Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • Allergy (Apr 2019)
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response
Hsin-Wei Liao, … , Scott Kopetz, Mien-Chie Hung
Hsin-Wei Liao, … , Scott Kopetz, Mien-Chie Hung
Published December 1, 2015; First published November 16, 2015
Citation Information: J Clin Invest. 2015;125(12):4529-4543. https://doi.org/10.1172/JCI82826.
View: Text | PDF
Categories: Research Article Cell biology Oncology

PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response

  • Text
  • PDF
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

Hsin-Wei Liao, Jung-Mao Hsu, Weiya Xia, Hung-Ling Wang, Ying-Nai Wang, Wei-Chao Chang, Stefan T. Arold, Chao-Kai Chou, Pei-Hsiang Tsou, Hirohito Yamaguchi, Yueh-Fu Fang, Hong-Jen Lee, Heng-Huan Lee, Shyh-Kuan Tai, Mhu-Hwa Yang, Maria P. Morelli, Malabika Sen, John E. Ladbury, Chung-Hsuan Chen, Jennifer R. Grandis, Scott Kopetz, Mien-Chie Hung

×

Figure 1

PRMT1 methylates EGFR at R198 and R200.

Options: View larger image (or click on image) Download as PowerPoint
PRMT1 methylates EGFR at R198 and R200.
(A) Illustration of EGFR extrace...
(A) Illustration of EGFR extracellular and intracellular domains that were individually subcloned with GST tag and were purified for in vitro methylation assay. (B) In vitro methylation assay showing methylation signal from each GST-tagged EGFR domain after incubation with purified GST-tagged PRMT1. Methylation signals were examined by fluorography. (C) In vitro methylation assay of WT EGFR and methylation-site single mutants. (D) In vitro methylation assay of WT EGFR and R198/200K double mutant. Data are representative of 3 independent experiments. (E) Sequence alignment of PRMT substrates, along with EGFR, showing a potential GAR motif on EGFR extracellular domain 2.
Follow JCI:
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts