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

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. GrandisScott Kopetz, Mien Chie Hung*

*此作品的通信作者

研究成果: Article同行評審

101 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)4529-4543
頁數15
期刊Journal of Clinical Investigation
125
發行號12
DOIs
出版狀態Published - 12月 2015

指紋

深入研究「PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response」主題。共同形成了獨特的指紋。

引用此