Transforming growth factor β1 enhances platelet aggregation through a non-transcriptional effect on the fibrinogen receptor

James B. Hoying, Moying Yin, Ronald Diebold, Ilona Ormsby, Ann Becker, Thomas Doetschman

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Upon activation, platelets store and release large amounts of the peptide transforming growth factor β1 (TGFβ1). The released TGFβ1 can then act on nearby vascular cells to mediate subsequent vessel repair. In addition, TGFβ1 may circulate to bone marrow and regulate megakaryocyte activity. It is not known what effect, if any, TGFβ1 has on platelets. Adult TGFβ1-deficient mice exhibit thrombocythemia and a mild bleeding disorder that is shown to result from faulty platelet aggregation. TGFβ1-deficient platelets are shown to contain functional receptors, and preincubation with recombinant TGFβ1 improves aggregation, demonstrating that TGFβ1 plays an active role in platelet aggregation. TGFβ1-deficient platelets fail to retain bound fibrinogen in response to aggregation agonists, but they possess normal levels of the α(IIb)/β3 fibrinogen receptor. Signaling from agonist receptors is normal because the platelets change shape, produce thromboxane A2, and present P-selectin in response to stimulation. Consequently, activation and maintenance of α(IIb)/β3 into a fibrinogen-binding conformation is impaired in the absence of TGFβ1. 4-Phorbol 12-myristate 13- acetate treatment and protein kinase C activity measurements suggest a defect downstream of protein kinase C in its activation cascade. Because platelets lack nuclei, these data demonstrate for the first time a non- transcriptionally mediated TGFβ1 signaling pathway that enhances the activation and maintenance of integrin function.

Original languageEnglish (US)
Pages (from-to)31008-31013
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number43
DOIs
StatePublished - Oct 22 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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