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

Nature Cell Biology volume 13, pages 174–181 (2011)Cite this article

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Abstract

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.

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Figure 1: EGFR Arg 1175 is monomethylated.
Figure 2: PRMT5 interacts with EGFR and methylates Arg 1175.
Figure 3: Suppression of Arg 1175 methylation promotes EGFR-mediated cell proliferation, migration and invasion.
Figure 4: Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation.
Figure 5: Suppression of Arg 1175 methylation inhibits SHP1 recruitment and prolongs ERK activation.

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Acknowledgements

This work was supported by the National Institute of Health (RO1 109311 and PO1 099031), the National Breast Cancer Foundation, The Sister Institution Fund of China Medical University and Hospital/MD Anderson Cancer Center, and grants from the National Science Council (NSC 96-3111-B-039, NSC 95-2311-B-039-002 and NSC 99-2632-B-039-001), the National Health Research Institutes (NHRI-EX97-9603BC), and Department of Health (DOH97-TD-G-111-041, DOH97-TD-I-111-TM003 and DOH100-TD-C-111-005) of Taiwan. In memoriam, S. Lin-Guo for her courageous fight against breast cancer.

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Author notes

  1. Chun-Te Chen, Chao-Kai Chou and Hsu-Ping Kuo: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    Jung-Mao Hsu, Chun-Te Chen, Chao-Kai Chou, Hsu-Ping Kuo, Hong-Jen Lee, Ying-Nai Wang, Mo Liu, Hsin-Wei Liao, Bin Shi & Mien-Chie Hung

  2. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA

    Jung-Mao Hsu, Chun-Te Chen, Chao-Kai Chou, Hsu-Ping Kuo, Hong-Jen Lee, Mo Liu, Hsin-Wei Liao & Mien-Chie Hung

  3. Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan

    Long-Yuan Li, Chun-Yi Lin & Mien-Chie Hung

  4. Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan

    Long-Yuan Li, Chun-Yi Lin & Mien-Chie Hung

  5. Department of Biotechnology, Asia University, Taichung 413, Taiwan

    Long-Yuan Li, Chang-Hai Tsai & Mien-Chie Hung

  6. Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan

    Chien-Chen Lai & Chang-Hai Tsai

  7. Science Park-Research Division, The University of Texas MD Anderson Cancer Center, Smithville, Texas 78957, USA

    Mark T. Bedford

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Contributions

J-M.H. carried out experimental design and most of the experimental work. J-M.H. and M-C.H. wrote the manuscript. C-K.C. conducted cell migration and invasion experiments. H-P.K. generated stable transfectants and carried out cell proliferation assays. C-T.C. conducted animal experiments. L-Y.L. and C-Y.L. generated antibodies. H-J.L., Y-N.W. and H-W.L. carried out sucrose gradient centrifugation and confocal microscopy analyses. M.L. and B.S. conducted immunoprecipitation assays. C-C.L. carried out mass spectrometry analyses. M.T.B. contributed to PRMT plasmids and reagents. C-H.T. and M-C.H. supervised the project.

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Correspondence to Mien-Chie Hung.

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The authors declare no competing financial interests.

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Hsu, JM., Chen, CT., Chou, CK. et al. Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation. Nat Cell Biol 13, 174–181 (2011). https://doi.org/10.1038/ncb2158

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