文章基本信息

标题：EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells
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作者：Sarmishtha De ; Josephine Kam Tai Dermawan ; George R. Stark 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：32
页码：11721-11726
DOI：10.1073/pnas.1412390111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Activation of nuclear factor {kappa}B (NF{kappa}B) is a central event in the responses of normal cells to inflammatory signals, and the abnormal constitutive activation of NF{kappa}B is important for the survival of most cancer cells. In nonmalignant human cells, EGF stimulates robust activation of NF{kappa}B. The kinase activity of the EGF receptor (EGFR) is required, because the potent and specific inhibitor erlotinib blocks the response. Down-regulating EGFR expression or inhibiting EGFR with erlotinib impairs constitutive NF{kappa}B activation in several different types of cancer cells and, conversely, increased activation of NF{kappa}B leads to erlotinib resistance in these cells. We conclude that EGF is an important mediator of NF{kappa}B activation in cancer cells. To explore the mechanism, we selected an erlotinib-resistant cell line in which the guanine nucleotide exchange factor Son of Sevenless 1 (SOS1), well known to be important for EGF-dependent signaling to MAP kinases, is overexpressed. Increased expression of SOS1 increases NF{kappa}B activation in several different types of cancer cells, and ablation of SOS1 inhibits EGF-induced NF{kappa}B activation in these cells, indicating that SOS1 is a functional component of the pathway connecting EGFR to NF{kappa}B activation. Importantly, the guanine nucleotide exchange activity of SOS1 is not required for NF{kappa}B activation.