TGFβ intercepts nuclear glycogen synthase kinase 3β to inhibit PDGF-induced DNA synthesis in mesangial cells

Abstract

Here, we demonstrate a mechanism of TGFβ-mediated inhibition of PDGF-induced DNA synthesis in mesangial cells. TGFβ significantly inhibited nuclear Akt phosphorylation without any effect on PDGF-stimulated phosphorylation of PDGFR at PI 3 kinase binding site (Tyr-751). Remarkably, TGFβ inhibited cyclin D1 and cyclin E expression with concomitant decrease in CDK2 activity induced by PDGF. More importantly, we demonstrate that TGFβ significantly abolished Akt-mediated serine-9 phosphorylation of glycogen synthase kinase 3β (GSK3β), thus prevented its inactivation. Expression of inactive GSK3βK85R mutant increased cyclin D1 expression and DNA synthesis similar to PDGF. These results provide the first evidence that TGFβ intercepts Akt kinase activity in the nucleus to block inactivation of GSK3β, leading to attenuation of PDGF-induced CDK2 activity and DNA synthesis.