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Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform.

Publication ,  Journal Article
Yan, D; Jin, Y
Published in: Neuron
November 8, 2012

MAPKKK dual leucine zipper-bearing kinases (DLKs) are regulators of synaptic development and axon regeneration. The mechanisms underlying their activation are not fully understood. Here, we show that C. elegans DLK-1 is activated by a Ca(2+)-dependent switch from inactive heteromeric to active homomeric protein complexes. We identify a DLK-1 isoform, DLK-1S, that shares identical kinase and leucine zipper domains with the previously described long isoform DLK-1L but acts to inhibit DLK-1 function by binding to DLK-1L. The switch between homo- or heteromeric DLK-1 complexes is influenced by Ca(2+) concentration. A conserved hexapeptide in the DLK-1L C terminus is essential for DLK-1 activity and is required for Ca(2+) regulation. The mammalian DLK-1 homolog MAP3K13 contains an identical C-terminal hexapeptide and can functionally complement dlk-1 mutants, suggesting that the DLK activation mechanism is conserved. The DLK activation mechanism is ideally suited for rapid and spatially controlled signal transduction in response to axonal injury and synaptic activity.

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Published In

Neuron

DOI

EISSN

1097-4199

Publication Date

November 8, 2012

Volume

76

Issue

3

Start / End Page

534 / 548

Location

United States

Related Subject Headings

  • Neurology & Neurosurgery
  • Neural Inhibition
  • Mutation
  • MAP Kinase Kinase Kinases
  • Isoenzymes
  • Humans
  • Enzyme Activation
  • Calcium
  • Caenorhabditis elegans Proteins
  • Caenorhabditis elegans
 

Citation

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Yan, D., & Jin, Y. (2012). Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform. Neuron, 76(3), 534–548. https://doi.org/10.1016/j.neuron.2012.08.043
Yan, Dong, and Yishi Jin. “Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform.Neuron 76, no. 3 (November 8, 2012): 534–48. https://doi.org/10.1016/j.neuron.2012.08.043.
Yan, Dong, and Yishi Jin. “Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform.Neuron, vol. 76, no. 3, Nov. 2012, pp. 534–48. Pubmed, doi:10.1016/j.neuron.2012.08.043.
Journal cover image

Published In

Neuron

DOI

EISSN

1097-4199

Publication Date

November 8, 2012

Volume

76

Issue

3

Start / End Page

534 / 548

Location

United States

Related Subject Headings

  • Neurology & Neurosurgery
  • Neural Inhibition
  • Mutation
  • MAP Kinase Kinase Kinases
  • Isoenzymes
  • Humans
  • Enzyme Activation
  • Calcium
  • Caenorhabditis elegans Proteins
  • Caenorhabditis elegans