title: Increased activity of phosphatase PP2A in the presence of the PlA2 polymorphism of alphaIIbbeta3.
abstract: Polymorphisms in alphaIIbbeta3 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 beta3 polymorphism, we examined regulation of intracellular signaling by alphaIIbbeta3, and studied the effects of a common beta subunit PlA2 polymorphism. We found that PP2A regulates alphaIIbbeta3 control of the ERK signaling in a polymorphism specific fashion. In CHO cells, exogenous expression of alphaIIbbeta3 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 alphaIIbbeta3-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 beta3-associated PP2A activity.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Huili
authors.initials: H
authors.lastname: Wang
authors.forename: Bin
authors.initials: B
authors.lastname: Yan
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Satterwhite
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.forename: Pascal J
authors.initials: PJ
authors.lastname: Goldschmidt-Clermont
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D016466:CHO Cells / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D054501:Group II Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D054466:Phospholipases A1 / Q000235:genetics / Q000378:metabolism; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic
chemical_list: D004791:Enzyme Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000255:Adenosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D054466:Phospholipases A1; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; D010749:Phosphoprotein Phosphatases