Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-β signaling Journal Article
| Authors: | Gao, S.; Alarcón, C.; Sapkota, G.; Rahman, S.; Chen, P. Y.; Goerner, N.; Macias, M. J.; Erdjument-Bromage, H.; Tempst, P.; Massague, J. |
| Article Title: | Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-β signaling |
| Abstract: | TGF-β induces phosphorylation of the transcription factors Smad2 and Smad3 at the C terminus as well as at an interdomain linker region. TGF-β-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-β-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-β-activated Smads and restricts the amplitude and duration of TGF-β gene responses, and in mouse embryonic stem cells, it limits the induction of mesoendodermal 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-β signal transduction. © 2009 Elsevier Inc. All rights reserved. |
| Keywords: | signal transduction; controlled study; human cell; nonhuman; protein domain; protein motif; proteins; animal cell; mouse; animals; mice; cells, cultured; signaling; smad2 protein; smad3 protein; transforming growth factor beta; embryo; embryonic stem cell; protein degradation; protein targeting; cell line; protein binding; rna interference; hela cells; phosphorylation; dna; regulatory mechanism; ubiquitination; amino acid sequence; molecular sequence data; sequence homology, amino acid; protein-serine-threonine kinases; immunoblotting; embryonic stem cells; half life time; mesoderm; serum and glucocorticoid regulated kinase 1; immediate-early proteins; phosphothreonine; ubiquitin protein ligase nedd4; amplitude modulation; endosomal sorting complexes required for transport; polyubiquitin; ubiquitin-protein ligases |
| Journal Title: | Molecular Cell |
| Volume: | 36 |
| Issue: | 3 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2009-11-13 |
| Start Page: | 457 |
| End Page: | 468 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2009.09.043 |
| PUBMED: | 19917253 |
| PROVIDER: | scopus |
| PMCID: | PMC2796330 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 7" - "Export Date: 30 November 2010" - "CODEN: MOCEF" - "Source: Scopus" |
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