Summary RIP1 is a central mediator of cell death in cell stress, but can also mediate cell survival by activating NF-κB. Here, we show that RIP1 is a switch in EGFR signaling. EGFRvIII is an oncogenic mutant that does not bind ligand and is co-expressed with EGFRwt in glioblastoma (GBM). EGFRvIII recruits ubiquitin ligases to RIP1 resulting in K63-linked ubiquitination of RIP1. RIP1 binds to TAK1 and NEMO forming a 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 novel negative regulation of EGFRvIII with dissociation of the EGFRvIII-RIP1 signalosome, loss of RIP1 ubiquitination, NF-κB activation, and association of RIP1 with FADD and Caspase-8. If EGFRwt is overexpressed with EGFRvIII, adding EGF leads to a RIP1 kinase dependent cell death. The EGFRwt-EGFRvIII-RIP1 interplay may regulate oncogenicity and vulnerability to targeted treatment in GBM.

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