Journal
CARCINOGENESIS
Volume 31, Issue 8, Pages 1456-1464Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgq100
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Funding
- National Science Council, Taiwan [NSC96-2320-B-006-025, 95-2320-B006-058-MY3]
- Ministry of Education Program for Promoting Academic Excellence in Universities, Taiwan [91-B-FA09-1-4]
- Department of Health, Executive Yuan, Taiwan [DOH-TD-B-111-004]
- National Health Research Institutes, Taiwan [NHRI-EX99-9930BI]
- National Institutes of Health, USA [R01CA 69065, U54CA11300]
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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.
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