PI 3-Kinase p110β Regulation of Platelet Integrin αIIbβ3

Abstract

Hemopoietic cells express relatively high levels of the type I phosphoinositide (PI) 3-kinase isoforms, with p110delta and gamma exhibiting specialized signaling functions in neutrophils, monocytes, mast cells, and lymphocytes. In platelets, p110beta appears to be the dominant PI 3-kinase isoform regulating platelet activation, irrespective of the nature of the primary platelet activating stimulus. Based on findings with isoform-selective p110beta pharmacological inhibitors and more recently with p110beta-deficient platelets, p110beta appears to primarily signal downstream of G(i)- and tyrosine kinase-coupled receptors. Functionally, inhibition of p110beta kinase function leads to a marked defect in integrin alpha(IIb)beta adhesion and reduced platelet thrombus formation in vivo. This defect in platelet adhesive function is not associated with increased bleeding, suggesting that therapeutic targeting of p110beta may represent a safe approach to reduce thrombotic complications in patients with cardiovascular disease.