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Caroline Pampolina, Archibald McNicol
Streptococcus sanguis-induced platelet activation involves two waves of tyrosine phosphorylation mediated by FcRIIA and IIb3
The low-affinity IgG receptor, FcRIIA, has been implicated in Streptococcus sanguis-induced platelet aggregation. Therefore, it is likely that signal transduction is at least partly mediated by FcRIIA activation and a tyrosine kinase-dependent pathway. In this study the signal transduction mechanisms associated with platelet activation in response to the oral bacterium, S. sanguis were characterised. In the presence of IgG, S. sanguis strain 201778 caused the tyrosine phosphorylation of FcRIIA 30s following stimulation, which led to the phosphorylation of Syk, LAT, and PLC2. These early events were dependent on Src family kinases but independent of either TxA2 or the engagement of the IIb3 integrin. During the lag phase prior to platelet aggregation, FcRIIA, Syk, LAT, and PLC2 were each dephosphorylated, but were re-phosphorylated as aggregation occurred. Platelet stimulation by 201778 also induced the tyrosine phosphorylation of PECAM-1, an ITIM-containing receptor that recruits protein tyrosine phosphatases. PECAM-1 co-precipitated with the protein tyrosine phosphatase SHP-1 in the lag phase. SHP-1 was also maximally tyrosine phosphorylated during this phase, suggesting a possible role for SHP-1 in the observed dephosphorylation events. As aggregation occurred, SHP-1 was dephosphorylated, while FcRIIA, Syk, LAT, and PLC2 were rephosphorylated in an RGDS-sensitive, and therefore IIb3-dependent, manner. Additionally, TxA2 release, 5-hydroxytryptamine secretion and phosphatidic acid formation were all blocked by RGDS. Aspirin also abolished these events, but only partially inhibited IIb3 -mediated re-phosphorylation. Therefore, S. sanguis -bound IgG cross links FcRIIA and initiates a signaling pathway that is down-regulated by PECAM-1-bound SHP-1. Subsequent engagement of IIb3 leads to SHP-1 dephosphorylation permiting a second wave of signaling leading to TxA2 release and consequent platelet aggregation.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 93, 05/2005
Pages: 932 - 939