PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response.
J Clin Invest
; 125(12): 4529-43, 2015 Dec.
Article
en En
| MEDLINE
| ID: mdl-26571401
Posttranslational modifications to the intracellular domain of the EGFR are known to regulate EGFR functions; however, modifications to the extracellular domain and their effects remain relatively unexplored. Here, we determined that methylation at R198 and R200 of the EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) enhances binding to EGF and subsequent receptor dimerization and signaling activation. In a mouse orthotopic colorectal cancer xenograft model, expression of a methylation-defective EGFR reduced tumor growth. Moreover, increased EGFR methylation sustained signaling activation and cell proliferation in the presence of the therapeutic EGFR monoclonal antibody cetuximab. In colorectal cancer patients, EGFR methylation level also correlated with a higher recurrence rate after cetuximab treatment and reduced overall survival. Together, these data indicate that R198/R200 methylation of the EGFR plays an important role in regulating EGFR functionality and resistance to cetuximab treatment.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteína-Arginina N-Metiltransferasas
/
Proteínas Represoras
/
Transducción de Señal
/
Neoplasias del Colon
/
Receptores ErbB
/
Cetuximab
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Clin Invest
Año:
2015
Tipo del documento:
Article
Pais de publicación:
Estados Unidos