New Modularity of DAP-Kinases: Alternative Splicing of the DRP-1 Gene Produces a ZIPk-Like Isoform
Open Access
- 8 March 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (2), e17344
- https://doi.org/10.1371/journal.pone.0017344
Abstract
DRP-1 and ZIPk are two members of the Death Associated Protein Ser/Thr Kinase (DAP-kinase) family, which function in different settings of cell death including autophagy. DAP kinases are very similar in their catalytic domains but differ substantially in their extra-catalytic domains. This difference is crucial for the significantly different modes of regulation and function among DAP kinases. Here we report the identification of a novel alternatively spliced kinase isoform of the DRP-1 gene, termed DRP-1β. The alternative splicing event replaces the whole extra catalytic domain of DRP-1 with a single coding exon that is closely related to the sequence of the extra catalytic domain of ZIPk. As a consequence, DRP-1β lacks the calmodulin regulatory domain of DRP-1, and instead contains a leucine zipper-like motif similar to the protein binding region of ZIPk. Several functional assays proved that this new isoform retained the biochemical and cellular properties that are common to DRP-1 and ZIPk, including myosin light chain phosphorylation, and activation of membrane blebbing and autophagy. In addition, DRP-1β also acquired binding to the ATF4 transcription factor, a feature characteristic of ZIPk but not DRP-1. Thus, a splicing event of the DRP-1 produces a ZIPk like isoform. DRP-1β is highly conserved in evolution, present in all known vertebrate DRP-1 loci. We detected the corresponding mRNA and protein in embryonic mouse brains and in human embryonic stem cells thus confirming the in vivo utilization of this isoform. The discovery of module conservation within the DAPk family members illustrates a parsimonious way to increase the functional complexity within protein families. It also provides crucial data for modeling the expansion and evolution of DAP kinase proteins within vertebrates, suggesting that DRP-1 and ZIPk most likely evolved from their ancient ancestor gene DAPk by two gene duplication events that occurred close to the emergence of vertebrates.Keywords
This publication has 35 references indexed in Scilit:
- Negative regulation of Caenorhabditis elegans epidermal damage responses by death-associated protein kinaseProceedings of the National Academy of Sciences, 2009
- The Draft Genome of Ciona intestinalis : Insights into Chordate and Vertebrate OriginsScience, 2002
- DAP-kinase induces apoptosis by suppressing integrin activity and disrupting matrix survival signalsThe Journal of cell biology, 2002
- The DAP-kinase family of proteins: study of a novel group of calcium-regulated death-promoting kinasesBiochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2002
- DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell deathThe Journal of cell biology, 2002
- HeLa ZIP kinase induces diphosphorylation of myosin II regulatory light chain and reorganization of actin filaments in nonmuscle cellsOncogene, 2001
- Dlk/ZIP kinase-induced apoptosis in human medulloblastoma cells: requirement of the mitochondrial apoptosis pathwayBritish Journal of Cancer, 2001
- Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling dimerization and calmodulin bindingThe EMBO Journal, 2001
- DAP Kinase—A Proapoptotic Gene That Functions as a Tumor SuppressorExperimental Cell Research, 2001
- C-terminal truncation of Dlk/ZIP kinase leads to abrogation of nuclear transport and high apoptotic activityOncogene, 1999