An unusual function of RON receptor tyrosine kinase as a transcriptional regulator in cooperation with EGFR in human cancer cells.
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.
Liu
Hsiao-Sheng
HS
Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
Hsu
Pei-Yin
PY
Lai
Ming-Derg
MD
Chang
Hong-Yi
HY
Ho
Chung-Liang
CL
Cheng
Hong-Lin
HL
Chen
Hsing-Ta
HT
Lin
Yan-Ju
YJ
Wu
Tsung-Jung
TJ
Tzai
Tzong-Shin
TS
Chow
Nan-Haw
NH
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
D028884:Karyopherins; D008156:Luciferases; D066246:ErbB Receptors; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases