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

Nat Cell Biol. 2011 Feb;13(2):174-81. doi: 10.1038/ncb2158. Epub 2011 Jan 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arginine / metabolism*
  • Enzyme Activation
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • HEK293 Cells
  • Humans
  • Methylation
  • Phosphorylation
  • Protein Methyltransferases / genetics
  • Protein Methyltransferases / metabolism
  • Protein-Arginine N-Methyltransferases
  • Tyrosine / metabolism*


  • Tyrosine
  • Arginine
  • Protein Methyltransferases
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases