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https://hdl.handle.net/2440/27524
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Type: | Journal article |
Title: | Sphingosine activates protein kinase A type II by a novel cAMP-independent mechanism |
Author: | Ma, Y. Pitson, S. Hercus, T. Murphy, J. Lopez, A. Woodcock, J. |
Citation: | Journal of Biological Chemistry, 2005; 280(28):26011-26017 |
Publisher: | Amer Soc Biochemistry Molecular Biology Inc |
Issue Date: | 2005 |
ISSN: | 0021-9258 1083-351X |
Statement of Responsibility: | Yuefang Ma, Stuart Pitson, Timothy Hercus, Jane Murphy, Angel Lopez, and Joanna Woodcock |
Abstract: | Protein kinase A (PKA) has long been recognized as playing a major role in many regulatory processes in cells through its activation by the ubiquitous second messenger cAMP. We show here a novel mode of activation of PKA type II that is independent of cAMP and is, instead, dependent on sphingosine. PKA type II is specifically activated by sphingosine and its analog, dimethylsphingosine, but not by sphingosine-1-phosphate or other lipids. Like cAMP, sphingosine activates PKA holoenzyme but not the catalytic subunit alone, suggesting that the activation is mediated by the regulatory subunits. However, sphingosine-activated PKA, but not cAMP-activated PKA, is inhibited by phosphatidylserine, suggesting a distinct mechanism of activation. Furthermore, unlike cAMP, sphingosine does not induce the dissociation of PKA holoenzyme into catalytic and regulatory subunits. Modulation of sphingosine levels in vivo results in alteration in basal membrane-associated PKA activity consistent with a direct effect of membrane sphingosine on PKA type II. Importantly, sphingosine-dependent but not cAMP-dependent activation of PKA specifically phosphorylates Ser58 of the multifunctional adapter protein 14-3-3zeta, promoting the conversion of dimeric 14-3-3 to a monomeric state, thus potentially modulating several biological functions. These results define a new mode of PKA activation that is sphingosine-dependent and mechanistically different from the classical cAMP-dependent activation of PKA. Furthermore, they suggest that stimuli that induce sphingosine accumulation and modulate phospholipid content at the cell membrane have the potential to activate PKA, thereby inducing the phosphorylation of distinct substrates and biological activities. |
Keywords: | Myocardium COS Cells NIH 3T3 Cells Cell Membrane Fibroblasts Animals Mice, Inbred BALB C Cattle Mice Ethanolamines Sphingosine Phosphotransferases (Alcohol Group Acceptor) Cyclic AMP-Dependent Protein Kinases Phospholipids Phosphatidylserines Lysophospholipids Serine 14-3-3 Proteins Cyclic AMP Immunoblotting Chromatography, Ion Exchange Electrophoresis, Polyacrylamide Gel Signal Transduction Gene Expression Regulation, Enzymologic Enzyme Activation Catalytic Domain Protein Structure, Tertiary Substrate Specificity Dimerization Phosphorylation Dose-Response Relationship, Drug Kinetics Lipid Metabolism Cyclic AMP-Dependent Protein Kinase Type II Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit |
Rights: | © 2005 by The American Society for Biochemistry and Molecular Biology, Inc. |
DOI: | 10.1074/jbc.M409081200 |
Published version: | http://dx.doi.org/10.1074/jbc.m409081200 |
Appears in Collections: | Aurora harvest 2 Molecular and Biomedical Science publications |
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