title: An unusual function of RON receptor tyrosine kinase as a transcriptional regulator in cooperation with EGFR in human cancer cells.
abstract: Homodimerization of RON (MST1R), a receptor tyrosine kinase, usually occurs in cells stimulated by a ligand and leads to the downstream activation of signaling pathways. Here we report that bladder cancer cells, in response to physiological stress, use an alternative mechanism for signaling activation. Time-course studies indicated that RON migrated directly from the membrane to the nucleus of bladder cancer cells in response to serum starvation. Biochemical and genetic studies implied that this nuclear internalization was complexed with epidermal growth factor receptor (EGFR) and required the docking of importins. In vivo analysis confirmed that nuclear RON was present in 38.4% (28/73) of primary bladder tumors. Chromatin immunoprecipitation (ChIP) on microarray analysis further revealed that this internalized complex bound to at least 134 target genes known to participate in three stress-responsive networks: p53, stress-activated protein kinase/c-jun N-terminal kinase and phosphatidylinositol 3-kinase/Akt. These findings suggest that RON, in a complex with EGFR, acts as a transcriptional regulator in response to acute disturbances (e.g. serum starvation) imposed on cancer cells. In an attempt to re-establish homeostasis, these cells bypass regular mechanisms required by ligand stimulation and trigger the RON-directed transcriptional response, which confers a survival advantage.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hsiao-Sheng
authors.initials: HS
authors.lastname: Liu
authors.forename: Pei-Yin
authors.initials: PY
authors.lastname: Hsu
authors.forename: Ming-Derg
authors.initials: MD
authors.lastname: Lai
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Chang
authors.forename: Chung-Liang
authors.initials: CL
authors.lastname: Ho
authors.forename: Hong-Lin
authors.initials: HL
authors.lastname: Cheng
authors.forename: Hsing-Ta
authors.initials: HT
authors.lastname: Chen
authors.forename: Yan-Ju
authors.initials: YJ
authors.lastname: Lin
authors.forename: Tsung-Jung
authors.initials: TJ
authors.lastname: Wu
authors.forename: Tzong-Shin
authors.initials: TS
authors.lastname: Tzai
authors.forename: Nan-Haw
authors.initials: NH
authors.lastname: Chow
mesh_terms: D015153:Blotting, Western; D002455:Cell Division; D019281:Dimerization; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D028884:Karyopherins / Q000378:metabolism; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D028884:Karyopherins; D008156:Luciferases; D066246:ErbB Receptors; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases