Thrombospondin-1 induces platelet activation through CD36-dependent inhibition of the cAMP/protein kinase A signaling cascade
Roberts, Wayne Magwenzi, S. Aburima, Ahmed Naseem, Khalid M.
Roberts, Wayne
Magwenzi, S.
Aburima, Ahmed
Naseem, Khalid M.
Publication Date
2010
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Keywords
Adenylate Cyclase, Antagonists & inhibitors, Alprostadil, pharmacology, Antigens, CD36, Metabolism, Blood platelets, Cytology, Drug effects, Enzymology, Cyclic AMP, Cyclic AMP-dependent protein kinases, Enzyme activation, Hemorheology, Humans, Peptides, Platelet activation, Platelet aggregation, Protein binding, Signal transduction, Thrombospondin 1, src-Family kinases, REF 2014
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Abstract
Cyclic adenosine monophosphate (cAMP)-dependent signaling modulates platelet function at sites of vascular injury. Here we show that thrombospondin-1 (TSP-1) prevents cAMP/protein kinase A (PKA) signaling through a CD36-dependent mechanism. Prostaglandin E(1) (PGE(1)) induced a robust inhibition of both platelet aggregation and platelet arrest under physiologic conditions of flow. Exogenous TSP-1 reduced significantly PGE(1)-mediated inhibition of both platelet aggregation and platelet arrest. TSP-1 prevented PGE(1)-stimulated cAMP accrual and phosphorylation of PKA substrates, through a mechanism requiring phosphodiesterase3A. TSP-1 also inhibited VASP phosphorylation stimulated by the nonhydrolyzable cAMP analog, 8-bromo-cAMP, indicating that it may regulate cAMP-mediated activation of PKA. The inhibitory effect of TSP-1 on cAMP signaling could be reproduced with a peptide possessing a CD36 binding sequence of TSP-1, while the effects of TSP-1 were prevented by a CD36 blocking antibody. TSP-1 and the CD36 binding peptide induced phosphorylation of Src kinases, p38 and JNK. Moreover, inhibition of Src kinases blocked TSP-1-mediated regulation of cAMP concentrations and the phosphorylation of VASP, indicating that TSP-1 modulated the cAMP/PKA signaling events through a tyrosine kinase-dependent pathway downstream of CD36. These data reveal a new role for TSP-1 in promoting platelet aggregation through modulation of the cAMP-PKA signaling pathway.
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Roberts, W., Magwenzi, S., Aburima, A., Naseem, K. M. (2010) Thrombospondin-1 induces platelet activation through CD36-dependent inhibition of the cAMP/protein kinase A signaling cascade. Blood, 116(20), 4297-4306.
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