title: Ron kinase transphosphorylation sustains MET oncogene addiction.
abstract: Receptors for the scatter factors HGF and MSP that are encoded by the MET and RON oncogenes are key players in invasive growth. Receptor cross-talk between Met and Ron occurs. Amplification of the MET oncogene results in kinase activation, deregulated expression of an invasive growth phenotype, and addiction to MET oncogene signaling (i.e., dependency on sustained Met signaling for survival and proliferation). Here we show that cancer cells addicted to MET also display constitutive activation of the Ron kinase. In human cancer cell lines coexpressing the 2 oncogenes, Ron is specifically transphosphorylated by activated Met. In contrast, Ron phosphorylation is not triggered in cells harboring constitutively active kinase receptors other than Met, including Egfr or Her2. Furthermore, Ron phosphorylation is suppressed by Met-specific kinase inhibitors (PHA-665752 or JNJ-38877605). Last, Ron phosphorylation is quenched by reducing cell surface expression of Met proteins by antibody-induced shedding. In MET-addicted cancer cells, short hairpin RNA-mediated silencing of RON expression resulted in decreased proliferation and clonogenic activity in vitro and tumorigenicity in vivo. Our findings establish that oncogene addiction to MET involves Ron transactivation, pointing to Ron kinase as a target for combinatorial cancer therapy.
authors.affiliation: Exploratory Research Laboratory, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, 10060 Candiolo, Turin, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Benvenuti
authors.forename: Luca
authors.initials: L
authors.lastname: Lazzari
authors.forename: Addolorata
authors.initials: A
authors.lastname: Arnesano
authors.forename: Giulia
authors.initials: G
authors.lastname: Li Chiavi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gentile
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D009857:Oncogenes; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D011720:Pyrazoles; D011724:Pyridazines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000494:pharmacology
chemical_list: C000599304:JNJ38877605; D011720:Pyrazoles; D011724:Pyridazines; D017978:Receptors, Growth Factor; D014230:Triazoles; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases