Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation

• Published in: Nature cell biology Vol. 13; no. 2; pp. 174 - 181
• Main Authors: Liu, Mo, Liao, Hsin-Wei, Shi, Bin, Li, Long-Yuan, Chen, Chun-Te, Lin, Chun-Yi, Tsai, Chang-Hai, Lai, Chien-Chen, Bedford, Mark T, Wang, Ying-Nai, Lee, Hong-Jen, Hung, Mien-Chie, Chou, Chao-Kai, Kuo, Hsu-Ping, Hsu, Jung-Mao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2011; Nature Publishing Group
• Subjects: 631/80/458; 631/80/86; Antibodies; Arginine - metabolism; Biological activity; Biomedical and Life Sciences; Cancer; Cancer Research; Cell Biology; Cellular proteins; Developmental Biology; Enzyme Activation; Epidermal growth factor; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Health aspects; HEK293 Cells; Humans; Kinases; letter; Life Sciences; Ligands; Methylation; Observations; Peptides; Phosphorylation; Physiology; Properties; Protein Methyltransferases - genetics; Protein Methyltransferases - metabolism; Protein synthesis; Protein-Arginine N-Methyltransferases; Proteins; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Signal transduction; Stem Cells; Tyrosine; Tyrosine - metabolism; United States; United States > US; Texas; China; Taiwan
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2158

Epidermal growth factor receptor (EGFR) can undergo post-translational modifications, including phosphorylation, glycosylation and ubiquitylation, leading to diverse physiological consequences and modulation of its biological activity. There is increasing evidence that methylation may parallel other post-translational modifications in the regulation of various biological processes. It is still not known, however, whether EGFR is regulated by this post-translational event. Here, we show that EGFR Arg 1175 is methylated by an arginine methyltransferase, PRMT5. Arg 1175 methylation positively modulates EGF-induced EGFR trans-autophosphorylation at Tyr 1173, which governs ERK activation. Abolishment of Arg 1175 methylation enhances EGF-stimulated ERK activation by reducing SHP1 recruitment to EGFR, resulting in augmented cell proliferation, migration and invasion of EGFR-expressing cells. Therefore, we propose a model in which the regulatory crosstalk between PRMT5-mediated Arg 1175 methylation and EGF-induced Tyr 1173 phosphorylation attenuates EGFR-mediated ERK activation.