The Nucleus-Localized Epidermal Growth Factor Receptor Is SUMOylated

Biochemistry. 2015 Aug 25;54(33):5157-66. doi: 10.1021/acs.biochem.5b00640. Epub 2015 Aug 14.


The epidermal growth factor receptor (EGFR) plays important roles in normal and cancer cell growth. The EGFR has principally two different signaling pathways: the canonical kinase route induced at the plasma membrane resulting in an intracellular phosphorylation cascade via MAPKs and PI3K and the more recently discovered pathway by which the receptor functions as a transcriptional co-activator inside the cell nucleus. Full length EGFR translocates to the inner nuclear membrane, via the endoplasmic reticulum, through association with the sec61β translocon. The c-myc (MYC) and cyclin D1 (CNND1) genes represent two target genes for nuclear EGFR (nEGFR). Here we show that EGFR is SUMOylated and that the SUMO-1-modified receptors are almost unexceptionally nuclear. Co-immunoprecipitation experiments suggest that EGFR is multi-SUMOylated. Using two mass spectrometry-based strategies (matrix-assisted laser desorption ionization time of flight and electrospray ionization liquid chromatography with tandem mass spectrometry), lysine 37 was identified as a SUMO-1-modified residue by both methods. A lysine 37 site mutant (K37R) was transfected into EGFR deficient cells. Total SUMOylation of EGFR was not altered in the K37R-transfected cells, confirming the presence of other SUMOylation sites. To gain preliminary insight into the possible functional role of EGFR SUMOylation, we compared the effect of expression of the wild-type EGFR with the K37R mutant on promoter activity and expression of CMYC and CNND1. Our results indicate that SUMO-1 modification may affect the transcriptional activity of EGFR, which might have additional impact on, e.g., cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Cell Line
  • Cell Nucleus / metabolism*
  • ErbB Receptors / chemistry
  • ErbB Receptors / metabolism*
  • Humans
  • Molecular Sequence Data
  • Protein Processing, Post-Translational*
  • SUMO-1 Protein / metabolism*
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Transcriptional Activation
  • Ubiquitins / metabolism


  • SUMO-1 Protein
  • SUMO2 protein, human
  • SUMO3 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Ubiquitins
  • ErbB Receptors