PPM1A Functions as a Smad Phosphatase to Terminate TGFβ Signaling

• Published in: Cell 2006-06, Vol.125 (5), p.915-928
• Main Authors: Lin, Xia, Duan, Xueyan, Liang, Yao-Yun, Su, Ying, Wrighton, Katharine H., Long, Jianyin, Hu, Min, Davis, Candi M., Wang, Jinrong, Brunicardi, F. Charles, Shi, Yigong, Chen, Ye-Guang, Meng, Anming, Feng, Xin-Hua
• Format: Article
• Language: English
• Subjects: Danio rerio
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2006.03.044

TGFβ signaling controls diverse normal developmental processes and pathogenesis of diseases including cancer and autoimmune and fibrotic diseases. TGFβ responses are generally mediated through transcriptional functions of Smads. A key step in TGFβ signaling is ligand-induced phosphorylation of receptor-activated Smads (R-Smads) catalyzed by the TGFβ type I receptor kinase. However, the potential of Smad dephosphorylation as a regulatory mechanism of TGFβ signaling and the identity of Smad-specific phosphatases remain elusive. Using a functional genomic approach, we have identified PPM1A/PP2Cα as a bona fide Smad phosphatase. PPM1A dephosphorylates and promotes nuclear export of TGFβ-activated Smad2/3. Ectopic expression of PPM1A abolishes TGFβ-induced antiproliferative and transcriptional responses, whereas depletion of PPM1A enhances TGFβ signaling in mammalian cells. Smad-antagonizing activity of PPM1A is also observed during Nodal-dependent early embryogenesis in zebrafish. This work demonstrates that PPM1A/PP2Cα, through dephosphorylation of Smad2/3, plays a critical role in terminating TGFβ signaling.