MAP3K12 explained

Mitogen-activated protein kinase 12 is an enzyme that in humans is encoded by the MAP3K12 gene.^{[1] [2]}

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,^[3] MAP2K7^[4] and MAPK8IP2.^[3]

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.^[5] 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.^[5] In addition, inhibition of DLK or JNK delays radial migration and disrupts the formation of the neocortex in mice.^[5] 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.^[5] 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.^[5] In neuronal migration DLK phosphorylates MAP2K4/7 which phosphorylates JNK, and also interacts with JIP which then interacts with MAP2K4/7 and JNK.^[5] There is a similar interaction for neuronal apoptosis, where DLK phosphorylates JIP3 and MAP2K7, which both phosphorylate JNK.^[5] It is evident then that DLK interactions are a versatile and critical part of neuronal development in mammals.

Further reading

• Reddy UR, Nycum L, Slavc I, Biegel JA . 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 . 7790002 . 10.1016/0888-7543(95)80069-X . free .
• Holzman LB, Merritt SE, Fan G . 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 . 10.1016/S0021-9258(18)47353-X . 7983011 . free .
• Hirai S, Izawa M, Osada S, Spyrou G, Ohno S . Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK. . Oncogene . 12 . 3 . 641–50 . 1996 . 8637721 .
• Mata M, Merritt SE, Fan G, Yu GG, Holzman LB . 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 . 8663324 . 10.1074/jbc.271.28.16888 . free .
• Sakuma H, Ikeda A, Oka S, Kozutsumi Y, Zanetta JP, Kawasaki T . 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 . 9353328 . 10.1074/jbc.272.45.28622 . free .
• Merritt SE, Mata M, Nihalani D, Zhu C, Hu X, Holzman LB . The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate. . J. Biol. Chem. . 274 . 15 . 10195–202 . 1999 . 10187804 . 10.1074/jbc.274.15.10195 . free .
• Reddy UR, Basu A, Bannerman P, Ikegaki N, Reddy CD, Pleasure D . ZPK inhibits PKA induced transcriptional activation by CREB and blocks retinoic acid induced neuronal differentiation. . Oncogene . 18 . 31 . 4474–84 . 1999 . 10442638 . 10.1038/sj.onc.1202813 . free .
• Douziech M, Laberge G, Grondin G, Daigle N, Blouin R . 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 . 10490457 . 10.1177/002215549904701008 . free .
• Fukuyama K, Yoshida M, Yamashita A, Deyama T, Baba M, Suzuki A, Mohri H, Ikezawa Z, Nakajima H, Hirai S, Ohno S . 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 . 10801814 . 10.1074/jbc.M001488200 . free .
• Hébert SS, Daviau A, Grondin G, Latreille M, Aubin RA, Blouin R . The mixed lineage kinase DLK is oligomerized by tissue transglutaminase during apoptosis. . J. Biol. Chem. . 275 . 42 . 32482–90 . 2000 . 10922377 . 10.1074/jbc.M006528200 . free .
• Figueroa C, Tarras S, Taylor J, Vojtek AB . Akt2 negatively regulates assembly of the POSH-MLK-JNK signaling complex. . J. Biol. Chem. . 278 . 48 . 47922–7 . 2004 . 14504284 . 10.1074/jbc.M307357200 . free .
• Itoh A, Wang Z, Ito Y, Reddy UR, Itoh T . SP3 acts as a positive regulator on the core promoter of human ZPK gene. . Biochem. Biophys. Res. Commun. . 313 . 3 . 612–8 . 2004 . 14697235 . 10.1016/j.bbrc.2003.11.152 .
• Graves PR, Winkfield KM, Haystead TA . Regulation of zipper-interacting protein kinase activity in vitro and in vivo by multisite phosphorylation. . J. Biol. Chem. . 280 . 10 . 9363–74 . 2005 . 15611134 . 10.1074/jbc.M412538200 . free .
• Robitaille H, Proulx R, Robitaille K, Blouin R, Germain L . 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 . 15695824 . 10.1074/jbc.M411619200 . free . 20.500.11794/16685 . free .
• Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE . A human protein-protein interaction network: a resource for annotating the proteome. . Cell . 122 . 6 . 957–68 . 2005 . 16169070 . 10.1016/j.cell.2005.08.029 . 11858/00-001M-0000-0010-8592-0 . 8235923 . free .

Notes and References

1. Reddy UR, Pleasure D . Cloning of a novel putative protein kinase having a leucine zipper domain from human brain . Biochem Biophys Res Commun . 202 . 1 . 613–20 . Aug 1994 . 8037767 . 10.1006/bbrc.1994.1972 . free .
2. Web site: Entrez Gene: MAP3K12 mitogen-activated protein kinase kinase kinase 12.
3. Yasuda J, Whitmarsh AJ, Cavanagh J, Sharma M, Davis RJ . The JIP group of mitogen-activated protein kinase scaffold proteins . Mol. Cell. Biol. . 19 . 10 . 7245–54 . Oct 1999 . 10490659 . 84717 . 10.1128/mcb.19.10.7245.
4. Merritt SE, Mata M, Nihalani D, Zhu C, Hu X, Holzman LB . The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate . J. Biol. Chem. . 274 . 15 . 10195–202 . Apr 1999 . 10187804 . 10.1074/jbc.274.15.10195 . free .
5. Tedeschi A, Bradke F . The DLK signalling pathway—a double-edged sword in neural development and regeneration . EMBO Reports . May 2013 . 14 . 7 . 605–614 . 10.1038/embor.2013.64 . 23681442 . 3701236.