title: USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7.
abstract: 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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kit Leng Lui
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Prasanna Vasudevan
authors.initials: PV
authors.lastname: Iyengar
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Jaynes
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Zul Fazreen Bin Adam
authors.initials: ZFBA
authors.lastname: Isa
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Brendan
authors.initials: B
authors.lastname: Pang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Tuan Zea
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore pieter_eichhorn@nus.edu.sg.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Pieter Johan Adam
authors.identifier: 0000-0001-5840-943X
authors.initials: PJA
authors.lastname: Eichhorn
mesh_terms: D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D000072017:Deubiquitinating Enzymes / Q000378:metabolism*; D005909:Glioblastoma / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D011379:Prognosis; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C501866:USP26 protein, human; D025801:Ubiquitin; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D000072017:Deubiquitinating Enzymes; D003546:Cysteine Endopeptidases
keywords: Smad7; TGF‐β; USP26