Please use this identifier to cite or link to this item: 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
Appears in Collections:Aurora harvest 2
Molecular and Biomedical Science publications

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