Document Detail

Phorbol 12-myristate 13-acetate-dependent protein kinase C delta-Tyr311 phosphorylation in cardiomyocyte caveolae.
MedLine Citation:
PMID:  18387943     Owner:  NLM     Status:  MEDLINE    
Protein kinase Cdelta (PKCdelta) activation is generally attributed to lipid cofactor-dependent allosteric activation mechanisms at membranes. However, recent studies indicate that PKCdelta also is dynamically regulated through tyrosine phosphorylation in H(2)O(2)- and phorbol 12-myristate 13-acetate (PMA)-treated cardiomyocytes. H(2)O(2) activates Src and related Src-family kinases (SFKs), which function as dual PKCdelta-Tyr(311) and -Tyr(332) kinases in vitro and contribute to H(2)O(2)-dependent PKCdelta-Tyr(311)/Tyr(332) phosphorylation in cardiomyocytes and in mouse embryo fibroblasts. H(2)O(2)-dependent PKCdelta-Tyr(311)/Tyr(332) phosphorylation is defective in SYF cells (deficient in SFKs) and restored by Src re-expression. PMA also promotes PKCdelta-Tyr(311) phosphorylation, but this is not associated with SFK activation or PKCdelta-Tyr(332) phosphorylation. Rather, PMA increases PKCdelta-Tyr(311) phosphorylation by delivering PKCdelta to SFK-enriched caveolae. Cyclodextrin treatment disrupts caveolae and blocks PMA-dependent PKCdelta-Tyr(311) phosphorylation, without blocking H(2)O(2)-dependent PKCdelta-Tyr(311) phosphorylation. The enzyme that acts as a PKCdelta-Tyr(311) kinase without increasing PKCdelta phosphorylation at Tyr(332) in PMA-treated cardiomyocytes is uncertain. Although in vitro kinase assays implicate c-Abl as a selective PKCdelta-Tyr(311) kinase, PMA-dependent PKCdelta-Tyr(311) phosphorylation persists in cardiomyocytes treated with the c-Abl inhibitor ST1571 and c-Abl is not detected in caveolae; these results effectively exclude a c-Abl-dependent process. Finally, we show that 1,2-dioleoyl-sn-glycerol mimics the effect of PMA to drive PKCdelta to caveolae and increase PKCdelta-Tyr(311) phosphorylation, whereas G protein-coupled receptor agonists such as norepinephrine and endothelin-1 do not. These results suggest that norepinephrine and endothelin-1 increase 1,2-dioleoyl-sn-glycerol accumulation and activate PKCdelta exclusively in non-caveolae membranes. Collectively, these results identify stimulus-specific PKCdelta localization and tyrosine phosphorylation mechanisms that could be targeted for therapeutic advantage.
Vitalyi O Rybin; Jianfen Guo; Zoya Gertsberg; Steven J Feinmark; Susan F Steinberg
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-04-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  283     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-06-23     Completed Date:  2008-08-18     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17777-88     Citation Subset:  IM    
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
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MeSH Terms
Cyclodextrins / pharmacology
Endothelins / metabolism
Enzyme Activation
Enzyme Inhibitors / pharmacology
Hydrogen Peroxide / pharmacology
Myocardium / metabolism
Myocytes, Cardiac / metabolism*
Norepinephrine / metabolism
Protein Kinase C-delta / chemistry*
Proto-Oncogene Proteins c-abl / antagonists & inhibitors
Rats, Wistar
Tetradecanoylphorbol Acetate / chemistry*
Tyrosine / chemistry*
Grant Support
Reg. No./Substance:
0/Cyclodextrins; 0/Endothelins; 0/Enzyme Inhibitors; 16561-29-8/Tetradecanoylphorbol Acetate; 51-41-2/Norepinephrine; 55520-40-6/Tyrosine; 7722-84-1/Hydrogen Peroxide; EC Proteins c-abl; EC Kinase C-delta

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