Ubiquitin Ligase Nedd4L Targets Activated Smad2/3 to Limit TGF-β Signaling

被引：316

作者：

Gao, Sheng ^{[1
]}

Alarcon, Claudio ^{[1
]}

Sapkota, Gopal ^{[1
]}

Rahman, Sadia ^{[1
,2
]}

Chen, Pan-Yu ^{[1
]}

Goerner, Nina ^{[4
]}

Macias, Maria J. ^{[4
]}

Erdjument-Bromage, Hediye ^{[2
]}

Tempst, Paul ^{[2
]}

Massague, Joan ^{[1
,3
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA

[4] Inst Res Biomed, Struct & Computat Biol Programme, Barcelona 08028, Spain

来源：

MOLECULAR CELL | 2009年 / 36卷 / 03期

基金：

美国国家卫生研究院;

关键词：

STRUCTURAL BASIS; BMP; DEGRADATION; MECHANISM; PROTEINS; FAMILY; PHOSPHORYLATION; SUPERFAMILY; RECOGNITION; INHIBITOR;

D O I：

10.1016/j.molcel.2009.09.043

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

TGF-beta induces phosphorylation of the transcription factors Smad2 and Smad3 at the C terminus as well as at an interdomain linker region. TGF-beta-induced linker phosphorylation marks the activated Smad proteins for proteasome-mediated destruction. Here, we identify Nedd4L as the ubiquitin ligase responsible for this step. Through its WW domain, Nedd4L specifically recognizes a TGF-beta-induced phosphoThr-ProTyr motif in the linker region, resulting in Smad2/3 polyubiquitination and degradation. Nedd4L is not interchangeable with Smurf1, a ubiquitin ligase that targets BMP-activated, linker-phosphorylated Smad1. Nedd4L limits the half-life of TGF-beta-activated Smads and restricts the amplitude and duration of TGF-beta gene responses, and in mouse embryonic stem cells, it limits the induction of meso-endodermal fates by Smad2/3-activating factors. Hierarchical regulation is provided by SGK1, which phosphorylates Nedd4L to prevent binding of Smad2/3. Previously identified as a regulator of renal sodium channels, Nedd4L is shown here to play a broader role as a general modulator of Smad turnover during TGF-beta signal transduction.

引用

页码：457 / 468

页数：12

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