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Basic Amino Acids Within the Juxtamembrane Domain of the Epidermal Growth Factor Receptor Regulate Receptor

Jordan D Mohr1,2, Alice Wagenknecht-Wiesner1, David A Holowka1

  • 1Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA.

The Protein Journal
|November 19, 2020
PubMed

Insights

Altering the charge of the juxtamembrane region of the epidermal growth factor receptor (EGFR) causes it to activate and form dimers. This suggests the charge normally inhibits EGFR dimerization.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Epidermal growth factor receptor (EGFR) dysregulation is implicated in human cancers, serving as both an oncogenic driver and a therapeutic target.
  • Previous studies demonstrated that mutations in the juxtamembrane (JX) region of EGFR can lead to constitutive receptor activation.

Purpose of the Study:

  • To investigate the role of electrostatic charge in the juxtamembrane region of EGFR in regulating receptor dimerization and activation.
  • To elucidate the structural requirements for the activation of constitutively active EGFR mutants.

Main Methods:

  • Utilized chemical crosslinking and immunoblotting techniques to analyze EGFR mutant constructs.
  • Employed conformationally-restricted receptor mutants to probe the coupling mechanisms during EGFR activation.

Main Results:

  • EGFR mutants with partial charge neutralization in the JX region form constitutive, phosphorylated dimers in both the plasma membrane and the endoplasmic reticulum (ER).
  • Activation of these EGFR dimers necessitates functional coupling between extracellular dimerization domains and intracellular tyrosine kinase domains.

Conclusions:

  • The electrostatic charge of the EGFR juxtamembrane region acts as a negative regulator of functional receptor dimerization.
  • Understanding these regulatory mechanisms provides insights into EGFR-driven oncogenesis and potential therapeutic strategies.
Keywords:
DimerizationEGFRElectrostatic regulationJuxtamembrane region

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