PPM1A functions as a Smad phosphatase to terminate TGFβ signaling (Publication with Expression of Concern. See vol. 166, 2016) (Publication with Expression of Concern. See vol. 165, pg. 498, 2016)

TGF beta signaling controls diverse normal developmental processes and pathogenesis of diseases including cancer and autoimmune and fibrotic diseases. TGF beta responses are generally mediated through transcriptional functions of Smads. A key step in TGF beta signaling is ligand-induced phosphorylation of receptor-activated Smads (R-Smads) catalyzed by the TGF beta type I receptor kinase. However, the potential of Smad dephosphorylation as a regulatory mechanism of TGF beta signaling and the identity of Smad-specific phosphatases remain elusive. Using a functional genomic approach, we have identified PPM1A/PP2C alpha as a bona fide Smad phosphatase. PPM1A dephosphorylates and promotes nuclear export of TGF beta-activated Smad2/3. Ectopic expression of PPM1A abolishes TGF beta-induced anti proliferative and transcriptional responses, whereas depletion of PPM1A enhances TGF beta signaling in mammalian cells. Smad-antagonizing activity of PPM1A is also observed during Nodal-dependent early embryogenesis in zebrafish. This work demonstrates that PPM1A/PP2C alpha, through dephosphorylation of Smad2/3, plays a critical role in terminating TGF beta signaling.