Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Rep. 2013 Aug 29;4(4):764-75. doi: 10.1016/j.celrep.2013.07.025. Epub 2013 Aug 22.
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.
RIP1 是细胞应激反应中细胞死亡的核心介质，但通过激活 NF-κB，也可以介导细胞存活。在这里，我们表明 RIP1 是 EGFR 信号的开关。EGFRvIII 是一种致癌突变体，它不与配体结合，并且与胶质母细胞瘤（GBM）中的 EGFRWT 共表达。EGFRvIII 将泛素连接酶招募到 RIP1，导致 RIP1 的 K63 连接泛素化。RIP1 与 TAK1 和 NEMO 结合，形成 EGFRvIII-RIP1 信号体，激活 NF-κB。RIP1 对于 EGFRvIII 介导的致癌性是必不可少的，并且与 GBM 中的 NF-κB 激活相关。令人惊讶的是，EGF 对 EGFRWT 的激活导致 EGFRvIII 的负调节，EGFRvIII-RIP1 信号体解离，RIP1 泛素化和 NF-κB 激活丧失，以及 RIP1 与 FADD 和 caspase-8 的关联。如果用 EGF 过表达 EGFRWT，则会导致 RIP1 激酶依赖性细胞死亡。EGFRWT-EGFRvIII-RIP1 的相互作用可能调节 GBM 中的致癌性和对靶向治疗的敏感性。
