Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

c-Jun N-terminal kinases/stress-activated protein kinases (JNKs/SAPKs) are mitogen-activated protein kinase (MAPK)-related protein kinases that are involved in several cellular events, including growth, differentiation, and apoptosis. Mixed lineage kinases (MLKs) form a family of protein kinases sharing two leucine zipper-like motifs and a kinase domain whose primary structure is similar to both the tyrosine-specific and the serine/threonine-specific kinase classes. We have reported that a member of the MLK family, MUK/DLK/ZPK, can activate JNK/SAPK in vivo, and here we show that another member of the MLK family, MST/MLK2, activates JNK/SAPK. Both MUK/DLK/ZPK and MST/MLK2 cause a slight activation of p38/Mpk2 when overexpressed in COS-1 cells, whereas MST/MLK2, but not MUK/DLK/ZPK, activates extracellular response kinase (ERK) to a certain degree. The activity of SEK1/MKK4/JNKK, a MAPK kinase class protein kinase designated as a direct activator of JNK/SAPK, is also induced by MUK/DLK/ZPK or MST/MLK2 overexpression. Furthermore, recombinant MST/MLK2 produced in bacteria directly phosphorylates and activates SEK1/MKK4/JNKK in vitro, showing that MST/MLK2 acts like a MAPK kinase kinase. Taken together, these results suggest that MLK family members are MAPK kinase kinases preferentially acting on the JNK/SAPK pathway.
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PMID:MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of c-Jun N-terminal kinase/stress-activated protein kinase. 918 38

C-Jun N-terminal kinase (JNK) is implicated in regulating the various cellular events during neural development that include differentiation, apoptosis and migration. MUK/DLK/ZPK is a MAP kinase kinase kinase (MAPKKK) enzyme that activates JNK via MAP kinase kinases (MAPKK) such as MKK7. 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. The only obvious exception is the liver, in which the protein is temporally expressed at around E11. The expression becomes obvious in the neurons of the brain and neural crest tissues at embryonic day 10 (E10) after neuron production is initiated. By E14, MUK/DLK/ZPK proteins are found in various neural tissues including the brain, spinal cord, sensory ganglia (such as trigeminal and dorsal root ganglia), and the sympathetic and visceral nerves. 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. The intensely overlapping localization of betaIII-tubulin and MUK/DLK/ZPK indicated that this protein kinase is tightly associated with the microtubules of neurons.
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PMID:Expression of MUK/DLK/ZPK, an activator of the JNK pathway, in the nervous systems of the developing mouse embryo. 1574 80

Motoneuron death after transection of the axons (axotomy) in neonates is believed to share the same mechanistic bases as naturally occurring programmed cell death during development. The c-Jun N-terminal kinase pathway is activated in both forms of motoneuron death, but it remains unknown to what extent these two forms of motoneuron death depend on this pathway and which upstream kinases are involved. We found that numbers of facial motoneurons are doubled in neonatal mice deficient in either ZPK/DLK (zipper protein kinase, also known as dual leucine zipper kinase), a mitogen-activated protein kinase kinase kinase, or in MKK4/MAP2K4, a mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, and that the facial motoneurons in those mutant mice are completely resistant to axotomy-induced death. Conditional deletion of MKK4/MAP2K4 in neurons further suggested that ZPK/DLK and MKK4/MAP2K4-dependent mechanisms underlying axotomy-induced death are motoneuron autonomous. Nevertheless, quantitative analysis of facial motoneurons during embryogenesis revealed that both ZPK/DLK and MKK4/MAP2K4-dependent and -independent mechanisms contribute to developmental elimination of excess motoneurons. In contrast to MKK4/MAP2K4, mice lacking MKK7/MAP2K7, another mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, conditionally in neurons did not have excess facial motoneurons. However, some MKK7/MAP2K7-deficient facial motoneurons were resistant to axotomy-induced death, indicating a synergistic effect of MKK7/MAP2K7 on axotomy-induced death of these facial motoneurons. Together, our study provides compelling evidence for the pivotal roles of the ZPK/DLK and MKK4/MAP2K4-dependent mechanism in axotomy-induced motoneuron death in neonates and also demonstrates that axotomy-induced motoneuron death is not identical to developmental motoneuron death with respect to the involvement of ZPK/DLK, MKK4/MAP2K4 and MKK7/MAP2K7.
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PMID:ZPK/DLK and MKK4 form the critical gateway to axotomy-induced motoneuron death in neonates. 2510 Jun 4