Reactive oxygen species mediate Met receptor transactivation by G protein-coupled receptors and the epidermal growth factor receptor in human carcinoma cells.

Abstract	Cross-communication between the Met receptor tyrosine kinase and the epidermal growth factor receptor (EGFR) has been proposed to involve direct association of both receptors and EGFR kinase-dependent phosphorylation. Here, we demonstrate that in human hepatocellular and pancreatic carcinoma cells the Met receptor becomes tyrosine phosphorylated not only upon EGF stimulation but also in response to G protein-coupled receptor (GPCR) agonists. Whereas specific inhibition of the EGFR kinase activity blocked EGF- but not GPCR agonist-induced Met receptor transactivation, it was abrogated in the presence of a reducing agent or treatment of cells with a NADPH oxidase inhibitor. Both GPCR ligands and EGF are further shown to increase the level of reactive oxygen species within the cell. Interestingly, stimulation of the Met receptor by either GPCR agonists, EGF or its cognate ligand HGF, resulted in release of Met-associated beta-catenin and in its Met-dependent translocation into the nucleus, as analyzed by small interfering RNA-mediated knockdown of the Met receptor. Our results provide a new molecular explanation for cell surface receptor cross-talk involving the Met receptor and thereby link the wide diversity of GPCRs and the EGFR to the oncogenic potential of Met signaling in human carcinoma cells.
Authors	Oliver M Fischer, Silvia Giordano, Paolo M Comoglio, Axel Ullrich
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 28 Pg. 28970-8 (Jul 09 2004) ISSN: 0021-9258 [Print] United States
PMID	15123705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	CTNNB1 protein, human Cytoskeletal Proteins Enzyme Inhibitors Ligands Proteins Proto-Oncogene Proteins RNA, Small Interfering Reactive Oxygen Species Receptors, G-Protein-Coupled Receptors, Growth Factor Trans-Activators beta Catenin Epidermal Growth Factor NADPH Oxidases ErbB Receptors MET protein, human Proto-Oncogene Proteins c-met Receptor Protein-Tyrosine Kinases
Topics	Animals Carcinoma (metabolism) Cell Fractionation Cell Line, Tumor Cytoskeletal Proteins (metabolism) Enzyme Inhibitors (metabolism) Epidermal Growth Factor (metabolism) ErbB Receptors (metabolism) Humans Ligands MAP Kinase Signaling System (physiology) NADPH Oxidases (metabolism) Phosphorylation Proteins (genetics, metabolism) Proto-Oncogene Proteins Proto-Oncogene Proteins c-met RNA, Small Interfering (metabolism) Reactive Oxygen Species (metabolism) Receptor Protein-Tyrosine Kinases (genetics, metabolism) Receptors, G-Protein-Coupled (metabolism) Receptors, Growth Factor Trans-Activators (metabolism) Transcriptional Activation beta Catenin

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