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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3346-3352
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
C-terminal peptide of thrombospondin-1 induces
platelet aggregation through the Fc receptor  -chain-associated
signaling pathway and by agglutination
David Tulasne,
Barbi A. Judd,
Mette Johansen,
Naoki Asazuma,
Denise Best,
Eric J. Brown,
Mark Kahn,
Gary A. Koretzky, and
Steve P. Watson
From the Department of Pharmacology, University of
Oxford, United Kingdom; Abramson Family Cancer Center
and Department of Medicine, University of Pennsylvania, Philadelphia;
and the Program in Host-Pathogen Interactions, University of
California, San Francisco.
A peptide from the C-terminal domain of thrombospondin-1
(Arg-Phe-Tyr-Val-Val-Met-Trp-Lys; known as 4N1-1) has been reported to
induce platelet aggregation and to bind to the integrin-associated protein (IAP), which is also known as CD47. In this study, it was
discovered that 4N1-1 or its derivative peptide, 4N1K, induces rapid phosphorylation of the Fc receptor (FcR)  chain, Syk,
SLP-76, and phospholipase C 2 in human platelets. A specific
inhibitor of Src family kinases, 4-amino-4-(4-methylphenyl)-7-(t-butyl) pyrazola[3,4-d]pyrimidine, prevented phosphorylation of these proteins, abolished platelet secretion, and reduced aggregation by
approximately 50%. A similar inhibition of aggregation to 4N1-1 was
obtained in the presence of Arg-Gly-Asp-Ser in mouse platelets deficient in FcR chain or SLP-76 and in patients with type I Glanzmann thrombasthenia. These results show that 4N1-1 signals through
a pathway similar to that used by the collagen receptor glycoprotein
(GP) VI. The  IIb 3-independent aggregation induced by 4N1-1 was
also observed in fixed platelets and platelets from patients with
Bernard-Soulier syndrome, which are deficient in GPIb. Surprisingly,
the ability of 4N1-1 to stimulate aggregation and tyrosine
phosphorylation was not altered in platelets pretreated with anti-IAP
antibodies and in IAP-deficient mice. These results show that the
C-terminal peptide of thrombospondin induces platelet aggregation
through the FcR -chain signaling pathway and through agglutination.
The latter pathway is independent of signaling events and does not use
GPIb or IIb3. Neither of these pathways is mediated by IAP.
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