Proteomic screen reveals Fbw7 as a modulator of the NF-κB pathway.
Proteomic screen reveals Fbw7 as a modulator of the NF-κB pathway.
复制标题
DOI：
10.1038/ncomms1975
复制
发表时间：
2012
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
Fbw 7是一种泛素连接酶，靶向几种癌蛋白进行蛋白水解，但Fbw 7底物的全部范围尚不清楚。在这里，我们表明，通过进行定量蛋白质组学与降解决定子基序搜索相结合，我们有效地筛选了一组更完整的Fbw 7靶标。我们确定了89个推定的Fbw 7底物，包括几种疾病相关蛋白。转录因子NF-κB2（p100/p52）是Fbw 7的候选底物之一。我们发现Fbw 7通过一个保守的降解决定子与p100相互作用，并以GSK 3 β磷酸化依赖的方式促进p100的降解。Fbw 7失活增加p100水平，在NF-κB通路刺激物存在下，这导致p52水平和活性增加。因此，凋亡阈值可以通过Fbw 7的损失以p100依赖性方式增加。总之，Fbw 7介导的p100破坏是限制对NF-κB2通路刺激反应的调节组分。Fbw 7是一种泛素连接酶，它靶向几种癌蛋白进行蛋白水解，因此对控制和预防肿瘤发生很重要。在这项研究中，Arabi及其同事对Fbw 7的靶点进行了蛋白质组学筛选，并将κ-B2的核因子确定为底物。
Fbw7 is a ubiquitin-ligase that targets several oncoproteins for proteolysis, but the full range of Fbw7 substrates is not known. Here we show that by performing quantitative proteomics combined with degron motif searches, we effectively screened for a more complete set of Fbw7 targets. We identify 89 putative Fbw7 substrates, including several disease-associated proteins. The transcription factor NF-κB2 (p100/p52) is one of the candidate Fbw7 substrates. We show that Fbw7 interacts with p100 via a conserved degron and that it promotes degradation of p100 in a GSK3β phosphorylation-dependent manner. Fbw7 inactivation increases p100 levels, which in the presence of NF-κB pathway stimuli, leads to increased p52 levels and activity. Accordingly, the apoptotic threshold can be increased by loss of Fbw7 in a p100-dependent manner. In conclusion, Fbw7-mediated destruction of p100 is a regulatory component restricting the response to NF-κB2 pathway stimulation. Fbw7 is a ubiquitin-ligase, which targets several oncoproteins for proteolysis, and is therefore important for the control and prevention of tumorigenesis. In this study, Arabi and colleagues carry out a proteomic screen of the targets of Fbw7, and identify Nuclear Factor of κ-B2 as a substrate.
登录
查看更多内容
影响因子：
64.8
作者：
Inuzuka, Hiroyuki;Shaik, Shavali;Onoyama, Ichiro;Gao, Daming;Tseng, Alan;Maser, Richard S.;Zhai, Bo;Wan, Lixin;Gutierrez, Alejandro;Lau, Alan W.;Xiao, Yonghong;Christie, Amanda L.;Aster, Jon;Settleman, Jeffrey;Gygi, Steven P.;Kung, Andrew L.;Look, Thomas;Nakayama, Keiichi I.;DePinho, Ronald A.;Wei, Wenyi
通讯作者：
Wei, Wenyi
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
51.1
作者：
Den Boer, Monique L.;van Slegtenhorst, Marjon;De Menezes, Renee X.;Cheok, Meyling H.;Buijs-Gladdines, Jessica G. C. A. M.;Peters, Susan T. C. J. M.;Van Zutven, Laura C. M.;Beverloo, H. Berna;Van der Spek, Peter J.;Escherich, Gaby;Horstmann, Martin A.;Janka-Schoub, Gritta E.;Kamps, Willem A.;Evans, William E.;Pieters, Rob
通讯作者：
Pieters, Rob
影响因子：
3.4
作者：
Eriksson, Hanna;Lengqvist, Johan;Jakobsson, Per-Johan
通讯作者：
Jakobsson, Per-Johan
DOI：
10.1073/pnas.0507809103
发表时间：
2006-06-13
影响因子：
11.1
作者：
Bernal-Mizrachi, Leon;Lovly, Christine M.;Ratner, Lee
通讯作者：
Ratner, Lee