Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification
Autor: | Isamu Okamoto, Kazuhiko Nakagawa, Junko Tanizaki, Kazuko Sakai |
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Rok vydání: | 2011 |
Předmět: |
MAPK/ERK pathway
Cancer Research Lung Neoplasms Receptor ErbB-3 Receptor ErbB-2 Apoptosis Receptor tyrosine kinase Cell Movement Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Humans Receptors Growth Factor Gene Silencing Epidermal growth factor receptor Phosphorylation heterodimerisation skin and connective tissue diseases Lung cancer Molecular Diagnostics Protein kinase B Cell Proliferation biology Cell growth Kinase Proto-Oncogene Proteins c-ret Gene Amplification Proto-Oncogene Proteins c-met medicine.disease Molecular biology trans-phosphorylation ErbB Receptors lung cancer Oncology Cancer research biology.protein Signal transduction Dimerization MET amplification Signal Transduction |
Zdroj: | British Journal of Cancer |
ISSN: | 1532-1827 0007-0920 |
Popis: | Background: MET is a receptor tyrosine kinase (RTK) whose gene is amplified in various tumour types. We investigated the roles and mechanisms of RTK heterodimerisation in lung cancer with MET amplification. Methods: With the use of an RTK array, we identified phosphorylated RTKs in lung cancer cells with MET amplification. We examined the roles and mechanisms of action of these RTKs with immunoprecipitation, annexin V binding, and cell migration assays. Results: We identified epidermal growth factor receptor (EGFR), human EGFR (HER)2, HER3, and RET in addition to MET as highly phosphorylated RTKs in lung cancer cells with MET amplification. Immunoprecipitation revealed that EGFR, HER2, HER3, and RET each formed a heterodimer exclusively with MET and that these associations were markedly reduced in extent by treatment with a MET kinase inhibitor. RNA interference-mediated depletion of EGFR, HER2, or HER3 induced apoptosis in association with inhibition of AKT and ERK signalling pathways, whereas depletion of HER2 or RET inhibited both cell migration and STAT3 signalling. Conclusion: Our data suggest that heterodimers of MET with EGFR, HER2, HER3, or RET have differential roles in tumour development, and they provide new insight into the function of trans-phosphorylated RTKs as heterodimerisation partners of MET in lung cancer with MET amplification. |
Databáze: | OpenAIRE |
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