Polymorphisms in alpha IIb beta 3 are important genetic factors that alter platelet biology and have been associated with susceptibility to thromboembolic disorders. To define the molecular mechanisms that lead to variance in thrombotic diathesis dictated by the beta 3 polymorphism, we examined regulation of intracellular signaling by alpha IIb beta 3, and studied the effects of a common beta subunit PlA2 polymorphism. We found that PP2A regulates alpha IIb beta 3 control of the ERK signaling in a polymorphism specific fashion. In CHO cells, exogenous expression of alpha IIb beta 3 reduced ATP-stimulated ERK phosphorylation and more so for PlA2 than PlA1. Interestingly, reduced level of ERK phosphorylation correlated with an increase in PP2A activity, with higher activity associated with PlA2 than PlA1. We tested the effect of PP2A on alpha IIb beta 3-dependent adhesion, and found that PP2A overexpression increased cell adhesion, while phosphatase inhibitors decreased cell adhesion. We propose that PlA2 alters cell signaling at least in part by increasing beta 3-associated PP2A activity. (C) 2007 Elsevier Inc. All rights reserved.