title: Opposing effect of EGFRWT on EGFRvIII-mediated NF-κB activation with RIP1 as a cell death switch.
abstract: RIP1 is a central mediator of cell death in response to cell stress but can also mediate cell survival by activating NF-κB. Here, we show that RIP1 acts as a switch in EGFR signaling. EGFRvIII is an oncogenic mutant that does not bind ligand and is coexpressed with EGFRWT in glioblastoma multiforme (GBM). EGFRvIII recruits ubiquitin ligases to RIP1, resulting in K63-linked ubiquitination of RIP1. RIP1 binds to TAK1 and NEMO, forming an EGFRvIII-RIP1 signalosome that activates NF-κB. RIP1 is essential for EGFRvIII-mediated oncogenicity and correlates with NF-κB activation in GBM. Surprisingly, activation of EGFRWT with EGF results in a negative regulation of EGFRvIII, with dissociation of the EGFRvIII-RIP1 signalosome, loss of RIP1 ubiquitination and NF-κB activation, and association of RIP1 with FADD and caspase-8. If EGFRWT is overexpressed with EGFRvIII, the addition of EGF leads to a RIP1 kinase-dependent cell death. The EGFRWT-EGFRvIII-RIP1 interplay may regulate oncogenicity and vulnerability to targeted treatment in GBM.
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Vineshkumar Thidil
authors: VT
authors: Puliyappadamba
authors: Sharmistha
authors: S
authors: Chakraborty
authors: Sandili S
authors: SS
authors: Chauncey
authors: Li
authors: L
authors: Li
authors: Kimmo J
authors: KJ
authors: Hatanpaa
authors: Bruce
authors: B
authors: Mickey
authors: Shayan
authors: S
authors: Noorani
authors: Hui-Kuo G
authors: HK
authors: Shu
authors: Sandeep
authors: S
authors: Burma
authors: David A
authors: DA
authors: Boothman
authors: Amyn A
authors: AA
authors: Habib
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism; D063646:Carcinogenesis; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D053181:Caspase 8; D066246:ErbB Receptors; D053200:Fas-Associated Death Domain Protein; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D000099151:MAP Kinase Kinase Kinase 7; C505533:FADD protein, human; C491731:IKBKG protein, human; C410723:epidermal growth factor receptor VIII
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