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Mouse Sphingosine Kinase 1a Is Negatively Regulated through Conventional PKC-Dependent Phosphorylation at S373 Residue

Title
Mouse Sphingosine Kinase 1a Is Negatively Regulated through Conventional PKC-Dependent Phosphorylation at S373 Residue
Authors
Oh, YS[Oh, Yong-Seok]Bae, SS[Bae, Sun Sik]Park, JB[Park, Jong Bae]Ha, SH[Ha, Sang Hoon]Ryu, SH[Ryu, Sung Ho]Suh, PG[Suh, Pann-Ghill]
DGIST Authors
Oh, YS[Oh, Yong-Seok]
Issue Date
2015-12-07
Citation
PLoS ONE, 10(12)
Type
Article
Article Type
Article
Keywords
AlanineAmino Acid SubstitutionControlled StudyEnzyme ActivationEnzyme ActivityEnzyme AssayEnzyme InhibitionEnzyme PhosphorylationEnzyme RegulationExtracellular MatrixGlutamic AcidIn Vitro StudyMouseNon-HumanPhorbol EsterPhosphopeptideProtein ExpressionProtein Kinase C (PKC)Protein Kinase C AlphaProtein Protein InteractionResidue AnalysisSerineSphingosine Kinase 1Sphingosine Kinase 1ASphingosine Kinase 2Unclassified Drug
ISSN
1932-6203
Abstract
Sphingosine kinase is a lipid kinase that converts sphingosine into sphingosine-1-phosphate, an important signaling molecule with intracellular and extracellular functions. Although diverse extracellular stimuli influence cellular sphingosine kinase activity, the molecular mechanisms underlying its regulation remain to be clarified. In this study, we investigated the phosphorylation-dependent regulation of mouse sphingosine kinase (mSK) isoforms 1 and 2. mSK1a was robustly phosphorylated in response to extracellular stimuli such as phorbol ester, whereas mSK2 exhibited a high basal level of phosphorylation in quiescent cells regardless of agonist stimulation. Interestingly, phorbol ester-induced phosphorylation of mSK1a correlated with suppression of its activity. Chemical inhibition of conventional PKCs (cPKCs) abolished mSK1a phosphorylation, while overexpression of PKCα, a cPKC isoform, potentiated the phosphorylation, in response to phorbol ester. Furthermore, an in vitro kinase assay showed that PKCα directly phosphorylated mSK1a. In addition, phosphopeptide mapping analysis determined that the S373 residue of mSK1a was the only site phosphorylated by cPKC. Interestingly, alanine substitution of S373 made mSK1a refractory to the inhibitory effect of phorbol esters, whereas glutamate substitution of the same residue resulted in a significant reduction in mSK1a activity, suggesting the significant role of this phosphorylation event. Taken together, we propose that mSK1a is negatively regulated through cPKC-dependent phosphorylation at S373 residue. © 2015 Oh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
URI
http://hdl.handle.net/20.500.11750/2800
DOI
10.1371/journal.pone.0143695
Publisher
Public Library of Science
Related Researcher
Files:
There are no files associated with this item.
Collection:
Brain and Cognitive SciencesETC1. Journal Articles


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