The N-terminal SH2 domain of Syk is required for (hem)ITAM, but not integrin, signaling in mouse platelets.
Blood
; 125(1): 144-54, 2015 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-25352128
ABSTRACT
We have used a novel knockin mouse to investigate the effect of disruption of phosphotyrosine binding of the N-terminal SH2 domain of Syk on platelet activation by GPVI, CLEC-2, and integrin αIIbß3. The Syk(R41Afl/fl) mouse was crossed to a PF4-Cre(+) mouse to induce expression of the Syk mutant in the megakaryocyte/platelet lineage. Syk(R41Afl/fl;PF4-Cre) mice are born at approximately 50% of the expected frequency and have a similar phenotype to Syk(fl/fl;PF4-Cre) mice, including blood-lymphatic mixing and chyloascites. Anastomosis of the venous and lymphatic vasculatures can be seen in the mesenteric circulation accounting for rapid and continuous mixing of the 2 vasculatures. Platelet activation by CLEC-2 and GPVI is abolished in Syk(R41Afl/fl;PF4-Cre) platelets. Syk phosphorylation on Tyr519/20 is blocked in CLEC-2-stimulated platelets, suggesting a model in which binding of Syk via its N-terminal SH2 domain regulates autophosphorylation. In contrast, outside-in signaling by integrin αIIbß3 is not altered, but it is inhibited in the presence of inhibitors of Src and Syk tyrosine kinases. These results demonstrate that αIIbß3 regulates Syk through an ITAM-independent pathway in mice and provide novel insight into the course of events underlying Syk activation and hemITAM phosphorylation by CLEC-2.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Plaquetas
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Proteínas Tirosina Quinases
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Glicoproteínas da Membrana de Plaquetas
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Complexo Glicoproteico GPIIb-IIIa de Plaquetas
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Lectinas Tipo C
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Peptídeos e Proteínas de Sinalização Intracelular
Limite:
Animals
Idioma:
En
Revista:
Blood
Ano de publicação:
2015
Tipo de documento:
Article