USP15 stabilizes TGF-β2 receptor I and promotes oncogenesis through the activation of TGF-β2 signaling in glioblastoma

Pieter J.A. Eichhorn, Laura Rodón, Alba Gonzàlez-Juncà, Annette Dirac, Magüi Gili, Elena Martínez-Sáez, Claudia Aura, Ignasi Barba, Vicente Peg, Aleix Prat, Isabel Cuartas, Jose Jimenez, David García-Dorado, Juan Sahuquillo, Réné Bernards, José Baselga, Joan Seoane

Research output: Contribution to journalArticleResearchpeer-review

221 Citations (Scopus)

Abstract

In advanced cancer, including glioblastoma, the transforming growth factor β2 (TGF-β2) pathway acts as an oncogenic factor and is considered to be a therapeutic target. Using a functional RNAi screen, we identified the deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) as a key component of the TGF-β2 signaling pathway. USP15 binds to the SMAD7-SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF-β2 receptor (Tβ2R-I), leading to an enhanced TGF-β2 signal. High expression of USP15 correlates with high TGF-β2 activity, and the USP15 gene is found amplified in glioblastoma, breast and ovarian cancer. USP15 amplification confers poor prognosis in individuals with glioblastoma. Downregulation or inhibition of USP15 in a patient-derived orthotopic mouse model of glioblastoma decreases TGF-β2 activity. Moreover, depletion of USP15 decreases the oncogenic capacity of patient-derived glioma-initiating cells due to the repression of TGF-β2 signaling. Our results show that USP15 regulates the TGF-β2 pathway and is a key factor in glioblastoma pathogenesis. © 2012 Nature America, Inc. All rights reserved.
Original languageEnglish
Pages (from-to)429-435
JournalNature Medicine
Volume18
Issue number3
DOIs
Publication statusPublished - 1 Mar 2012

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