https://scholars.lib.ntu.edu.tw/handle/123456789/384877
標題: | Constitutive and ligand-induced EGFR signalling triggers distinct and mutually exclusive downstream signalling networks | 作者: | Chakraborty, Sharmistha Li, Li Puliyappadamba, Vineshkumar Thidil Guo, Gao Hatanpaa, Kimmo J. Mickey, Bruce Souza, Rhonda F. Vo, Peggy Herz, Joachim MEI-RU CHEN Boothman, David A. Pandita, Tej K. Wang, David H. Sen, Ganes C. Habib, Amyn A. |
公開日期: | 2014 | 卷: | 5 | 來源出版物: | Nature Communications | 摘要: | Epidermal growth factor receptor (EGFR) overexpression plays an important oncogenic role in cancer. Regular EGFR protein levels are increased in cancer cells and the receptor then becomes constitutively active. However, downstream signals generated by constitutively activated EGFR are unknown. Here we report that the overexpressed EGFR oscillates between two distinct and mutually exclusive modes of signalling. Constitutive or non-canonical EGFR signalling activates the transcription factor IRF3 leading to expression of IFI27, IFIT1 and TRAIL. Ligand-mediated activation of EGFR switches off IRF3-dependent transcription, activates canonical extracellular signal-regulated kinase (ERK) and Akt signals, and confers sensitivity to chemotherapy and virus-induced cell death. Mechanistically, the distinct downstream signals result from a switch of EGFR-associated proteins. EGFR constitutively complexes with IRF3 and TBK1 leading to TBK1 and IRF3 phosphorylation. Addition of epidermal growth factor dissociates TBK1, IRF3 and EGFR leading to a loss of IRF3 activity, Shc-EGFR association and ERK activation. Finally, we provide evidence for non-canonical EGFR signalling in glioblastoma. ? 2014 Macmillan Publishers Limited. All rights reserved. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-84923344806&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/384877 |
DOI: | 10.1038/ncomms6811 | SDG/關鍵字: | beta interferon; cetuximab; epidermal growth factor receptor; erlotinib; interferon regulatory factor 27; interferon regulatory factor 3; ligand; mitogen activated protein kinase; protein kinase B; STAT1 protein; STAT2 protein; temozolomide; thapsigargin; transcription factor; unclassified drug; antineoplastic agent; carrier protein; EGFR protein, human; epidermal growth factor; epidermal growth factor receptor; IFI27 protein, human; IFIT1 protein, human; interferon regulatory factor 3; IRF3 protein, human; membrane protein; mitogen activated protein kinase; protein kinase B; protein serine threonine kinase; protein Shc; TBK1 protein, human; TNFSF10 protein, human; tumor necrosis factor related apoptosis inducing ligand; cytology; gene expression; growth regulator; ligand; protein; signal; Article; biological activity; cell death; chemotherapy; controlled study; cytokine release; endoplasmic reticulum stress; gene overexpression; glioblastoma; human; human tissue; innate immunity; intracellular space; ligand binding; oscillation; protein phosphorylation; signal transduction; transcription initiation; upregulation; apoptosis; brain tumor; drug effects; gene expression regulation; genetics; metabolism; pathology; phosphorylation; primary cell culture; signal transduction; tumor cell line; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Carrier Proteins; Cell Line, Tumor; Epidermal Growth Factor; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Interferon Regulatory Factor-3; Membrane Proteins; Phosphorylation; Primary Cell Culture; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Receptor, Epidermal Growth Factor; Shc Signaling Adaptor Proteins; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand |
顯示於: | 醫學系 |
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