Role of the p110δ PI 3-kinase in integrin and ITAM receptor signalling in platelets

We have investigated the function of the p110δ catalytic subunit of phosphoinositide 3-kinase (PI 3-kinase) in platelets using p110δ knock-out (p110δ–/–) mice and p110δ knock-in (p110δD910A/D910A) mice, which express a catalytically inactive form of the enzyme. Aggregation to threshold concentrations of the GPVI-specific agonist, CRP, was partially reduced in p110δ–/– and p110δD910A/D910A platelets. This inhibition was overcome by higher concentrations of CRP. The degree of inhibition was considerably weaker than that induced by LY294002 and wortmannin, which inhibit all isoforms of PI 3-kinase. p110δ–/– platelets showed decreased spreading on fibrinogen- or von Willebrand factor (VWF)-coated surfaces under static conditions, whereas they spread normally on collagen. LY294002 had a more pronounced inhibitory effect on spreading on all three surfaces. Adhesion and aggregate formation of p110δ–/– platelets to collagen or fibrinogen/VWF at intermediate/high rates of shear were normal. This study demonstrates...