Figure 1.

USP15 in the regulation of TGF-β and BMP signaling. (a) USP15 binds to SMAD7 and opposes SMURF2-mediated ubiquitination of TβRI. The deubiquitination and stabilization of TβRI by USP15 promotes TGF-β activity and triggers the downstream gene expression to stimulate cell proliferation, migration wound healing, and glioblastoma pathogenesis [13]. (b) Upon activation by BMP ligands, the receptor-regulated R-SMADs undergo phosphorylation, bind to SMAD4, and enter the nucleus to induce target gene transcription. SMAD6 is a negative regulator that competes with SMAD4 to bind to R-SMADs and induces SMURF1-mediated ubiquitination and degradation of R-SMADs. Through its interaction with SMAD6, USP15 deubiquitinates and stabilizes BMPR1 and R-SMADs to enhance the BMP signaling and elicit target gene expression [39].