A hierarchical network of Src, Syk, Btk and PKC controls GPVI-dependent human platelet activation

Introduction Src family kinases (SFKs), spleen tyrosine kinase (Syk) and Bruton´s tyrosine kinase (Btk) play central roles in the activation of immune cells and platelets. Glycoprotein VI (GPVI) stimulation activates platelet SFKs, Syk and Btk resulting in phospholipase Cγ (PLCγ) and protein kinase C (PKC) activation. However, their functional hierarchy and cross-talk in platelets are not well understood. Recently, selective Syk and Btk inhibitors showed potency to treat thrombosis, cancers and immuno-inflammatory diseases. Using such inhibitors, we investigated hierarchy of Syk, Btk and PKC with respect to their downstream effectors in GPVI-stimulated human platelets.