Tyrosine phosphorylation of mig6 reduces its inhibition of the epidermal growth factor receptor

ACS Chem Biol. 2013 Nov 15;8(11):2372-6. doi: 10.1021/cb4005707. Epub 2013 Sep 6.


Under physiological conditions, epidermal growth factor receptor (EGFR) tyrosine kinase activity is tightly controlled through the coordinated action of both positive and negative regulators. Aberrant EGFR activation occurs frequently in many cancer types, and the endogenous EGFR feedback inhibitor, Mig6/RALT, is more efficiently phosphorylated by oncogenic EGFR variants. We have utilized expressed protein ligation to generate semisynthetic Tyr394 phosphorylated and unphosphorylated forms of the Mig6 protein and shown that phosphorylation of Mig6 reduces its ability to inhibit purified, near full-length EGFR (tEGFR). We also demonstrate that the kinetic parameters of tEGFR are similar whether solubilized in detergent or reconstitutued in nanodisc bilayers. These findings suggest a mechanism by which EGFR and its family members evade negative regulation by Mig6 under pathological conditions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adaptor Proteins, Signal Transducing / pharmacology
  • Amino Acid Sequence
  • Biological Assay
  • ErbB Receptors / antagonists & inhibitors*
  • Humans
  • Models, Biological
  • Mutation
  • Phosphorylation
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / metabolism*
  • Tumor Suppressor Proteins / pharmacology
  • Tyrosine / metabolism*


  • Adaptor Proteins, Signal Transducing
  • ERRFI1 protein, human
  • Tumor Suppressor Proteins
  • Tyrosine
  • ErbB Receptors