Cleavage of glycogen synthase kinase‐3beta by matrix metalloproteinase‐2 enhances its kinase activity

Abstract

Matrix metalloproteinase (MMP)‐2 is localized to the sarcomere of cardiomyocytes and contributes to myocardial ischemia‐reperfusion injury by degrading sarcomeric and cytoskeletal proteins. Oxidative stress mediates its damaging effects through activation of MMP‐2 within the cardiomyocyte and subsequent proteolysis of susceptible intracellular targets. Glycogen synthase kinase (GSK)‐3β is involved in growth, death & metabolism and susceptible to proteolytic cleavage. We determined whether GSK‐3β is a proteolytic substrate of MMP‐2 and how this cleavage affects its kinase activity.Incubation of MMP‐2 and GSK‐3β resulted in a time‐ and concentration‐dependant cleavage of GSK‐3β with significant increase in GSK‐3β kinase activity. Dephosphorylation of GSK‐3β with λ‐phosphatase prevented MMP‐2 mediated augmented kinase activity. H2O2 treated H9c2 cardiomyoblasts showed increased levels and activity of MMP‐2 accompanied by significant reduction in GSK‐3β protein levels and increased kinase activity.The data indicate that GSK‐3β is a target of MMP‐2 and that its cleavage by MMP‐2 enhances GSK‐3β kinase activity. GSK‐3β dephosphorylation studies suggest that MMP‐2 may cleave off the inhibitory serine‐9 residue. This MMP‐2 mediated augmentation of GSK‐3β kinase activity may contribute to cardiac dysfunction as a result of myocardial oxidative stress injury. This work was supported by CIHR.