Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform.
Journal Article (Journal Article)
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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Duke Authors
Cited Authors
- Yan, D; Jin, Y
Published Date
- November 8, 2012
Published In
Volume / Issue
- 76 / 3
Start / End Page
- 534 - 548
PubMed ID
- 23141066
Pubmed Central ID
- PMC3508676
Electronic International Standard Serial Number (EISSN)
- 1097-4199
Digital Object Identifier (DOI)
- 10.1016/j.neuron.2012.08.043
Language
- eng
Conference Location
- United States