PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response
Arold, Stefan T.
Morelli, Maria P.
Ladbury, John E.
Grandis, Jennifer R.
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Permanent link to this recordhttp://hdl.handle.net/10754/599404
MetadataShow full item record
AbstractPosttranslational 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.
CitationLiao H-W, Hsu J-M, Xia W, Wang H-L, Wang Y-N, et al. (2015) PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response. Journal of Clinical Investigation 125: 4529–4543. Available: http://dx.doi.org/10.1172/JCI82826.
SponsorsWe thank Jennifer L. Hsu for critical reading of the manuscript; Su Zhang, Jian-Guang Shi, Zhen-Bo Han, and Jin-Fong Lee for technical assistance; Zhen Fan for providing GEO and HT29 colorectal cancer cell line; Xiangbo Wan for providing patient samples; The National Cancer Institute for providing colorectal tissue microarrays; The Cancer Center Support Grant–funded (CA016672) Characterized Cell Line Core for performing STR DNA fingerprinting; and ShRNA/ORFeome Core Facility for providing shRNA constructs. Funding was provided by NIH (CA109311, CA099031, and CCSG CA16672 to M.C. Hung; P50CA097190 to J.R. Grandis); Cancer Prevention and Research Institute of Texas (RP150245); The University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund (to M.C. Hung); Ministry of Science and Technology, International Research-intensive Centers of Excellence in Taiwan (I-RiCE; MOST 104-2911-I-002-302); Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence (MOHW104-TDU-B-212-124-002); Center for Biological Pathways; and the American Cancer Society (to J.R. Grandis). Research by S.T. Arold reported in this publication was supported by KAUST.
PubMed Central IDPMC4665782
- Old dog, new tricks: extracellular domain arginine methylation regulates EGFR function.
- Authors: Epstein DM, Buck E
- Issue date: 2015 Dec
- The role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 triple-negative breast cancer cells.
- Authors: Nakai K, Xia W, Liao HW, Saito M, Hung MC, Yamaguchi H
- Issue date: 2018 Jan
- Increased TGF-α as a mechanism of acquired resistance to the anti-EGFR inhibitor cetuximab through EGFR-MET interaction and activation of MET signaling in colon cancer cells.
- Authors: Troiani T, Martinelli E, Napolitano S, Vitagliano D, Ciuffreda LP, Costantino S, Morgillo F, Capasso A, Sforza V, Nappi A, De Palma R, D'Aiuto E, Berrino L, Bianco R, Ciardiello F
- Issue date: 2013 Dec 15
- Novel toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors.
- Authors: Damiano V, Caputo R, Bianco R, D'Armiento FP, Leonardi A, De Placido S, Bianco AR, Agrawal S, Ciardiello F, Tortora G
- Issue date: 2006 Jan 15
- Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation.
- Authors: Patel D, Bassi R, Hooper A, Prewett M, Hicklin DJ, Kang X
- Issue date: 2009 Jan