TGFbeta intercepts nuclear glycogen synthase kinase 3beta to inhibit PDGF-induced DNA synthesis in mesangial cells.
Here, we demonstrate a mechanism of TGFbeta-mediated inhibition of PDGF-induced DNA synthesis in mesangial cells. TGFbeta significantly inhibited nuclear Akt phosphorylation without any effect on PDGF-stimulated phosphorylation of PDGFR at PI 3 kinase binding site (Tyr-751). Remarkably, TGFbeta inhibited cyclin D1 and cyclin E expression with concomitant decrease in CDK2 activity induced by PDGF. More importantly, we demonstrate that TGFbeta significantly abolished Akt-mediated serine-9 phosphorylation of glycogen synthase kinase 3beta (GSK3beta), thus prevented its inactivation. Expression of inactive GSK3betaK85R mutant increased cyclin D1 expression and DNA synthesis similar to PDGF. These results provide the first evidence that TGFbeta intercepts Akt kinase activity in the nucleus to block inactivation of GSK3beta, leading to attenuation of PDGF-induced CDK2 activity and DNA synthesis.
Das
Falguni
F
Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
Mahimainathan
Lenin
L
Ghosh-Choudhury
Nandini
N
Venkatesan
Balachandar
B
Kasinath
Balakuntalam S
BS
Abboud
Hanna E
HE
Ghosh Choudhury
Goutam
G
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D004247:DNA; D017479:Receptors, Platelet-Derived Growth Factor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D051357:Cyclin-Dependent Kinase 2; D038362:Glycogen Synthase Kinase 3