Kinase Subfamily LZK

Kinase Classification: Group TKL: Family MLK: : Subfamily LZK

Evolution

LZK is found throughout the holozoa. The two vertebrate members are LZK (MAP3K13) and DLK (MAP3K12).

Domain Structure

Most animal LZKs have a kinase domain in the middle, flanked by unannotated regions. Human DLK ("Dual Leucine Zipper Kinase")was reported to have two degenerate leucine zipper regions just C-terminal to the kinase domain [1]. These are variably conserved in LZK and in invertebrate homologs. The DLK leucine zippers are involved in homodimerization [2].

Kelch domains are seen in some sponge members, and PB1 domains in plants. A C-terminal semi-conserved region contains an identical hexapeptide (SDGLSD) in worm and human LZK and in worm is required for Ca modulation of function [3]

Functions

Human DLK is largely brain specific, particularly in the cerebellum, while LZK is expressed throughout the body, and at a higher level in the brain.

C. elegans DLK-1 is involved in synaptic development [4] and axon regeneration [5, 6] through modulation of microtubule activity [4, 7]. Mouse DLK is also implicated in axonal regeneration [8]. A pathway including DLK-1, MKK-4 (a MEK4 MAPKK) and PMK-3 (p38 MAPK), mak-2 (MAPKAPK kinase) as well as the ubiquitin ligase RPM-1 is involved in nematode presynaptic development [9].

C. elegans DLK-1 has two opposing splice isoforms, and a Ca-mediated activation switches from heteromeric to active homomeric complexes. [3]

References

1. Holzman LB, Merritt SE, and 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. 1994 Dec 9;269(49):30808-17.
2. Nihalani D, Merritt S, and Holzman LB. Identification of structural and functional domains in mixed lineage kinase dual leucine zipper-bearing kinase required for complex formation and stress-activated protein kinase activation. J Biol Chem. 2000 Mar 10;275(10):7273-9. DOI:10.1074/jbc.275.10.7273 |
3. Yan D and Jin Y. Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform. Neuron. 2012 Nov 8;76(3):534-48. DOI:10.1016/j.neuron.2012.08.043 |
4. Kurup N, Yan D, Goncharov A, and Jin Y. Dynamic microtubules drive circuit rewiring in the absence of neurite remodeling. Curr Biol. 2015 Jun 15;25(12):1594-605. DOI:10.1016/j.cub.2015.04.061 |
5. Chen L, Wang Z, Ghosh-Roy A, Hubert T, Yan D, O'Rourke S, Bowerman B, Wu Z, Jin Y, and Chisholm AD. Axon regeneration pathways identified by systematic genetic screening in C. elegans. Neuron. 2011 Sep 22;71(6):1043-57. DOI:10.1016/j.neuron.2011.07.009 |
6. Hammarlund M, Nix P, Hauth L, Jorgensen EM, and Bastiani M. Axon regeneration requires a conserved MAP kinase pathway. Science. 2009 Feb 6;323(5915):802-6. DOI:10.1126/science.1165527 |
7. Ghosh-Roy A, Goncharov A, Jin Y, and Chisholm AD. Kinesin-13 and tubulin posttranslational modifications regulate microtubule growth in axon regeneration. Dev Cell. 2012 Oct 16;23(4):716-28. DOI:10.1016/j.devcel.2012.08.010 |
8. Itoh A, Horiuchi M, Bannerman P, Pleasure D, and Itoh T. Impaired regenerative response of primary sensory neurons in ZPK/DLK gene-trap mice. Biochem Biophys Res Commun. 2009 May 29;383(2):258-62. DOI:10.1016/j.bbrc.2009.04.009 |
9. Nakata K, Abrams B, Grill B, Goncharov A, Huang X, Chisholm AD, and Jin Y. Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development. Cell. 2005 Feb 11;120(3):407-20. DOI:10.1016/j.cell.2004.12.017 |