Opposing Effect of EGFRWT on EGFRvIII-Mediated NF-kappa B Activation with RIP1 as a Cell Death Switch

• Type of Material: Article
• Authors: Vineshkumar Thidil Puliyappadamba, University of Texas Southwestern; Sharmistha Chakraborty, University of Texas Southwestern; Sandili S. Chauncey, University of Texas Southwestern; Li Li, University of Texas Southwestern; Kimmo J. Hatanpaa, University of Texas Southwestern; Bruce Mickey, University of Texas Southwestern; Shayan Noorani, University of Texas Southwestern; Hui-Kuo Shu, Emory University; Sandeep Burma, University of Texas Southwestern; David A. Boothman, University of Texas Southwestern; Amyn A. Habib, University of Texas Southwestern
• Language: English
• Date: 2013-08-01
• Publisher: Elsevier (Cell Press): OAJ
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 The Authors. Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2013.07.025
• Title of Journal or Parent Work: Cell Reports
• ISSN: 2211-1247
• Volume: 4
• Issue: 4
• Start Page: 764
• End Page: 775
• Grant/Funding Information: This work was supported in part by NIH grants RO1 NS062080 to AH, by RO1 grants CA139217 and CA102792 to DAB, and RO1 CA149461 to SB and by grants from National Aeronautics and Space Administration (NNX13AI13G) and the Cancer Prevention and Research Institute of Texas (RP100644) to SB.
• Keywords: RIPOPTOSOME; EXPRESSION; FACTOR-RECEPTOR; Cell Biology; UBIQUITINATION; IDENTIFICATION; PATHWAY; EPIDERMAL-GROWTH-FACTOR; Life Sciences & Biomedicine; Science & Technology; CANCER-CELLS; ALPHA-DEPENDENT APOPTOSIS; SURVIVAL
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology; Biology, Neuroscience

Abstract

RIP1 is a central mediator of cell death in response tocell 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, resultingin K63-linked ubiquitination of RIP1. RIP1 binds toTAK1 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