Abstract
Integrin-associated protein (IAP or CD47) is a receptor for the cell/platelet-binding domain (CBD) of thrombospondin-1 (TS1), the most abundant protein of platelet alpha granules. Although it associates with alphaIIbbeta3, IAP has no known function in platelets. TS1, the CBD, and an IAP agonist peptide (4N1K) from the CBD of TS1 activate the platelet integrin alphaIIbbeta3, resulting in platelet spreading on immobilized fibrinogen, stimulation of platelet aggregation, and enhanced tyrosine phosphorylation of focal adhesion kinase. Furthermore, 4N1K peptide selectively stimulates the phosphorylation of LYN and SYK and their association with FAK. The phosphorylation of SYK is blocked by pertussis toxin, implicating a Gi-like heterotrimeric G protein. IAP solublized from membranes of unstimulated platelets binds specifically to an affinity column of 4N1K peptide. Both alphaIIb and beta3 integrin subunits and c-Src bind along with IAP. This complex of proteins is also detected with immunoprecipitation. Activation of platelets with the agonist peptide 4N1K results in the association of FAK with the IAP-alphaIIbbeta3 complex. Thus an important function of TS1 in platelets is that of a secreted costimulator of alphaIIbbeta3 whose unique properties result in its localization to the platelet surface and the fibrin clot.
Highlights
Integrin-associated protein (IAP)1 is important in host defense where it is required for integrin-dependent functions of polymorphonuclear leukocytes (1)
We have recently discovered that IAP is a receptor for the COOH-terminal cell binding domain (CBD) of the thrombospondins (TSs) including TS1 (5), the most abundant protein of platelet ␣ granules (6)
We find that TS1, the recombinant CBD, and active IAP binding peptides such as 4N1K (Fig. 1B) stimulate the spreading of platelets adherent to fibrinogen
Summary
Integrin-associated protein (IAP)1 is important in host defense where it is required for integrin-dependent functions of polymorphonuclear leukocytes (1). We find that IAP stimulation by its agonist 4N1K activates ␣IIb3 as judged by enhanced binding of the conformationally sensitive mAb PAC-1 (13–15) resulting in spreading of platelets on fibrinogen-coated surfaces, aggregation of stirred platelets (12), and assembly of a signaling complex containing IAP, the integrin, c-Src, FAK, and SYK.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
