Tyrosine phosphorylation of the human glutathione S-transferase P1 by epidermal growth factor receptor.
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.
Mesh Terms:
Amino Acid Sequence, Animals, Antineoplastic Agents, Base Sequence, Binding Sites, Breast Neoplasms, Cell Line, Tumor, Cell-Free System, Cisplatin, Drug Resistance, Neoplasm, Enzyme Activation, Female, Glioma, Glutathione S-Transferase pi, Humans, Mice, Mice, Nude, Models, Molecular, Molecular Sequence Data, Neoplasm Transplantation, Phosphorylation, Protein Conformation, Quinazolines, RNA, Small Interfering, Receptor, Epidermal Growth Factor, Recombinant Proteins, Signal Transduction, Static Electricity, Transplantation, Heterologous, Tyrosine
Amino Acid Sequence, Animals, Antineoplastic Agents, Base Sequence, Binding Sites, Breast Neoplasms, Cell Line, Tumor, Cell-Free System, Cisplatin, Drug Resistance, Neoplasm, Enzyme Activation, Female, Glioma, Glutathione S-Transferase pi, Humans, Mice, Mice, Nude, Models, Molecular, Molecular Sequence Data, Neoplasm Transplantation, Phosphorylation, Protein Conformation, Quinazolines, RNA, Small Interfering, Receptor, Epidermal Growth Factor, Recombinant Proteins, Signal Transduction, Static Electricity, Transplantation, Heterologous, Tyrosine
J. Biol. Chem.
Date: Jun. 19, 2009
PubMed ID: 19254954
View in: Pubmed Google Scholar
Download Curated Data For This Publication
204375
Switch View:
- Interactions 4