TY - JOUR
T1 - TGFβ intercepts nuclear glycogen synthase kinase 3β to inhibit PDGF-induced DNA synthesis in mesangial cells
AU - Das, Falguni
AU - Mahimainathan, Lenin
AU - Ghosh-Choudhury, Nandini
AU - Venkatesan, Balachandar
AU - Kasinath, Balakuntalam S.
AU - Abboud, Hanna E.
AU - Ghosh Choudhury, Goutam
N1 - Funding Information:
This work was supported by grants from the NIH RO1 DK50190, Juvenile Diabetes Research Foundation and VA Merit Review Grants to GGC. He is a Research Career Scientist in the Department of Veterans Affairs. NGC is supported by NIH RO1 AR52425, VA Merit Review and Morisson Trust grants. BSK is supported by Grants from NIH O’Brien Kidney Center, NIH RO1 DK077295, American Diabetes Association and VA Research Service Merit Review grant. HEA is supported by NIH RO1 DK 33665 and VA Merit Review Grant.
PY - 2007/11/13
Y1 - 2007/11/13
N2 - 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.
AB - 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.
KW - Akt kinase
KW - CDK2
KW - Cyclin D1
KW - GSK3β
KW - Glomerulonephritis
KW - Mitogenesis
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U2 - 10.1016/j.febslet.2007.10.014
DO - 10.1016/j.febslet.2007.10.014
M3 - Article
C2 - 17961557
AN - SCOPUS:35548958658
SN - 0014-5793
VL - 581
SP - 5259
EP - 5267
JO - FEBS Letters
JF - FEBS Letters
IS - 27
ER -