TY - JOUR
T1 - USP15 stabilizes TGF-β2 receptor I and promotes oncogenesis through the activation of TGF-β2 signaling in glioblastoma
AU - Eichhorn, Pieter J.A.
AU - Rodón, Laura
AU - Gonzàlez-Juncà, Alba
AU - Dirac, Annette
AU - Gili, Magüi
AU - Martínez-Sáez, Elena
AU - Aura, Claudia
AU - Barba, Ignasi
AU - Peg, Vicente
AU - Prat, Aleix
AU - Cuartas, Isabel
AU - Jimenez, Jose
AU - García-Dorado, David
AU - Sahuquillo, Juan
AU - Bernards, Réné
AU - Baselga, José
AU - Seoane, Joan
PY - 2012/3/1
Y1 - 2012/3/1
N2 - 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.
AB - 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.
U2 - 10.1038/nm.2619
DO - 10.1038/nm.2619
M3 - Article
SN - 1078-8956
VL - 18
SP - 429
EP - 435
JO - Nature Medicine
JF - Nature Medicine
IS - 3
ER -
