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MAP3K12
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	5CEN, 5CEP, 5CEQ, 5CEO
Identifiers
Aliases	MAP3K12, DLK, MEKK12, MUK, ZPK, ZPKP1, mitogen-activated protein kinase kinase kinase 12, HP09298
External IDs	OMIM: 600447; MGI: 1346881; HomoloGene: 4592; GeneCards: MAP3K12; OMA:MAP3K12 - orthologs
Gene location (Human)
Chr.	Chromosome 12 (human)
End	53,500,063 bp
Gene location (Mouse)
Chr.	Chromosome 15 (mouse)
End	102,425,499 bp
RNA expression pattern
	Top expressed in
	right hemisphere of cerebellum; ; gastric mucosa; ; right uterine tube; ; right ovary; ; right frontal lobe; ; anterior pituitary; ; canal of the cervix; ; cerebellar vermis; ; body of uterus; ; left ovary;
	Top expressed in
	ascending aorta; ; aortic valve; ; supraoptic nucleus; ; otic placode; ; submandibular gland; ; internal carotid artery; ; lobe of cerebellum; ; tunica media of zone of aorta; ; external carotid artery; ; intercostal muscle;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	transferase activity; protein kinase activity; nucleotide binding; protein homodimerization activity; kinase activity; protein binding; MAP kinase kinase kinase activity; ATP binding; protein kinase binding; protein serine/threonine kinase activity; signal transducer activity; JUN kinase kinase kinase activity;
Cellular component	cytoplasm; cytosol; membrane; growth cone; plasma membrane; axon;
Biological process	intracellular signal transduction; phosphorylation; protein phosphorylation; JNK cascade; peptidyl-serine phosphorylation; protein autophosphorylation; peptidyl-threonine phosphorylation; negative regulation of motor neuron apoptotic process; MAPK cascade; positive regulation of transcription, DNA-templated; positive regulation of ERK1 and ERK2 cascade;
	Sources:Amigo / QuickGO
Orthologs
	7786
	26404
	ENSG00000139625
	ENSMUSG00000023050
	Q12852
	Q60700
	NM_001193511; NM_006301
	NM_001163643; NM_009582; NM_001358844
	NP_001180440; NP_006292
	NP_001157115; NP_033608; NP_001345773
	Wikidata
View/Edit Human	View/Edit Mouse

Mitogen-activated protein kinase 12 is an enzyme that in humans is encoded by the MAP3K12 gene.^[5]^[6]

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.^[6]

Interactions

MAP3K12 has been shown to interact with MAPK8IP1,^[7] MAP2K7^[8] and MAPK8IP2.^[7]

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.^[9] 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.^[9] In addition, inhibition of DLK or JNK delays radial migration and disrupts the formation of the neocortex in mice.^[9] 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.^[9] 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.^[9] In neuronal migration DLK phosphorylates MAP2K4/7 which phosphorylates JNK, and also interacts with JIP which then interacts with MAP2K4/7 and JNK.^[9] There is a similar interaction for neuronal apoptosis, where DLK phosphorylates JIP3 and MAP2K7, which both phosphorylate JNK.^[9] It is evident then that DLK interactions are a versatile and critical part of neuronal development in mammals.