| First Author | Wannemacher KM | Year | 2010 |
| Journal | Blood | Volume | 116 |
| Issue | 25 | Pages | 5707-15 |
| PubMed ID | 20855865 | Mgi Jnum | J:167397 |
| Mgi Id | MGI:4868167 | Doi | 10.1182/blood-2010-04-279943 |
| Citation | Wannemacher KM, et al. (2010) Diminished contact-dependent reinforcement of Syk activation underlies impaired thrombus growth in mice lacking Semaphorin 4D. Blood 116(25):5707-15 |
| abstractText | We recently reported that Semaphorin 4D (Sema4D) and its receptors are expressed on the platelet surface and showed that Sema4D((-/-)) mice have a selective defect in collagen-induced platelet aggregation and an impaired vascular injury response. Here we investigated the mechanisms involved, tested the role of platelet-platelet contacts in Sema4D-mediated events, and examined the relationship between Sema4D-dependent signaling and integrin alpha(IIb)beta(3) outside-in signaling. The results show that spleen tyrosine kinase (Syk) activation, an early step in collagen signaling via the glycoprotein VI (GPVI)/FcRgamma complex, is greatly reduced in Sema4D((-/-)) platelets and can be restored by adding soluble Sema4D. Earlier events, including FcRgamma phosphorylation, occur normally; later events are impaired. In contrast, when engagement of alpha(IIb)beta(3) was blocked, Sema4D((-/-)) and control platelets were indistinguishable in assays of Syk activation, adhesion, spreading on collagen, and activation of alpha(IIb)beta(3). Finally, we found that, unlike the Sema4D knockout, alpha(IIb)beta(3) blockade inhibited FcRgamma phosphorylation and that stimulating aggregation with Mn(2+) failed to normalize Syk activation in the absence of Sema4D. Collectively, these results show that alpha(IIb)beta(3) and Sema4D jointly promote collagen responses by amplifying Syk activation, partly by forming integrin-mediated contacts that enable the binding of Sema4D to its receptors and partly through integrin outside-in signaling. These 2 processes are interdependent, but distinguishable. |
