Encyclopedia of Signaling Molecules

2012 Edition
| Editors: Sangdun Choi

DLK (Dual Leucine Zipper-Bearing Kinase)

  • Jean-Philippe Couture
  • Richard Blouin
Reference work entry
DOI: https://doi.org/10.1007/978-1-4419-0461-4_402


Historical Background

DLK is a serine/threonine kinase that belongs to the mixed-lineage kinase (MLK) family of mitogen-activated protein kinase kinase kinases (MAPKKKs) (Gallo and Johnson 2002). It was discovered in 1994 as a protein differentially expressed during the retinoic-acid-induced neuronal differentiation of human NT2 teratocarcinoma cells and originally denoted zipper protein kinase (ZPK, Reddy and Pleasure 1994). Parallel and subsequent studies led to the identification and cloning of the mouse and rat homologs of ZPK, respectively termed DLK (Holzman et al. 1994) and MAP kinase upstream kinase (MUK, Hirai et al. 1996).

Structure, Expression, and Subcellular Localization

DLK is a 120 kDa protein that shares with other MLKs structural characteristics unique among...
This is a preview of subscription content, log in to check access.



We thank the Natural Sciences and Engineering Research Council of Canada for its financial support. We also apologize to our colleagues whose work could not be cited due to space limitations.


  1. Collins CA, Wairkar YP, Johnson SL, DiAntonio A. Highwire restrains synaptic growth by attenuating a MAP kinase signal. Neuron. 2006;51:57–69.PubMedCrossRefGoogle Scholar
  2. Couture JP, Daviau A, Fradette J, Blouin R. The mixed-lineage kinase DLK is a key regulator of 3T3-L1 adipocyte differentiation. PLoS ONE. 2009;4:e4743.PubMedCrossRefGoogle Scholar
  3. Daviau A, Proulx R, Robitaille K, Di Fruscio M, Tanguay RM, Landry J, et al. Down-regulation of the mixed-lineage dual leucine zipper-bearing kinase by heat shock protein 70 and its co-chaperone CHIP. J Biol Chem. 2006;281:31467–77.PubMedCrossRefGoogle Scholar
  4. Daviau A, Di Fruscio M, Blouin R. The mixed-lineage kinase DLK undergoes Src-dependent tyrosine phosphorylation and activation in cells exposed to vanadate or platelet-derived growth factor (PDGF). Cell Signal. 2009;21:577–87.PubMedCrossRefGoogle Scholar
  5. Eto K, Kawauchi T, Osawa M, Tabata H, Nakajima K. Role of dual leucine zipper-bearing kinase (DLK/MUK/ZPK) in axonal growth. Neurosci Res. 2010;66:37–45.PubMedCrossRefGoogle Scholar
  6. Fukuyama K, Yoshida M, Yamashita A, Deyama T, Baba M, Suzuki A, et al. MAPK upstream kinase (MUK)-binding inhibitory protein, a negative regulator of MUK/dual leucine zipper-bearing kinase/leucine zipper protein kinase. J Biol Chem. 2000;275:21247–54.PubMedCrossRefGoogle Scholar
  7. Gallo KA, Johnson GL. Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol. 2002;3:663–72.PubMedCrossRefGoogle Scholar
  8. Hammarlund M, Nix P, Hauth L, Jorgensen EM, Bastiani M. Axon regeneration requires a conserved MAP kinase pathway. Science. 2009;323:802–6.PubMedCrossRefGoogle Scholar
  9. Hirai S, Izawa M, Osada S, Spyrou G, Ohno S. Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK. Oncogene. 1996;12:641–50.PubMedGoogle Scholar
  10. Hirai S, Kawaguchi A, Hirasawa R, Baba M, Ohnishi T, Ohno S. MAPK-upstream protein kinase (MUK) regulates the radial migration of immature neurons in telencephalon of mouse embryo. Development. 2002;129:4483–95.PubMedGoogle Scholar
  11. Hirai S, de Cui F, Miyata T, Ogawa M, Kiyonari H, Suda Y, et al. The c-Jun N-terminal kinase activator dual leucine zipper kinase regulates axon growth and neuronal migration in the developing cerebral cortex. J Neurosci. 2006;26:11992–2002.PubMedCrossRefGoogle Scholar
  12. 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. 1994;269:30808–17.PubMedGoogle Scholar
  13. Miller BR, Press C, Daniels RW, Sasaki Y, Milbrandt J, DiAntonio A. A dual leucine kinase-dependent axon self-destruction program promotes Wallerian degeneration. Nat Neurosci. 2009;12:387–9.PubMedCrossRefGoogle Scholar
  14. Nadeau A, Grondin G, Blouin R. In situ hybridization analysis of ZPK gene expression during murine embryogenesis. J Histochem Cytochem. 1997;45:107–18.PubMedCrossRefGoogle Scholar
  15. Nakata K, Abrams B, Grill B, Goncharov A, Huang X, Chisholm AD, et al. Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development. Cell. 2005;120:407–20.PubMedCrossRefGoogle Scholar
  16. Reddy UR, Pleasure D. Cloning of a novel putative protein kinase having a leucine zipper domain from human brain. Biochem Biophys Res Commun. 1994;202:613–20.PubMedCrossRefGoogle Scholar
  17. 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. 2005;280:12732–41.PubMedCrossRefGoogle Scholar
  18. Robitaille K, Daviau A, Lachance G, Couture JP, Blouin R. Calphostin C-induced apoptosis is mediated by a tissue transglutaminase-dependent mechanism involving the DLK/JNK signaling pathway. Cell Death Differ. 2008;15:1522–31.PubMedCrossRefGoogle Scholar
  19. Xu Z, Maroney AC, Dobrzanski P, Kukekov NV, Greene LA. The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis. Mol Cell Biol. 2001;21:4713–24.PubMedCrossRefGoogle Scholar
  20. Xu Z, Kukekov NV, Greene LA. Regulation of apoptotic c-Jun N-terminal kinase signaling by a stabilization-based feed-forward loop. Mol Cell Biol. 2005;25:9949–59.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Département de BiologieUniversité de SherbrookeSherbrookeCanada