The amplitude of transforming growth factor‐β (TGF‐β) signal is tightly regulated to ensure appropriate physiological responses. As part of negative feedback loop SMAD7, a direct transcriptional target of downstream TGF‐β signaling acts as a scaffold to recruit the E3 ligase SMURF2 to target the TGF‐β receptor complex for ubiquitin‐mediated degradation. Here, we identify the deubiquitinating enzyme USP26 as a novel integral component of this negative feedback loop. We demonstrate that TGF‐β rapidly enhances the expression of USP26 and reinforces SMAD7 stability by limiting the ubiquitin‐mediated turnover of SMAD7. Conversely, knockdown of USP26 rapidly degrades SMAD7 resulting in TGF‐β receptor stabilization and enhanced levels of p‐SMAD2. Clinically, loss of USP26 correlates with high TGF‐β activity and confers poor prognosis in glioblastoma. Our data identify USP26 as a novel negative regulator of the TGF‐β pathway and suggest that loss of USP26 expression may be an important factor in glioblastoma pathogenesis.

Adaptive responses have been demonstrated to limit activity to targeted therapies. Saei et al. show that loss of USP28/FBW7-mediated BRAF degradation is observed in a proportion of melanoma patients and can be responsible for resistance through upregulation of MAPK signaling pathway.

Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFβ receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers.