@article{b1b8778b0f4944ecaaa091c2b97062e5,
title = "FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination",
abstract = "The assembly of the Smad complex is critical for TGFβ signaling, yet the mechanisms that inactivate or empower nuclear Smad complexes are less understood. By means of siRNA screen we identified FAM (USP9x), a deubiquitinase acting as essential and evolutionarily conserved component in TGFβ and bone morphogenetic protein signaling. Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits Smad4 by impeding association with phospho-Smad2. FAM reverts this negative modification, re-empowering Smad4 function. FAM opposes the activity of Ectodermin/Tif1γ (Ecto), a nuclear factor for which we now clarify a prominent role as Smad4 monoubiquitin ligase. Our study points to Smad4 monoubiquitination and deubiquitination as a way for cells to set their TGFβ responsiveness: loss of FAM disables Smad4-dependent responses in several model systems, with Ecto being epistatic to FAM. This defines a regulative ubiquitination step controlling Smads that is parallel to those impinging on R-Smad phosphorylation.",
keywords = "DEVBIO, PROTEINS, SIGNALING",
author = "Sirio Dupont and Anant Mamidi and Michelangelo Cordenonsi and Marco Montagner and Luca Zacchigna and Maddalena Adorno and Graziano Martello and Stinchfield, {Michael J.} and Sandra Soligo and Leonardo Morsut and Masafumi Inui and Stefano Moro and Nicola Modena and Francesco Argenton and Stuart Newfeld and Stefano Piccolo",
note = "Funding Information: We are indebted to Caroline Hill for thoughtful discussions. We are grateful to S. Wood, K. Kaibuchi, F. Francis, A. Moustakas, P. Ten Dijke, C. Hill, M. Brattain, J. Massague, and C. Chang for gifts of reagents and Angela Bachi for comments. A special thanks to Anna Cabrelle for technical assistance with the FACS. Thanks to Oliver Wessely and Giorgio Bressan for reading the manuscript. We are also grateful to Chemical Computing Group and in particular to Dr. Andrea Bortolato for his assistance in molecular modeling. This work is supported by TELETHON-Italy (GGP07218), Cariparo Foundation Excellence Grant, ASI, and Swissbridge grants (to S.P.), and by an AIRC grant (to S.D.). A.M. is recipient of a Marie Curie Epiplast Carcinoma RTN network fellowship. S.J.N. is supported by the NIH (grant CA095875) and SFAz (grant CAA0285-08); F.A. is supported by EU grant LSH-CT-2003-503496. ",
year = "2009",
month = jan,
day = "9",
doi = "10.1016/j.cell.2008.10.051",
language = "English (US)",
volume = "136",
pages = "123--135",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "1",
}