@article{620854aabd5343e4ac34ee24ab1d7080,
title = "PPM1A Functions as a Smad Phosphatase to Terminate TGFβ Signaling",
abstract = "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.",
author = "Xia Lin and Xueyan Duan and Liang, {Yao Yun} and Ying Su and Wrighton, {Katharine H.} and Jianyin Long and Min Hu and Davis, {Candi M.} and Jinrong Wang and Brunicardi, {F. Charles} and Yigong Shi and Chen, {Ye Guang} and Anming Meng and Feng, {Xin Hua}",
note = "Funding Information: We thank Bryan Cullen, Kazusa DNA Research Institute, Yibing Kang, Soo-Kyung Lee, Edward Leof, Fang Liu, David Loskutoff, Joan Massagu{\'e}, Kohei Miyazono, Alexandra Newton, Anita Roberts, Danny Reinberg, Zhou Songyang, Peter ten Dijke, Bert Vogelstein, Xiao-Fan Wang, Malcolm Whitman, and Lan Xu for various reagents (details are available in the Supplemental Data ). This research was supported by the NIH (R01DK073932 and R21CA11293 to X.L., R01CA82171 to Y. Shi, R01GM63773 and R01CA108454 to X.-H.F.), the National Natural Science Foundation of China (Distinguished Young Scholar Fund #30428002 to X.-H.F. and #30125021 to Y.-G.C., Grant #30430360 to Y.-G.C., and Grant #90208002 to A.M.), and 973 Program (2005CB522502 to A.M. and 2004CB720002 to Y.-G.C.). K.H.W. was supported by an American Heart Association (Texas Affiliate) Postdoctoral Fellowship. C.M.D. was supported by an NIH Minority Research Supplement (via R01GM63773). X.L. is a recipient of the Baylor Breast Center SPORE Career Development Award. Y.-G.C. is a recipient of the Li Foundation Heritage Prize. X.-H.F is a Leukemia & Lymphoma Society Scholar. ",
year = "2006",
month = jun,
day = "2",
doi = "10.1016/j.cell.2006.03.044",
language = "English (US)",
volume = "125",
pages = "915--928",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}