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

Zhihong Wang1, Lily L Raines, Richard M Hooy

  • 1Department of Pharmacology and Molecular Sciences, Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.

ACS Chemical Biology
|September 6, 2013
PubMed

Insights

Phosphorylation of Mig6 reduces its ability to inhibit epidermal growth factor receptor (EGFR) tyrosine kinase. This suggests a mechanism for how cancer cells evade EGFR negative regulation by Mig6.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Epidermal growth factor receptor (EGFR) activity is tightly regulated by positive and negative feedback mechanisms.
  • Aberrant EGFR activation is common in many cancers.
  • Mig6 (also known as RALT) is an endogenous inhibitor of EGFR, but its phosphorylation by oncogenic EGFR variants can impair its function.

Purpose of the Study:

  • To investigate the effect of Mig6 phosphorylation on its inhibitory activity against purified EGFR.
  • To characterize the behavior of near full-length EGFR (tEGFR) in different biochemical environments.

Main Methods:

  • Semisynthetic production of Tyr394 phosphorylated and unphosphorylated Mig6 using expressed protein ligation.
  • Biochemical assays to measure the inhibitory activity of Mig6 against purified tEGFR.
  • Characterization of tEGFR kinetics in detergent solution and reconstituted nanodisc bilayers.

Main Results:

  • Phosphorylation of Mig6 at Tyr394 significantly reduces its ability to inhibit purified tEGFR.
  • The kinetic parameters of tEGFR remain consistent in both detergent-solubilized and nanodisc-reconstituted states.
  • These findings indicate that Mig6 phosphorylation impairs its negative feedback on EGFR.

Conclusions:

  • Mig6 phosphorylation by oncogenic EGFR variants is a mechanism by which cancer cells can evade negative feedback regulation.
  • EGFR and its family members may exploit this mechanism to promote uncontrolled proliferation in pathological conditions.

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