Opposing effect of EGFRWT on EGFRvIII-mediated NF-κB activation with RIP1 as a cell death switch

Vineshkumar Thidil Puliyappadamba, Sharmistha Chakraborty, SandiliS Chauncey, Li Li, Kimmo J. Hatanpaa, Bruce Mickey, Shayan Noorani, Hui Kuo G Shu, Sandeep Burma, David A. Boothman, Amyn A. Habib

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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

Original languageEnglish (US)
Pages (from-to)764-775
Number of pages12
JournalCell Reports
Volume4
Issue number4
DOIs
StatePublished - Aug 29 2013

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Cell death
Cell Death
Chemical activation
Switches
Glioblastoma
Ubiquitination
Epidermal Growth Factor
epidermal growth factor receptor VIII
Caspase 8
Ligases
Ubiquitin
Cell Survival
Phosphotransferases
Cells
Association reactions
Ligands

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Opposing effect of EGFRWT on EGFRvIII-mediated NF-κB activation with RIP1 as a cell death switch. / Puliyappadamba, Vineshkumar Thidil; Chakraborty, Sharmistha; Chauncey, SandiliS; Li, Li; Hatanpaa, Kimmo J.; Mickey, Bruce; Noorani, Shayan; Shu, Hui Kuo G; Burma, Sandeep; Boothman, David A.; Habib, Amyn A.

In: Cell Reports, Vol. 4, No. 4, 29.08.2013, p. 764-775.

Research output: Contribution to journalArticle

Puliyappadamba, Vineshkumar Thidil ; Chakraborty, Sharmistha ; Chauncey, SandiliS ; Li, Li ; Hatanpaa, Kimmo J. ; Mickey, Bruce ; Noorani, Shayan ; Shu, Hui Kuo G ; Burma, Sandeep ; Boothman, David A. ; Habib, Amyn A. / Opposing effect of EGFRWT on EGFRvIII-mediated NF-κB activation with RIP1 as a cell death switch. In: Cell Reports. 2013 ; Vol. 4, No. 4. pp. 764-775.
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AU - Mickey, Bruce

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