Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-β signaling

Sheng Gao, Claudio Alarcón, Gopal Sapkota, Sadia Rahman, Pan-Yu Chen, Nina Goerner, Maria J Macias, Hediye Erdjument-Bromage, Paul Tempst, Joan Massagué

    Research output: Contribution to journalArticlepeer-review

    282 Citations (Scopus)


    TGF-ß induces phosphorylation of the transcription factors Smad2 and Smad3 at the C terminus as well as at an interdomain linker region. TGF-ß-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-ß-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-ß-activated Smads and restricts the amplitude and duration of TGF-ß 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-ß signal transduction.

    Original languageEnglish
    Pages (from-to)457-468
    Number of pages12
    JournalMolecular Cell
    Issue number3
    Publication statusPublished - 13 Nov 2009


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