Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase.
Smad proteins are key intracellular signaling effectors for the transforming growth factor-beta superfamily of peptide growth factors. Following receptor-induced activation, Smads move into the nucleus to activate transcription of a select set of target genes. The activity of Smad proteins must be tightly regulated to exert the biological effects of different ligands in a timely manner. Here, we report the identification of Smurf2, a new member of the Hect family of E3 ubiquitin ligases. Smurf2 selectively interacts with receptor-regulated Smads and preferentially targets Smad1 for ubiquitination and proteasome-mediated degradation. At higher expression levels, Smurf2 also decreases the protein levels of Smad2, but not Smad3. In Xenopus embryos, ectopic Smurf2 expression specifically inhibits Smad1 responses and thereby affects embryonic patterning by bone morphogenetic protein signals. These findings suggest that Smurf2 may regulate the competence of a cell to respond to transforming growth factor-beta/bone morphogenetic protein signaling through a distinct degradation pathway that is similar to, yet independent of, Smurf1.
Zhang
Y
Y
Laboratory of Cellular and Molecular Biology, Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892, USA.
Chang
C
C
Gehling
D J
DJ
Hemmati-Brivanlou
A
A
Derynck
R
R
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003001:Cloning, Molecular; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019992:Databases as Topic; D006801:Humans; D008025:Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009865:Oocytes / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D051785:Smad Proteins; D051898:Smad1 Protein; D051899:Smad2 Protein; D013379:Substrate Specificity; D015534:Trans-Activators / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D029867:Xenopus Proteins; D014982:Xenopus laevis
D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; C497402:MXD1 protein, Xenopus; D011994:Recombinant Proteins; C497399:SMAD1 protein, human; C497782:SMAD2 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; D051899:Smad2 Protein; C497785:Smad2 protein, Xenopus; D015534:Trans-Activators; D029867:Xenopus Proteins; C067713:lactacystin; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; D000111:Acetylcysteine