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

被引：506

作者：

Dupont, Sirio ^{[1
]}

Mamidi, Anant ^{[1
]}

Cordenonsi, Michelangelo ^{[1
]}

Montagner, Marco ^{[1
]}

Zacchigna, Luca ^{[1
]}

Adorno, Maddalena ^{[1
]}

Martello, Graziano ^{[1
]}

Stinchfield, Michael J. ^{[2
]}

Soligo, Sandra ^{[1
]}

Morsut, Leonardo ^{[1
]}

Inui, Masafumi ^{[1
]}

Moro, Stefano ^{[4
]}

Modena, Nicola ^{[3
]}

Argenton, Francesco ^{[3
]}

Newfeld, Stuart J. ^{[2
]}

Piccolo, Stefano ^{[1
]}

机构：

[1] Univ Padua, Sch Med, Dept Histol Microbiol & Med Biotechnol, I-35131 Padua, Italy

[2] Arizona State Univ, Sch Life Sci, Tempe, AZ 85287 USA

[3] Univ Padua, Dept Biol, I-35131 Padua, Italy

[4] Univ Padua, Dept Pharmaceut Sci, Mol Modeling Sect, I-35131 Padua, Italy

来源：

CELL | 2009年 / 136卷 / 01期

关键词：

GROWTH-FACTOR-BETA; FAT-FACETS GENE; UBIQUITIN LIGASE; TUMOR-CELLS; INDUCTION; CANCER; PHOSPHORYLATION; PATHWAYS; RECEPTOR; P53;

D O I：

10.1016/j.cell.2008.10.051

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The assembly of the Smad complex is critical for TGF beta 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 TGFb 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/Tif1 gamma (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 TGF beta 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.

引用

页码：123 / 135

页数：13

共 36 条

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