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The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation
Author(s) -
Seo Su Ryeon,
Lallemand François,
Ferrand Nathalie,
Pessah Marcia,
L'Hoste Sébastien,
Camonis Jacques,
Atfi Azeddine
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600398
Subject(s) - ubiquitin ligase , ubiquitin , microbiology and biotechnology , gene silencing , corepressor , signal transduction , ubiquitin protein ligases , r smad , dna ligase , chemistry , biology , transcription factor , repressor , biochemistry , gene , endoglin , stem cell , cd34
Ubiquitin‐dependent degradation plays an important role in the negative regulation of TGF‐β signaling. Here, we identify Tiul1 (for T GIF i nteracting u biquitin l igase 1 ), a novel E3 ubiquitin ligase that inhibits TGF‐β signaling by targeting both the activated receptor and Smad2 for degradation. Tiul1 associates constitutively with Smad7 and induces degradation of the activated type I receptor without affecting the expression levels of Smad7. Tiul1 can also interact with Smad2 and the nuclear corepressor TGIF upon activation of TGF‐β signaling. Like Smad7, the steady‐state levels of TGIF are not affected by Tiul1, but the interaction of Tiul1 with TGIF allows this ubiquitin ligase to target Smad2 for degradation. Consistent with this, overexpression of Tiul1 suppressed TGF‐β‐induced growth arrest and transcriptional responses. In addition, silencing of Tiul1 or TGIF genes by siRNA resulted in suppression of the TGF‐β‐dependent degradation of Smad2 and an enhancement of TGF‐β‐mediated gene expression. These results reveal a new role for TGIF as a component of a ubiquitin ligase complex that mediates the degradation of Smad2 in response to TGF‐β signaling.