Disease relevance of Map3k12

• A novel role for mixed-lineage kinase-like mitogen-activated protein triple kinase alpha in neoplastic cell transformation and tumor development [1].

High impact information on Map3k12

• Here, we demonstrate that MLK-like mitogen-activated protein triple kinase (MLTK)-alpha, a member of the MLK family, induced neoplastic cell transformation and tumorigenesis in athymic nude mice [1].
• Tissue transglutaminase triggers oligomerization and activation of dual leucine zipper-bearing kinase in calphostin C-treated cells to facilitate apoptosis [2].
• Previously, no member of the mixed-lineage kinase (MLK) protein family was known to function as an oncogene [1].
• MAPK-upstream protein kinase (MUK) regulates the radial migration of immature neurons in telencephalon of mouse embryo [3].
• In COS-1 cells, MUK/DLK/ZPK overexpression impairs the radial organization of microtubules without massive depolymerization [3].

Biological context of Map3k12

• Because the catalytic domain of dual leucine zipper-bearing kinase (DLK) bears sequence similarity to members of the mitogen-activated protein (MAP) kinase kinase kinase subfamily, this protein kinase was investigated for its ability to activate MAP kinase pathways [4].
• To investigate the potential role of this protein kinase in developmental processes, we have analyzed the spatial and temporal patterns of expression of the ZPK gene in mouse embryos of different gestational ages [5].
• Taken together, these observations raise the possibility that the ZPK gene product is involved in the establishment and/or maintenance of a fully cytodifferentiated state in a variety of cell lineages [5].
• Since DLK has been shown to function in the mitogen activated signaling (MAP) pathway, these results provide the first evidence for the involvement of this signaling pathway in fracture healing [6].
• In situ hybridization analysis of ZPK gene expression during murine embryogenesis [5].

Anatomical context of Map3k12

• The intensely overlapping localization of betaIII-tubulin and MUK/DLK/ZPK indicated that this protein kinase is tightly associated with the microtubules of neurons [7].
• We show here that the expression of MUK/DLK/ZPK protein in the developing mouse embryo is almost totally specific for the neural tissues, including central, peripheral, and autonomic nervous systems [7].
• The localization of MUK/DLK/ZPK protein in neural cells almost consistently overlapped that of betaIII-tubulin, a neuron specific tubulin isoform, and both proteins were more concentrated in axons than in cell bodies and dendrites [7].
• In situ hybridization analysis of mouse brain sections revealed specific association of ZPK mRNA with neuronal cell populations, primarily in the hippocampus, the cerebral cortex, and the Purkinje cell layer of the cerebellum [8].
• These findings demonstrate a transient stimulation of ZPK/DLK/MUK gene expression that correlates with the growth response of hepatocyte subpopulations in regenerating liver [9].

Associations of Map3k12 with chemical compounds

• Kainate receptor activation induces mixed lineage kinase-mediated cellular signaling cascades via post-synaptic density protein 95 [10].
• ZPK is a recently described serine/threonine protein kinase that is thought to be involved in the regulation of cell proliferation and differentiation [11].
• Combined depletion of TG2 and DLK further alters calphostin C effects on JNK activity, Bax translocation, caspase-3 activation, PARP cleavage and cell viability, demonstrating an obligatory role for TG2 and DLK in calphostin C-induced apoptosis [12].

Regulatory relationships of Map3k12

• Consistent with its specificity in activating SAPK, DLK activated Elk-1 but not Sap1a-mediated transcription [4].
• Dual leucine zipper-bearing kinase (DLK) activates p46SAPK and p38mapk but not ERK2 [4].
• The Hsp70 co-chaperone CHIP, an E3 ubiquitin ligase, seems to be indispensable for this process since Hsp70 failed to induce DLK degradation in COS-7 cells expressing a CHIP mutant unable to catalyze ubiquitination or in immortalized fibroblasts derived from CHIP knock-out mice [13].

Other interactions of Map3k12

• In NIH3T3 cells, activation of SAPK by v-Src was markedly attenuated by coexpression of K185A, a catalytically inactive mutant of DLK, suggesting that this mutant could function in a dominant negative fashion in a pathway that leads from v-Src to SAPKs [4].
• In a series of co-transfection experiments, activation of p46(SAPK) by DLK was not inhibited by dominant negative mutants of Rac1 and Cdc42Hs, PAK65-R, or PAK65-A, but was attenuated by MEKK1(K432M) [4].
• In situ hybridization studies demonstrated strong expression of ZPK mRNA in brain and in a variety of embryonic organs that rely on epitheliomesenchymal interactions for their development, including skin, intestine, pancreas, and kidney [5].

Analytical, diagnostic and therapeutic context of Map3k12

• By Northern blot analysis, we detected expression of ZPK mRNA in the brain of adult mice, but not in any other tissue tested [8].
• We show here, using gene targeting in mice, that DLK is indispensable for establishing axon tracts, especially those originating from neocortical pyramidal neurons of the cerebrum [14].

References