[HTML][HTML] PPM1A functions as a Smad phosphatase to terminate TGFβ signaling

X Lin, X Duan, YY Liang, Y Su, KH Wrighton, J Long… - Cell, 2006 - cell.com
X Lin, X Duan, YY Liang, Y Su, KH Wrighton, J Long, M Hu, CM Davis, J Wang…
Cell, 2006cell.com
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 …
Summary
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.
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