Transforming growth factor beta1 enhances platelet aggregation through a non-transcriptional effect on the fibrinogen receptor.
Upon activation, platelets store and release large amounts of the peptide transforming growth factor beta1 (TGFbeta1). The released TGFbeta1 can then act on nearby vascular cells to mediate subsequent vessel repair. In addition, TGFbeta1 may circulate to bone marrow and regulate megakaryocyte activity. It is not known what effect, if any, TGFbeta1 has on platelets. Adult TGFbeta1-deficient mice exhibit thrombocythemia and a mild bleeding disorder that is shown to result from faulty platelet aggregation. TGFbeta1-deficient platelets are shown to contain functional receptors, and preincubation with recombinant TGFbeta1 improves aggregation, demonstrating that TGFbeta1 plays an active role in platelet aggregation. TGFbeta1-deficient platelets fail to retain bound fibrinogen in response to aggregation agonists, but they possess normal levels of the alpha(IIb)/beta(3) fibrinogen receptor. Signaling from agonist receptors is normal because the platelets change shape, produce thromboxane A(2), and present P-selectin in response to stimulation. Consequently, activation and maintenance of alpha(IIb)/beta(3) into a fibrinogen-binding conformation is impaired in the absence of TGFbeta1. 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 TGFbeta1 signaling pathway that enhances the activation and maintenance of integrin function.
Hoying
J B
JB
Program of Excellence in Molecular Biology, Department of Molecular Genetics, University of Cincinnati, Cincinnati, Ohio 45267-0524, USA.
Yin
M
M
Diebold
R
R
Ormsby
I
I
Becker
A
A
Doetschman
T
T
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D003433:Crosses, Genetic; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005340:Fibrinogen / Q000378:metabolism; D066298:In Vitro Techniques; D008533:Megakaryocytes / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016513:Mice, SCID; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology*; D010976:Platelet Count; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology*; D015398:Signal Transduction; D013917:Thrombin / Q000494:pharmacology; D013921:Thrombocytopenia / Q000097:blood / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000494:pharmacology* / Q000502:physiology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016212:Transforming Growth Factor beta; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D003094:Collagen; D013917:Thrombin