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

doi:10.1038/nm.2619

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

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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.

Idioma original	Anglès
Pàgines (de-a)	429-435
Revista	Nature Medicine
Volum	18
Número	3
DOIs	https://doi.org/10.1038/nm.2619
Estat de la publicació	Publicada - 1 de març 2012

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10.1038/nm.2619

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Eichhorn, P. J. A., Rodón, L., Gonzàlez-Juncà, A., Dirac, A., Gili, M., Martínez-Sáez, E., Aura, C., Barba, I., Peg, V., Prat, A., Cuartas, I., Jimenez, J., García-Dorado, D., Sahuquillo, J., Bernards, R., Baselga, J., & Seoane, J. (2012). USP15 stabilizes TGF-β2 receptor I and promotes oncogenesis through the activation of TGF-β2 signaling in glioblastoma. Nature Medicine, 18(3), 429-435. https://doi.org/10.1038/nm.2619

@article{ce49eb8ba9ae4c94a8567ac9cad12057,

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

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. {\textcopyright} 2012 Nature America, Inc. All rights reserved.",

author = "Eichhorn, \{Pieter J.A.\} and Laura Rod{\'o}n and Alba Gonz{\`a}lez-Junc{\`a} and Annette Dirac and Mag{\"u}i Gili and Elena Mart{\'i}nez-S{\'a}ez and Claudia Aura and Ignasi Barba and Vicente Peg and Aleix Prat and Isabel Cuartas and Jose Jimenez and David Garc{\'i}a-Dorado and Juan Sahuquillo and R{\'e}n{\'e} Bernards and Jos{\'e} Baselga and Joan Seoane",

year = "2012",

month = mar,

day = "1",

doi = "10.1038/nm.2619",

language = "English",

volume = "18",

pages = "429--435",

journal = "Nature Medicine",

issn = "1078-8956",

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Eichhorn, PJA, Rodón, L, Gonzàlez-Juncà, A, Dirac, A, Gili, M, Martínez-Sáez, E, Aura, C, Barba, I, Peg, V, Prat, A, Cuartas, I, Jimenez, J, García-Dorado, D, Sahuquillo, J, Bernards, R, Baselga, J & Seoane, J 2012, 'USP15 stabilizes TGF-β2 receptor I and promotes oncogenesis through the activation of TGF-β2 signaling in glioblastoma', Nature Medicine, vol. 18, núm. 3, pàg. 429-435. https://doi.org/10.1038/nm.2619

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.

UR - https://www.scopus.com/pages/publications/84858004513

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 -

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

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