interactions of MAP3K12


Analytical, diagnostic and therapeutic context of MAP3K12


  1. 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]
  2. The mitogen-activated protein kinase kinase kinase dual leucine zipper-bearing kinase (DLK) acts as a key regulator of keratinocyte terminal differentiation. Robitaille, H., Proulx, R., Robitaille, K., Blouin, R., Germain, L. J. Biol. Chem. (2005) [Pubmed]
  3. Inhibition of mixed-lineage kinase (MLK) activity during G2-phase disrupts microtubule formation and mitotic progression in HeLa cells. Cha, H., Dangi, S., Machamer, C.E., Shapiro, P. Cell. Signal. (2006) [Pubmed]
  4. Mixed lineage kinase-c-jun N-terminal kinase signaling pathway: a new therapeutic target in Parkinson's disease. Silva, R.M., Kuan, C.Y., Rakic, P., Burke, R.E. Mov. Disord. (2005) [Pubmed]
  5. Usefulness of AgNOR counts in diagnosing epithelial dysplasia. Ray, J.G., Chattopadhyay, A., Caplan, D.J. J. Oral Pathol. Med. (2003) [Pubmed]
  6. Mixed-lineage kinases: a target for the prevention of neurodegeneration. Wang, L.H., Besirli, C.G., Johnson, E.M. Annu. Rev. Pharmacol. Toxicol. (2004) [Pubmed]
  7. The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis. Xu, Z., Maroney, A.C., Dobrzanski, P., Kukekov, N.V., Greene, L.A. Mol. Cell. Biol. (2001) [Pubmed]
  8. Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells. Shacka, J.J., Sahawneh, M.A., Gonzalez, J.D., Ye, Y.Z., D'Alessandro, T.L., Estévez, A.G. Cell Death Differ. (2006) [Pubmed]
  9. The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate. Merritt, S.E., Mata, M., Nihalani, D., Zhu, C., Hu, X., Holzman, L.B. J. Biol. Chem. (1999) [Pubmed]
  10. 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]
  11. MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest. Gross, E.A., Callow, M.G., Waldbaum, L., Thomas, S., Ruggieri, R. J. Biol. Chem. (2002) [Pubmed]
  12. SP3 acts as a positive regulator on the core promoter of human ZPK gene. Itoh, A., Wang, Z., Ito, Y., Reddy, U.R., Itoh, T. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  13. Characterization of dual leucine zipper-bearing kinase, a mixed lineage kinase present in synaptic terminals whose phosphorylation state is regulated by membrane depolarization via calcineurin. Mata, M., Merritt, S.E., Fan, G., Yu, G.G., Holzman, L.B. J. Biol. Chem. (1996) [Pubmed]
  14. Molecular cloning and functional expression of a cDNA encoding a new member of mixed lineage protein kinase from human brain. Sakuma, H., Ikeda, A., Oka, S., Kozutsumi, Y., Zanetta, J.P., Kawasaki, T. J. Biol. Chem. (1997) [Pubmed]
  15. Localization of the mixed-lineage kinase DLK/MUK/ZPK to the Golgi apparatus in NIH 3T3 cells. Douziech, M., Laberge, G., Grondin, G., Daigle, N., Blouin, R. J. Histochem. Cytochem. (1999) [Pubmed]
  16. Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein (CREB) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line. Oetjen, E., Lechleiter, A., Blume, R., Nihalani, D., Holzman, L., Knepel, W. Diabetologia (2006) [Pubmed]
  17. Identification of structural and functional domains in mixed lineage kinase dual leucine zipper-bearing kinase required for complex formation and stress-activated protein kinase activation. Nihalani, D., Merritt, S., Holzman, L.B. J. Biol. Chem. (2000) [Pubmed]
  18. The mixed lineage kinase leucine-zipper protein kinase exhibits a differentiation-associated localization in normal human skin and induces keratinocyte differentiation upon overexpression. Germain, L., Fradette, J., Robitaille, H., Guignard, R., Grondin, G., Nadeau, A., Blouin, R. J. Invest. Dermatol. (2000) [Pubmed]
  19. Localization of the human zipper protein kinase gene (ZPK) to chromosome 12q13 by fluorescence in situ hybridization and somatic cell hybrid analysis. Reddy, U.R., Nycum, L., Slavc, I., Biegel, J.A. Genomics (1995) [Pubmed]
  20. Identification, molecular cloning, and characterization of dual leucine zipper bearing kinase. A novel serine/threonine protein kinase that defines a second subfamily of mixed lineage kinases. Holzman, L.B., Merritt, S.E., Fan, G. J. Biol. Chem. (1994) [Pubmed]
  21. The c-Jun N-terminal kinase activator dual leucine zipper kinase regulates axon growth and neuronal migration in the developing cerebral cortex. Hirai, S., Cui, d.e. .F., Miyata, T., Ogawa, M., Kiyonari, H., Suda, Y., Aizawa, S., Banba, Y., Ohno, S. J. Neurosci. (2006) [Pubmed]
  22. Lamellar keratitis following laser-assisted in situ keratomileusis. Chao, C.W., Azar, D.T. Ophthalmology clinics of North America. (2002) [Pubmed]
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