Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation.
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.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jung-Mao
JM
Hsu
Chun-Te
CT
Chen
Chao-Kai
CK
Chou
Hsu-Ping
HP
Kuo
Long-Yuan
LY
Li
Chun-Yi
CY
Lin
Hong-Jen
HJ
Lee
Ying-Nai
YN
Wang
Mo
M
Liu
Hsin-Wei
HW
Liao
Bin
B
Shi
Chien-Chen
CC
Lai
Mark T
MT
Bedford
Chang-Hai
CH
Tsai
Mien-Chie
MC
Hung
D001120:Arginine / Q000378:metabolism*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008745:Methylation; D010766:Phosphorylation; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases; D014443:Tyrosine / Q000378:metabolism*
D014443:Tyrosine; D001120:Arginine; D011496:Protein Methyltransferases; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
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