DOI: 10.1182/blood.v93.8.2645. Genetic and Pharmacological Analyses of Syk Function in IIbβ3 Signaling in Platelets

Genetic and Pharmacological Analyses of Syk Function in IIbβ3 Signaling in Platelets

10.1182/blood.v93.8.2645

Crossref journal-article

American Society of Hematology

Blood (234)

Abstract

AbstractAgonists induce inside-out IIbβ3signaling resulting in fibrinogen binding and platelet aggregation. These in turn trigger outside-in signaling resulting in further platelet stimulation. Because the Syk tyrosine kinase is activated during both phases of integrin signaling, we evaluated its role in IIbβ3 function in murine platelets rendered null for Syk by gene targeting and in human platelets incubated with piceatannol, a tyrosine kinase inhibitor reportedly selective for Syk. Both Syk null murine platelets and piceatannol-treated human platelets exhibited a partial, but statistically significant defect in activation of IIbβ3 by adenine diphosphate (ADP) ± epinephrine as assessed by fibrinogen binding. Syk null platelets adhered normally to immobilized fibrinogen, and mice with these platelets exhibited normal tail bleeding times. In contrast, piceatannol treatment of human platelets completely inhibited platelet adhesion to immobilized fibrinogen. The discrepancy in extent of integrin dysfunction between murine and human platelet models may be due to lack of specificity of piceatannol, because this compound inhibited the activity of Src and FAK as well as Syk and also reduced tyrosine phosphorylation of multiple platelet proteins. These results provide genetic evidence that Syk plays a role in IIbβ3 signaling in platelets and pharmacological evidence that, although piceatannol also inhibits IIbβ3 signaling, it does so by inhibtion of multiple protein tyrosine kinases.

Bibliography

Law, D. A., Nannizzi-Alaimo, L., Ministri, K., Hughes, P. E., Forsyth, J., Turner, M., Shattil, S. J., Ginsberg, M. H., Tybulewicz, V. L. J., & Phillips, D. R. (1999). Genetic and Pharmacological Analyses of Syk Function in îIIbÎ²3 Signaling in Platelets. Blood, 93(8), 2645â2652.

Authors 10

Debbie A. Law (first)
Lisa Nannizzi-Alaimo (additional)
Kathleen Ministri (additional)
Paul E. Hughes (additional)
Jane Forsyth (additional)
Martin Turner (additional)
Sanford J. Shattil (additional)
Mark H. Ginsberg (additional)
Victor L.J. Tybulewicz (additional)
David R. Phillips (additional)

References 32 Referenced 118

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{'key': '2020021216204428000_B15', 'first-page': '573a', 'article-title': 'Beta3 integrin knockout mice display a Glanzmann thrombasthenia phenotype.', 'volume': '90', 'author': 'Hodivala-Dilke', 'year': '1997', 'journal-title': 'Blood'} / Blood / Beta3 integrin knockout mice display a Glanzmann thrombasthenia phenotype. by Hodivala-Dilke (1997)
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Dates

Type	When
Created	5 years, 10 months ago (Oct. 14, 2019, 6:54 a.m.)
Deposited	1 year, 11 months ago (Sept. 21, 2023, 12:50 p.m.)
Indexed	1 year ago (Aug. 10, 2024, 5:46 a.m.)
Issued	26 years, 4 months ago (April 15, 1999)
Published	26 years, 4 months ago (April 15, 1999)
Published Print	26 years, 4 months ago (April 15, 1999)

Funders 0

None

BibTeX

@article{Law_1999, title={Genetic and Pharmacological Analyses of Syk Function in IIbβ3 Signaling in Platelets}, volume={93}, ISSN={0006-4971}, url={http://dx.doi.org/10.1182/blood.v93.8.2645}, DOI={10.1182/blood.v93.8.2645}, number={8}, journal={Blood}, publisher={American Society of Hematology}, author={Law, Debbie A. and Nannizzi-Alaimo, Lisa and Ministri, Kathleen and Hughes, Paul E. and Forsyth, Jane and Turner, Martin and Shattil, Sanford J. and Ginsberg, Mark H. and Tybulewicz, Victor L.J. and Phillips, David R.}, year={1999}, month=apr, pages={2645–2652} }

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