Glycogen synthase kinase-3beta negatively regulates TGF-beta1 and Angiotensin II-mediated cellular activity through interaction with Smad3.
Glycogen synthase kinase-3beta (GSK3beta) is a major negative modulator of cardiac hypertrophy. Here we report that GSK3beta physically and functionally interacts with Smad3. The interaction between GSK3beta and Smad3 may participate in the negative regulation of transforming growth factor beta1 (TGF-beta1) and Angiotensin II-induced transcription and apoptosis. GSK3beta 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. GSK3beta counteracted the pro-apoptotic effect of Smad3 and attenuated Angiotensin II-induced apoptosis in cardiac myocytes. Furthermore, stimulation of these cells with TGF-beta1 and Angiotensin II led to the endogenous Smad3 disassociating from GSK3beta and inactivating GSK3beta by phosphorylation of its Ser9. These results uncovered a novel mechanism for the GSK3beta negative regulation of TGF-beta1/Smad3 and Angiotensin II/Smad3-mediated transcription and apoptosis by the identification of a crosstalk between GSK3beta and Smad3 signal pathway.
Hua
Fang
F
Molecular Immunology and Pharmacology Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, PR China.
Zhou
Junlan
J
Liu
Jinwen
J
Zhu
Chuanjiang
C
Cui
Bing
B
Lin
Heng
H
Liu
Yuying
Y
Jin
Wen
W
Yang
Hongzhen
H
Hu
Zhuowei
Z
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3