title: Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells.
abstract: Under normal physiologic conditions, the glutathione S-transferase P1 (GSTP1) protein exists intracellularly as a dimer in reversible equilibrium with its monomeric subunits. In the latter form, GSTP1 binds to the mitogen-activated protein kinase, JNK, and inhibits JNK downstream signaling. In tumor cells, which frequently are characterized by constitutively high GSTP1 expression, GSTP1 undergoes phosphorylation by epidermal growth factor receptor (EGFR) at tyrosine residues 3, 7, and 198. Here we report on the effect of this EGFR-dependent GSTP1 tyrosine phosphorylation on the interaction of GSTP1 with JNK, on the regulation of JNK downstream signaling by GSTP1, and on tumor cell survival. Using in vitro and in vivo growing human brain tumors, we show that tyrosine phosphorylation shifts the GSTP1 dimer-monomer equilibrium to the monomeric state and facilitates the formation of the GSTP1-JNK complex, in which JNK is functionally inhibited. Targeted mutagenesis and functional analysis demonstrated that the increased GSTP1 binding to JNK results from phosphorylation of the GSTP1 C-terminal Tyr-198 by EGFR and is associated with a >2.5-fold decrease in JNK downstream signaling and a significant suppression of both spontaneous and drug-induced apoptosis in the tumor cells. The findings define a novel mechanism of regulatory control of JNK signaling that is mediated by the EGFR/GSTP1 cross-talk and provides a survival advantage for tumors with activated EGFR and high GSTP1 expression. The results lay the foundation for a novel strategy of dual EGFR/GSTP1 for treating EGFR+ve, GSTP1 expressing GBMs.
authors.affiliation: From the Departments of Neurosurgery and.
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Okamura
authors.affiliation: From the Departments of Neurosurgery and.
authors.forename: Gamil
authors.initials: G
authors.lastname: Antoun
authors.affiliation: From the Departments of Neurosurgery and the Preston Robert Tisch Brain Tumor Center.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.affiliation: From the Departments of Neurosurgery and the Preston Robert Tisch Brain Tumor Center, Duke Cancer Institute and Duke University School of Medicine, Durham, North Carolina 27710.
authors.forename: Henry
authors.initials: H
authors.lastname: Friedman
authors.affiliation: From the Departments of Neurosurgery and the Preston Robert Tisch Brain Tumor Center, Duke Cancer Institute and Duke University School of Medicine, Durham, North Carolina 27710 Pathology and.
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.affiliation: From the Departments of Neurosurgery and the Preston Robert Tisch Brain Tumor Center, Duke Cancer Institute and Duke University School of Medicine, Durham, North Carolina 27710 Pathology and francis.aliosman@duke.edu.
authors.forename: Francis
authors.initials: F
authors.lastname: Ali-Osman
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D051549:Glutathione S-Transferase pi / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; C512478:EGFR protein, human; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases
keywords: apoptosis; brain tumor; c-Jun N-terminal kinase (JNK); epidermal growth factor receptor (EGFR); phosphorylation