title: AIP4 restricts transforming growth factor-beta signaling through a ubiquitination-independent mechanism.
abstract: Smad7 functions as an intracellular antagonist in transforming growth factor-beta (TGF-beta) signaling. In addition to interacting stably with the activated TGF-beta type I receptor (TbetaRI) to prevent phosphorylation of the receptor-regulated Smads (Smad2 and Smad3), Smad7 also induces degradation of the activated TbetaRI through association with different E3 ubiquitin ligases. Using the two-hybrid screen, we identified atrophin 1-interacting protein 4 (AIP4) as an E3 ubiquitin ligase that specifically targets Smad7 for ubiquitin-dependent degradation without affecting the turnover of the activated TbetaRI. Surprisingly, we found that despite the ability to degrade Smad7, AIP4 can inhibit TGF-beta signaling, presumably by enhancing the association of Smad7 with the activated TbetaRI. Consistent with this notion, expression of a catalytic mutant of AIP4, which is unable to induce ubiquitination and degradation of Smad7, also stabilizes the TbetaRI.Smad7 complex, resulting in inhibition of TGF-beta signaling. The ability of AIP4 to enhance the inhibitory function of Smad7 independent of its ubiquitin ligase activity reveals a new mechanism by which E3 ubiquitin ligases may function to turn off TGF-beta signaling.
authors.affiliation: INSERM U482, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.
authors.forename: François
authors.initials: F
authors.lastname: Lallemand
authors.forename: Su Ryeon
authors.initials: SR
authors.lastname: Seo
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ferrand
authors.forename: Marcia
authors.initials: M
authors.lastname: Pessah
authors.forename: Sebastien
authors.initials: S
authors.lastname: L'Hoste
authors.forename: Georges
authors.initials: G
authors.lastname: Rawadi
authors.forename: Sergio
authors.initials: S
authors.lastname: Roman-Roman
authors.forename: Jacques
authors.initials: J
authors.lastname: Camonis
authors.forename: Azeddine
authors.initials: A
authors.lastname: Atfi
mesh_terms: D000818:Animals; D019556:COS Cells; D002384:Catalysis; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D017353:Gene Deletion; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D009154:Mutation; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D051906:Smad7 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D012097:Repressor Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C432966:ITCH protein, human; C498342:SMURF1 protein, human; C471641:SMURF2 protein, human; C471642:WWP1 protein, human; D044767:Ubiquitin-Protein Ligases