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Platelet Aggregation Pathway
Eph kinases are a family of receptor tyrosine kinases with an extracellular domain that binds their ligand, the ephrins, and an intracellular kinase domain. The ephrins are also expressed on the cell surface, so that interaction between Eph kinases and ephrins occurs at the interface between neighboring cells. Binding of ephrins to Eph kinases stimulates signaling in both directions across the interface between cells, in both the receptor expressing and the ligand expressing cells. Eph kinases and ephrins are involved in several biological processes, and their role in neuronal development has been extensively examined. Both Eph kinases (EphA4 and EphB1) and ephrins (ephrinB1) are expressed on platelets, suggesting that activation of eph kinases by ephrins may play a role in clotting when platelets are brought into close proximity in the developing clot. Platelet activation progresses in stages with an early stage that is stimulated by soluble factors like ADP acting through GPCRs and is reversible and later stages with stronger interaction between platelets that may require interaction between Eph kinases and ephrins. One of the molecular targets of signaling by Eph kinases and ephrins is the actin cytoskeleton, which also plays a role in platelet activation. Clustering Eph kinases or ephrins in platelets stimulated cytoskeletal changes as well as other markers of platelet activation during clotting such as secretion of alpha-granules to release clotting factors. Clustering ephrins together activated Rap1b, a ras gene family member that may regulate integrins. Platelet activation caused Eph kinases to bind to src family members Fyn and Lyn and also with the cell adhesion molecule L1. Failure of the ephrins/Eph kinase pathway to function normally in platelets may result in loosely associated platelets and improper clot formation. Eph kinases and ephrins are also expressed on the vascular wall by endothelial cells, suggesting that signaling by these proteins may also play a role in the interaction of platelets with the vascular wall and clot formation in the vasculature. (NCI Thesaurus/BIOCARTA)
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