Tyrosine phosphorylation of the human glutathione S-transferase P1 by epidermal growth factor receptor

J Biol Chem. 2009 Jun 19;284(25):16979-16989. doi: 10.1074/jbc.M808153200. Epub 2009 Mar 2.


Epidermal growth factor receptor (EGFR) gene amplification, mutations, and/or aberrant activation are frequent abnormalities in malignant gliomas and other human cancers and have been associated with an aggressive clinical course and a poor therapeutic outcome. Elevated glutathione S-transferase P1 (GSTP1), a major drug-metabolizing and stress response signaling protein, is also associated with drug resistance and poor clinical outcome in gliomas and other cancers. Here, we provide evidence that GSTP1 is a downstream EGFR target and that EGFR binds to and phosphorylates tyrosine residues in the GSTP1 protein in vitro and in vivo. Mass spectrometry and mutagenesis analyses in a cell-free system and in gliomas cells identified Tyr-7 and Tyr-198 as major EGFR-specific phospho-acceptor residues in the GSTP1 protein. The phosphorylation increased GSTP1 enzymatic activity significantly, and computer-based modeling showed a corresponding increase in electronegativity of the GSTP1 active site. In human glioma and breast cancer cells, epidermal growth factor stimulation rapidly increased GSTP1 tyrosine phosphorylation and decreased cisplatin sensitivity. Lapatinib, a clinically active EGFR inhibitor, significantly reversed the epidermal growth factor-induced cisplatin resistance. These data define phosphorylation and activation of GSTP1 by EGFR as a novel, heretofore unrecognized component of the EGFR signaling network and a novel mechanism of tumor drug resistance, particularly in tumors with elevated GSTP1 and/or activated EGFR.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / pharmacology
  • Base Sequence
  • Binding Sites
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell-Free System
  • Cisplatin / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Enzyme Activation
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Female
  • Glioma / drug therapy
  • Glioma / genetics
  • Glioma / metabolism
  • Glutathione S-Transferase pi / antagonists & inhibitors
  • Glutathione S-Transferase pi / chemistry*
  • Glutathione S-Transferase pi / genetics
  • Glutathione S-Transferase pi / metabolism*
  • Humans
  • Lapatinib
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Phosphorylation
  • Protein Conformation
  • Quinazolines / pharmacology
  • RNA, Small Interfering / genetics
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Static Electricity
  • Transplantation, Heterologous
  • Tyrosine / chemistry


  • Antineoplastic Agents
  • Quinazolines
  • RNA, Small Interfering
  • Recombinant Proteins
  • Lapatinib
  • Tyrosine
  • GSTP1 protein, human
  • Glutathione S-Transferase pi
  • ErbB Receptors
  • Cisplatin