FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination

Sirio Dupont, Anant Mamidi, Michelangelo Cordenonsi, Marco Montagner, Luca Zacchigna, Maddalena Adorno, Graziano Martello, Michael J. Stinchfield, Sandra Soligo, Leonardo Morsut, Masafumi Inui, Stefano Moro, Nicola Modena, Francesco Argenton, Stuart Newfeld, Stefano Piccolo

Research output: Contribution to journalArticle

306 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)123-135
Number of pages13
JournalCell
Volume136
Issue number1
DOIs
StatePublished - Jan 9 2009

Fingerprint

Bone Morphogenetic Proteins
Ubiquitination
Ligases
Small Interfering RNA
Lysine
Phosphorylation
Enzymes
Association reactions
Deubiquitinating Enzymes

Keywords

  • DEVBIO
  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Dupont, S., Mamidi, A., Cordenonsi, M., Montagner, M., Zacchigna, L., Adorno, M., ... Piccolo, S. (2009). FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination. Cell, 136(1), 123-135. https://doi.org/10.1016/j.cell.2008.10.051

FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination. / Dupont, Sirio; Mamidi, Anant; Cordenonsi, Michelangelo; Montagner, Marco; Zacchigna, Luca; Adorno, Maddalena; Martello, Graziano; Stinchfield, Michael J.; Soligo, Sandra; Morsut, Leonardo; Inui, Masafumi; Moro, Stefano; Modena, Nicola; Argenton, Francesco; Newfeld, Stuart; Piccolo, Stefano.

In: Cell, Vol. 136, No. 1, 09.01.2009, p. 123-135.

Research output: Contribution to journalArticle

Dupont, S, Mamidi, A, Cordenonsi, M, Montagner, M, Zacchigna, L, Adorno, M, Martello, G, Stinchfield, MJ, Soligo, S, Morsut, L, Inui, M, Moro, S, Modena, N, Argenton, F, Newfeld, S & Piccolo, S 2009, 'FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination', Cell, vol. 136, no. 1, pp. 123-135. https://doi.org/10.1016/j.cell.2008.10.051
Dupont S, Mamidi A, Cordenonsi M, Montagner M, Zacchigna L, Adorno M et al. FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination. Cell. 2009 Jan 9;136(1):123-135. https://doi.org/10.1016/j.cell.2008.10.051
Dupont, Sirio ; Mamidi, Anant ; Cordenonsi, Michelangelo ; Montagner, Marco ; Zacchigna, Luca ; Adorno, Maddalena ; Martello, Graziano ; Stinchfield, Michael J. ; Soligo, Sandra ; Morsut, Leonardo ; Inui, Masafumi ; Moro, Stefano ; Modena, Nicola ; Argenton, Francesco ; Newfeld, Stuart ; Piccolo, Stefano. / FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination. In: Cell. 2009 ; Vol. 136, No. 1. pp. 123-135.
@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",
year = "2009",
month = "1",
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",

}

TY - JOUR

T1 - FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination

AU - Dupont, Sirio

AU - Mamidi, Anant

AU - Cordenonsi, Michelangelo

AU - Montagner, Marco

AU - Zacchigna, Luca

AU - Adorno, Maddalena

AU - Martello, Graziano

AU - Stinchfield, Michael J.

AU - Soligo, Sandra

AU - Morsut, Leonardo

AU - Inui, Masafumi

AU - Moro, Stefano

AU - Modena, Nicola

AU - Argenton, Francesco

AU - Newfeld, Stuart

AU - Piccolo, Stefano

PY - 2009/1/9

Y1 - 2009/1/9

N2 - 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.

AB - 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.

KW - DEVBIO

KW - PROTEINS

KW - SIGNALING

UR - http://www.scopus.com/inward/record.url?scp=58149093172&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149093172&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2008.10.051

DO - 10.1016/j.cell.2008.10.051

M3 - Article

VL - 136

SP - 123

EP - 135

JO - Cell

JF - Cell

SN - 0092-8674

IS - 1

ER -