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PMID:17416590

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Citation

Isenberg, JS, Jia, Y, Fukuyama, J, Switzer, CH, Wink, DA and Roberts, DD (2007) Thrombospondin-1 inhibits nitric oxide signaling via CD36 by inhibiting myristic acid uptake. J. Biol. Chem. 282:15404-15

Abstract

Although CD36 is generally recognized to be an inhibitory signaling receptor for thrombospondin-1 (TSP1), the molecular mechanism for transduction of this signal remains unclear. Based on evidence that myristic acid and TSP1 each modulate endothelial cell nitric oxide signaling in a CD36-dependent manner, we examined the ability of TSP1 to modulate the fatty acid translocase activity of CD36. TSP1 and a CD36 antibody that mimics the activity of TSP1 inhibited myristate uptake. Recombinant TSP1 type 1 repeats were weakly inhibitory, but an anti-angiogenic peptide derived from this domain potently inhibited myristate uptake. This peptide also inhibited membrane translocation of the myristoylated CD36 signaling target Fyn and activation of Src family kinases. Myristate uptake stimulated cGMP synthesis via endothelial nitric-oxide synthase and soluble guanylyl cyclase. CD36 ligands blocked myristate-stimulated cGMP accumulation in proportion to their ability to inhibit myristate uptake. TSP1 also inhibited myristate-stimulated cGMP synthesis by engaging its receptor CD47. Myristate stimulated endothelial and vascular smooth muscle cell adhesion on type I collagen via the NO/cGMP pathway, and CD36 ligands that inhibit myristate uptake blocked this response. Therefore, the fatty acid translocase activity of CD36 elicits proangiogenic signaling in vascular cells, and TSP1 inhibits this response by simultaneously inhibiting fatty acid uptake via CD36 and downstream cGMP signaling via CD47.

Links

PubMed PMC2430148 Online version:10.1074/jbc.M701638200

Keywords

Antigens, CD36/metabolism; Antigens, CD47/metabolism; Biological Transport, Active/drug effects; Biological Transport, Active/physiology; Cells, Cultured; Cyclic GMP/metabolism; Endothelial Cells/cytology; Endothelial Cells/metabolism; Fatty Acid Transport Proteins/metabolism; Humans; Myristic Acid/metabolism; Neovascularization, Physiologic/drug effects; Neovascularization, Physiologic/physiology; Nitric Oxide/metabolism; Nitric Oxide Synthase Type III/metabolism; Peptides/metabolism; Peptides/pharmacology; Proto-Oncogene Proteins c-fyn/metabolism; Signal Transduction/drug effects; Signal Transduction/physiology; Thrombospondin 1/metabolism; Thrombospondin 1/pharmacology; src-Family Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CD36

involved_in

GO:0019934: cGMP-mediated signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CD36

involved_in

GO:0001954: positive regulation of cell-matrix adhesion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CD36

involved_in

GO:0007263: nitric oxide mediated signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CD36

involved_in

GO:0044539: long-chain fatty acid import into cell

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSP1

involved_in

GO:0001953: negative regulation of cell-matrix adhesion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSP1

involved_in

GO:0010754: negative regulation of cGMP-mediated signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSP1

involved_in

GO:0010751: negative regulation of nitric oxide mediated signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSP1

involved_in

GO:0010748: negative regulation of long-chain fatty acid import across plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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