title: Thrombspondin acts via integrin-associated protein to activate the platelet integrin alphaIIbbeta3.
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.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chung
authors.forename: A G
authors.initials: AG
authors.lastname: Gao
authors.forename: W A
authors.initials: WA
authors.lastname: Frazier
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology; D002846:Chromatography, Affinity; D004792:Enzyme Precursors / Q000378:metabolism; D005340:Fibrinogen; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D009637:Masoprocol / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D037342:Pertussis Toxin; D015539:Platelet Activation; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D000072377:Syk Kinase; D019699:Thrombospondins; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019699:Thrombospondins; D010566:Virulence Factors, Bordetella; D009637:Masoprocol; D005340:Fibrinogen; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D007213:Indomethacin