Cooperative Inhibition of Bone Morphogenetic Protein Signaling by Smurf1 and Inhibitory Smads

Abstract

Smad ubiquitin regulatory factor (Smurf) 1 binds to receptor-regulated Smads for bone morphogenetic proteins (BMPs) Smad1/5 and promotes their degradation. In addition, Smurf1 associates with transforming growth factor-β type I receptor through the inhibitory Smad (I-Smad) Smad7 and induces their degradation. Herein, we examined whether Smurf1 negatively regulates BMP signaling together with the I-Smads Smad6/7. Smurf1 and Smad6 cooperatively induced secondary axes in Xenopus embryos. Using a BMP-responsive promoter-reporter construct in mammalian cells, we found that Smurf1 cooperated with I-Smad in inhibiting BMP signaling and that the inhibitory activity of Smurf1 was not necessarily correlated with its ability to bind to Smad1/5 directly. Smurf1 bound to BMP type I receptors via I-Smads and induced ubiquitination and degradation of these receptors. Moreover, Smurf1 associated with Smad1/5 indirectly through I-Smads and induced their ubiquitination and degradation. Smurf1 thus controls BMP signaling with and without I-Smads through multiple mechanisms.

NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-β (transforming growth factor-β) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-β type I receptor

“…Smurf1 induces ubiquitination and degradation of Smads 1 and 5, and of TβR-I and BMPR-Is through interacting I-Smads [13,17,39]. Smurf2 induces ubiquitin-mediated degradation of Smad1 and TβR-I; moreover, it has also been shown to induce degradation of Smad2 and SnoN [14][15][16]21].…”

Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling

“…We hypothesized that the inhibitory Smads, Smad6 and Smad7, may be involved in TGF-β1-induced MyD88 degradation, because I-Smads are known to recruit the Smurf E3 ubiquitin ligase proteins 6,9,10 . The ubiquitination and degradation of endogenous MyD88 protein in SMAD6 knockdown or SMAD7 knockdown primary peritoneal macrophages was examined to determine whether the I-Smads are involved in regulation of MyD88 levels.…”

The BMP signaling and in vivo bone formation

“…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).…”

“…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). Recent report showed that the E3 ligase complex SCF β-TrCP1 is responsible for Smad4 ubiquitination and degradation (Wan et al, 2004).…”