title: PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response.
abstract: 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.
authors.forename: Hsin-Wei
authors.initials: HW
authors.lastname: Liao
authors.forename: Jung-Mao
authors.initials: JM
authors.lastname: Hsu
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Hung-Ling
authors.initials: HL
authors.lastname: Wang
authors.forename: Ying-Nai
authors.initials: YN
authors.lastname: Wang
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chang
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Arold
authors.forename: Chao-Kai
authors.initials: CK
authors.lastname: Chou
authors.forename: Pei-Hsiang
authors.initials: PH
authors.lastname: Tsou
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Yueh-Fu
authors.initials: YF
authors.lastname: Fang
authors.forename: Hong-Jen
authors.initials: HJ
authors.lastname: Lee
authors.forename: Heng-Huan
authors.initials: HH
authors.lastname: Lee
authors.forename: Shyh-Kuan
authors.initials: SK
authors.lastname: Tai
authors.forename: Mhu-Hwa
authors.initials: MH
authors.lastname: Yang
authors.forename: Maria P
authors.initials: MP
authors.lastname: Morelli
authors.forename: Malabika
authors.initials: M
authors.lastname: Sen
authors.forename: John E
authors.initials: JE
authors.lastname: Ladbury
authors.forename: Chung-Hsuan
authors.initials: CH
authors.lastname: Chen
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D064593:Heterografts; D006801:Humans; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D012097:Repressor Proteins; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab