Thrombospondin-1 acts via IAP/CD47 to synergize with collagen in alpha2beta1-mediated platelet activation.
Integrin-associated protein (IAP; or CD47) is a receptor for the cell binding domain (CBD) of thrombospondin-1 (TS1). In platelets, IAP associates with and regulates the function of alphaIIbbeta3 integrin (Chung et al, J Biol Chem 272:14740, 1997). We test here the possibility that CD47 may also modulate the function of platelet integrin alpha2beta1, a collagen receptor. The CD47 agonist peptide, 4N1K (KRFYVVMWKK), derived from the CBD, synergizes with soluble collagen in aggregating platelet-rich plasma. 4N1K and intact TS1 also induce the aggregation of washed, unstirred platelets on immobilized collagen with a rapid increase in tyrosine phosphorylation. The effects of TS1 and 4N1K on platelet aggregation are absolutely dependent on IAP, as shown by the use of platelets from IAP-/- mice. Prostaglandin E1 (PGE1) prevents 4N1K-dependent aggregation on immobilized collagen but does not inhibit the 4N1K peptide stimulation of alpha2beta1-dependent platelet spreading. Finally, a detergent-stable, physical association of IAP and alpha2beta1 integrin is detected by coimmunoprecipitation. These results imply a role for IAP and TS1 in the early activation of platelets upon adhesion to collagen.
Department of Biochemistry and Molecular Biophysics and Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
J
J
Chung
X Q
XQ
Wang
F P
FP
Lindberg
W A
WA
Frazier
D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000187:drug effects* / Q000494:pharmacology; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000187:drug effects* / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology*; D003902:Detergents / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000502:physiology*; D046911:Macromolecular Substances; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects*; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D038981:Receptors, Collagen; D019700:Thrombospondin 1 / Q000494:pharmacology*
C120273:4N1K peptide; D015703:Antigens, CD; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; C497895:Cd47 protein, mouse; D003902:Detergents; D016023:Integrins; D046911:Macromolecular Substances; D009842:Oligopeptides; D010446:Peptide Fragments; D038981:Receptors, Collagen; D019700:Thrombospondin 1; C082835:thrombin receptor peptide (42-47); D003094:Collagen; C058161:glycyl-arginyl-glycyl-aspartyl-seryl-proline; C058347:glycyl-arginyl-glycyl-glutamyl-seryl-proline; D000527:Alprostadil