Available structures
PDBOrtholog search: PDBe RCSB
AliasesMAP3K12, DLK, MEKK12, MUK, ZPK, ZPKP1, mitogen-activated protein kinase kinase kinase 12, HP09298
External IDsOMIM: 600447 MGI: 1346881 HomoloGene: 4592 GeneCards: MAP3K12
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 12: 53.48 – 53.5 MbChr 15: 102.41 – 102.43 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

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


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]


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.


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000139625Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023050Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Reddy UR, Pleasure D (Aug 1994). "Cloning of a novel putative protein kinase having a leucine zipper domain from human brain". Biochem Biophys Res Commun. 202 (1): 613–20. doi:10.1006/bbrc.1994.1972. PMID 8037767.
  6. ^ a b "Entrez Gene: MAP3K12 mitogen-activated protein kinase kinase kinase 12".
  7. ^ a b Yasuda J, Whitmarsh AJ, Cavanagh J, Sharma M, Davis RJ (Oct 1999). "The JIP group of mitogen-activated protein kinase scaffold proteins". Mol. Cell. Biol. 19 (10): 7245–54. doi:10.1128/mcb.19.10.7245. PMC 84717. PMID 10490659.
  8. ^ Merritt SE, Mata M, Nihalani D, Zhu C, Hu X, Holzman LB (Apr 1999). "The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate". J. Biol. Chem. 274 (15): 10195–202. doi:10.1074/jbc.274.15.10195. PMID 10187804.
  9. ^ a b c d e f g Tedeschi A, Bradke F (May 2013). "The DLK signalling pathway—a double-edged sword in neural development and regeneration". EMBO Reports. 14 (7): 605–614. doi:10.1038/embor.2013.64. PMC 3701236. PMID 23681442.

Further reading