USP26 regulates TGF‐β signaling by deubiquitinating and stabilizing SMAD7

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...

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Veröffentlicht in:EMBO reports 2017-05, Vol.18 (5), p.797-808
Hauptverfasser: Kit Leng Lui, Sarah, Iyengar, Prasanna Vasudevan, Jaynes, Patrick, Isa, Zul Fazreen Bin Adam, Pang, Brendan, Tan, Tuan Zea, Eichhorn, Pieter Johan Adam
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Sprache:eng
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Zusammenfassung: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. Synopsis As part of a negative feedback loop TGF‐β induces SMAD7 and complexes with SMURF2 to degrade the TGF‐β receptor. TGF‐β signaling also induces expression of USP26, which deubiquitinates and stabilizes SMAD7 resulting in downregulation of TGF‐β activity. TGF‐β enhances USP26 expression in breast cancer and glioblastoma. USP26 acts as a negative regulator of the TGF‐β pathway by stabilizing SMAD7. USP26 is mutated in glioblastoma and may be used as a biomarker for TGF‐β inhibitors. Graphical Abstract As part of a negative feedback loop TGF‐β induces SMAD7 and complexes with SMURF2 to degrade the TGF‐β receptor. TGF‐β signaling also induces expression of USP26, which deubiquitinates and stabilizes SMAD7 resulting in downregulation of TGF‐β activity.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.201643270