title: Constitutive and ligand-induced EGFR signalling triggers distinct and mutually exclusive downstream signalling networks.
abstract: 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.
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Vineshkumar Thidil
authors.initials: VT
authors.lastname: Puliyappadamba
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Gao
authors.initials: G
authors.lastname: Guo
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.affiliation: Department of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Mickey
authors.affiliation: 1] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [3] Esophageal Diseases Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [4] VA North Texas Health Care System, Dallas, Texas 75216, USA.
authors.forename: Rhonda F
authors.initials: RF
authors.lastname: Souza
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Peggy
authors.initials: P
authors.lastname: Vo
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.affiliation: Department of Microbiology, Graduate Institute, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Mei-Ru
authors.initials: MR
authors.lastname: Chen
authors.affiliation: 1] Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [3] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
authors.affiliation: 1] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [3] Esophageal Diseases Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [4] VA North Texas Health Care System, Dallas, Texas 75216, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Wang
authors.affiliation: Department of Molecular Genetics, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
authors.affiliation: 1] Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [3] VA North Texas Health Care System, Dallas, Texas 75216, USA.
authors.forename: Amyn A
authors.initials: AA
authors.lastname: Habib
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; C406887:IFI27 protein, human; C484290:IFIT1 protein, human; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D055765:Shc Signaling Adaptor Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C403191:TBK1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases