Biology:MAP3K12

Generic protein structure example

Mitogen-activated protein kinase 12 is an enzyme that in humans is encoded by the MAP3K12 gene.

Function

The protein encoded by this gene is a member of serine/threonine protein kinase family. This kinase contains a leucine-zipper domain, and is predominately expressed in neuronal cells. The phosphorylation state of this kinase in synaptic terminals was shown to be regulated by membrane depolarization via calcineurin. This kinase forms heterodimers with leucine zipper containing transcription factors, such as cAMP responsive element binding protein (CREB) and MYC, and thus may play a regulatory role in PKA or retinoic acid induced neuronal differentiation.

Interactions

MAP3K12 has been shown to interact with MAPK8IP1, MAP2K7 and MAPK8IP2.

Role in development

MAP3K12, otherwise known as DLK, can initiate coordinated signalling cascades that culminate in the phosphorylation of C-Jun N-terminal kinases or JNK. Several experiments have implicated this interaction as having a role in the developing mammalian nervous system. For example, neuronal migration and axon growth are critical components of neuronal development. DLK null mice have defects in neuronal migration, hypoplasia of several different axonal tracts and reduced axon number in various areas of the brain such as the cingulum and internal capsule. In addition, inhibition of DLK or JNK delays radial migration and disrupts the formation of the neocortex in mice. Another important function of the developing mammalian nervous system is neuronal apoptosis. The absence of DLK also protects cultured mice sensory neurons from apoptosis that would normally be triggered by a lack of NGF. This, among other experiments, heavily implicates it as having a role in neuronal apoptosis.

DLK has several different interactions that contribute to mammalian nervous system development. For axon growth, DLK phosphorylates MAP2K4/7 which then phosphorylates JNK, activating it. In neuronal migration DLK phosphorylates MAP2K4/7 which phosphorylates JNK, and also interacts with JIP which then interacts with MAP2K4/7 and JNK. There is a similar interaction for neuronal apoptosis, where DLK phosphorylates JIP3 and MAP2K7, which both phosphorylate JNK. It is evident then that DLK interactions are a versatile and critical part of neuronal development in mammals.

Further reading

• "Localization of the human zipper protein kinase gene (ZPK) to chromosome 12q13 by fluorescence in situ hybridization and somatic cell hybrid analysis.". Genomics 25 (2): 597–8. 1995. doi:10.1016/0888-7543(95)80069-X. PMID 7790002. 
• "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.". J. Biol. Chem. 269 (49): 30808–17. 1995. doi:10.1016/S0021-9258(18)47353-X. PMID 7983011. 
• "Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK.". Oncogene 12 (3): 641–50. 1996. PMID 8637721. 
• "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.". J. Biol. Chem. 271 (28): 16888–96. 1996. doi:10.1074/jbc.271.28.16888. PMID 8663324. 
• "Molecular cloning and functional expression of a cDNA encoding a new member of mixed lineage protein kinase from human brain.". J. Biol. Chem. 272 (45): 28622–9. 1997. doi:10.1074/jbc.272.45.28622. PMID 9353328. 
• "The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate.". J. Biol. Chem. 274 (15): 10195–202. 1999. doi:10.1074/jbc.274.15.10195. PMID 10187804. 
• "ZPK inhibits PKA induced transcriptional activation by CREB and blocks retinoic acid induced neuronal differentiation.". Oncogene 18 (31): 4474–84. 1999. doi:10.1038/sj.onc.1202813. PMID 10442638. 
• "Localization of the mixed-lineage kinase DLK/MUK/ZPK to the Golgi apparatus in NIH 3T3 cells.". J. Histochem. Cytochem. 47 (10): 1287–96. 1999. doi:10.1177/002215549904701008. PMID 10490457. 
• "MAPK upstream kinase (MUK)-binding inhibitory protein, a negative regulator of MUK/dual leucine zipper-bearing kinase/leucine zipper protein kinase.". J. Biol. Chem. 275 (28): 21247–54. 2000. doi:10.1074/jbc.M001488200. PMID 10801814. 
• "The mixed lineage kinase DLK is oligomerized by tissue transglutaminase during apoptosis.". J. Biol. Chem. 275 (42): 32482–90. 2000. doi:10.1074/jbc.M006528200. PMID 10922377. 
• "Akt2 negatively regulates assembly of the POSH-MLK-JNK signaling complex.". J. Biol. Chem. 278 (48): 47922–7. 2004. doi:10.1074/jbc.M307357200. PMID 14504284. 
• "SP3 acts as a positive regulator on the core promoter of human ZPK gene.". Biochem. Biophys. Res. Commun. 313 (3): 612–8. 2004. doi:10.1016/j.bbrc.2003.11.152. PMID 14697235. 
• "Regulation of zipper-interacting protein kinase activity in vitro and in vivo by multisite phosphorylation.". J. Biol. Chem. 280 (10): 9363–74. 2005. doi:10.1074/jbc.M412538200. PMID 15611134. 
• "The mitogen-activated protein kinase kinase kinase dual leucine zipper-bearing kinase (DLK) acts as a key regulator of keratinocyte terminal differentiation.". J. Biol. Chem. 280 (13): 12732–41. 2005. doi:10.1074/jbc.M411619200. PMID 15695824. 
• "A human protein-protein interaction network: a resource for annotating the proteome.". Cell 122 (6): 957–68. 2005. doi:10.1016/j.cell.2005.08.029. PMID 16169070.