Quantitative analysis of the TNF-α-induced phosphoproteome reveals AEG-1/MTDH/LYRIC as an IKKβ substrate.
Quantitative analysis of the TNF-α-induced phosphoproteome reveals AEG-1/MTDH/LYRIC as an IKKβ substrate.
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TNF-α诱导的磷蛋白组的定量分析揭示了AEG-1/MTDH/歌词作为IKKβ底物。
DOI：
10.1038/ncomms7658
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发表时间：
2015-04-07
影响因子：
16.6
通讯作者：
Swiercz, Jakub M.
中科院分区：
文献类型：
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作者：
Krishnan, Ramesh K.;Nolte, Hendrik;Sun, Tianliang;Kaur, Harmandeep;Sreenivasan, Krishnamoorthy;Looso, Mario;Offermanns, Stefan;Krueger, Marcus;Swiercz, Jakub M.
核因子-κB（IκB）激酶（IKK）复合物的抑制剂是经典NF-κB信号级联的关键调节剂，对基本细胞功能（包括应激和免疫应答）至关重要。大多数IKK复合物功能归因于NF-κB激活;然而，越来越多的证据表明NF-κB通路不依赖信号传导。本文将联合收割机定量质谱与随机森林生物信息学相结合，对MCF-7乳腺癌细胞中TNF-α-IKKβ诱导的磷酸化蛋白质组进行了剖析。我们总共鉴定了超过20，000个磷酸化位点，其中101%在TNF-α刺激下受到调节。我们鉴定了各种潜在的新型IKKβ底物，包括激酶和细胞运输调节因子。此外，我们还发现其中一个候选物AEG-1/MTDH/LYRIC被IKKβ直接磷酸化在丝氨酸298上。我们提供的证据表明，IKKβ介导的AEG-1磷酸化对于IκBα降解以及NF-κ B依赖性基因表达和细胞增殖是必不可少的，这与癌症患者的体内生存有关。 炎性细胞因子如TNF-α通过调节激酶IKKβ影响炎症、细胞凋亡和肿瘤发展。Krishnan和Nolte等人应用定量蛋白质组学鉴定潜在的IKKβ靶点，并揭示IKKβ对AEG-1的磷酸化是控制NF-κB信号传导的机制。
The inhibitor of the nuclear factor-κB (IκB) kinase (IKK) complex is a key regulator of the canonical NF-κB signalling cascade and is crucial for fundamental cellular functions, including stress and immune responses. The majority of IKK complex functions are attributed to NF-κB activation; however, there is increasing evidence for NF-κB pathway-independent signalling. Here we combine quantitative mass spectrometry with random forest bioinformatics to dissect the TNF-α-IKKβ-induced phosphoproteome in MCF-7 breast cancer cells. In total, we identify over 20,000 phosphorylation sites, of which ∼1% are regulated up on TNF-α stimulation. We identify various potential novel IKKβ substrates including kinases and regulators of cellular trafficking. Moreover, we show that one of the candidates, AEG-1/MTDH/LYRIC, is directly phosphorylated by IKKβ on serine 298. We provide evidence that IKKβ-mediated AEG-1 phosphorylation is essential for IκBα degradation as well as NF-κB-dependent gene expression and cell proliferation, which correlate with cancer patient survival in vivo. Inflammatory cytokines such as TNF-α influence inflammation, apoptosis and tumour development through regulation of the kinase IKKβ. Krishnan and Nolte et al. apply quantitative proteomics to identify potential IKKβ targets, and reveal phosphorylation of AEG-1 by IKKβ as a mechanism controlling NF-κB signalling.
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