Glycogen synthase kinase-3β negatively regulates TGF-β1 and Angiotensin II-mediated cellular activity through interaction with Smad3

Glycogen synthase kinase-3β (GSK3β) is a major negative modulator of cardiac hypertrophy. Here we report that GSK3β physically and functionally interacts with Smad3. The interaction between GSK3β and Smad3 may participate in the negative regulation of transforming growth factor β1 (TGF-β1) and Angiotensin II-induced transcription and apoptosis. GSK3β interacted directly with Smad3 to sequester it outside the nucleus and prevent its nuclear translocation. This resulted in the suppression of Smad3-mediated transcriptional activity and gene expression. GSK3β counteracted the pro-apoptotic effect of Smad3 and attenuated Angiotensin II-induced apoptosis in cardiac myocytes. Furthermore, stimulation of these cells with TGF-β1 and Angiotensin II led to the endogenous Smad3 disassociating from GSK3β and inactivating GSK3β by phosphorylation of its Ser9. These results uncovered a novel mechanism for the GSK3β negative regulation of TGF-β1/Smad3 and Angiotensin II/Smad3-mediated transcription and apoptosis by the identification of a crosstalk between GSK3β and Smad3 signal pathway.