Smurf1 Interacts with Transforming Growth Factor-β Type I Receptor through Smad7 and Induces Receptor Degradation

Abstract

Smad7 is an inhibitory Smad that acts as a negative regulator of signaling by the transforming growth factor-␤ (TGF-␤) superfamily proteins. Smad7 is induced by TGF-␤, stably interacts with activated TGF-␤ type I receptor (T␤R-I), and interferes with the phosphorylation of receptor-regulated Smads. Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic proteinspecific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with T␤R-I via Smad7, with subsequent enhancement of turnover of T␤R-I and Smad7. These results thus reveal a novel function of Smad7, i.e. induction of degradation of T␤R-I through recruitment of an E3 ligase to the receptor.

Regulation of cell proliferation by Smad proteins

“…Upon recruitment of the Smad7/Smurf complex to the activated TGF-b receptor, Smurf1 or Smurf2 induces TGF-b receptor degradation via proteasomal and lysosomal pathways. Thus, similar as found for Smad2 which mediates the degradation of SnoN via the recruitment of Smurf2 (Bonni et al, 2001), Smad7 may also function as an adaptor protein to mediate the selective degradation of a Smad interacting protein (Kavsak et al, 2000;Ebisawa et al, 2001). Other inhibitory mechanisms of I-Smads have been reported, including competition of Smad6 with Smad4 for complex formation with phosphorylated Smad1 (Hata et al, 1998a).…”

“…More recently, another mechanism by which I-Smads inhibit TGF-b/ Smad signaling has been reported. Smad7 (via its PYmotif) has been found to constitutively interact with (WW-domains in) HECT-domain ubiquitin ligase, Smurf 2, and more recently Smurf 1 (Kavsak et al, 2000;Ebisawa et al, 2001). Upon recruitment of the Smad7/Smurf complex to the activated TGF-b receptor, Smurf1 or Smurf2 induces TGF-b receptor degradation via proteasomal and lysosomal pathways.…”

Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-β1-mediated growth suppression in adult T-cell leukemia/lymphoma

“…Several reports have described the mechanism by which I-Smads inhibit TGF-b1 signaling. I-Smads located in the cytoplasm have been reported to bind TGF-b type I receptors, recruit E3 ubiquitin ligases (Smurfs) to type I receptors or bind to phosphorylated Smad1 and inhibit the formation of the R-Smad/Co-Smad complex (Hata et al, 1998;Souchelnytskyi et al, 1998;Kavsak et al, 2000;Ebisawa et al, 2001). Conversely, I-Smads Figure 6 ZEB1 regulates the duration of Smad-dependent transcription.…”

The BMP signaling and in vivo bone formation

“…Smurf1 was identified by the yeast two-hybrid assay by its ability to interact with Smads 1 and 5 (Zhu et al, 1999) and later immunoprecipitation studies show that Smurf1 has much higher affinity to bind Smads 6 and 7 (Ebisawa et al, 2001). Smurf1 is a member of the Hect domain family of E3 ubiquitin ligases.…”

“…Mutations of the PY motif of Smads 1 and 5 proteins prevent them to interact with Smurf1 and inhibit the degradation of these Smad proteins (Zhu et al, 1999). Smurf1 is located in the nucleus and it is exported to the cell membrane and cytoplasm when it binds Smad6 or 7 and induces the degradation of type I TGFβ and BMP receptors and Smads 1 and 5 (Ebisawa et al, 2001;Suzuki et al, 2002;Murakami et al, 2003). Several lines of evidence suggest that Smurf1 may have synergistic effect with Smad6 and inhibit BMP signaling (Murakami et al, 2003;Horiki et al, 2004).…”