TY - JOUR
T1 - Opposing effect of EGFRWT on EGFRvIII-mediated NF-κB activation with RIP1 as a cell death switch
AU - Puliyappadamba, Vineshkumar Thidil
AU - Chakraborty, Sharmistha
AU - Chauncey, Sandili S.
AU - Li, Li
AU - Hatanpaa, Kimmo J.
AU - Mickey, Bruce
AU - Noorani, Shayan
AU - Shu, Hui Kuo G.
AU - Burma, Sandeep
AU - Boothman, David A.
AU - Habib, Amyn A.
PY - 2013/8/29
Y1 - 2013/8/29
N2 - 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
AB - 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
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U2 - 10.1016/j.celrep.2013.07.025
DO - 10.1016/j.celrep.2013.07.025
M3 - Article
C2 - 23972990
AN - SCOPUS:84883276560
VL - 4
SP - 764
EP - 775
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 4
ER -