期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/ncomms7658
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资金
- International Max Planck Research School (IMPRS) of Max-Planck-Institute for Heart and Lung Research
- German Research Foundation (DFG) [SW 148/1-1]
- Excellence Cluster Cardio-Pulmonary System (ECCPS)
The inhibitor of the nuclear factor-kappa B (I kappa B) kinase (IKK) complex is a key regulator of the canonical NF-kappa B signalling cascade and is crucial for fundamental cellular functions, including stress and immune responses. The majority of IKK complex functions are attributed to NF-kappa B activation; however, there is increasing evidence for NF-kappa B pathway-independent signalling. Here we combine quantitative mass spectrometry with random forest bioinformatics to dissect the TNF-alpha-IKK beta-induced phosphoproteome in MCF-7 breast cancer cells. In total, we identify over 20,000 phosphorylation sites, of which similar to 1% are regulated up on TNF-alpha stimulation. We identify various potential novel IKK beta substrates including kinases and regulators of cellular trafficking. Moreover, we show that one of the candidates, AEG-1/MTDH/LYRIC, is directly phosphorylated by IKK beta on serine 298. We provide evidence that IKK beta-mediated AEG-1 phosphorylation is essential for I kappa B alpha degradation as well as NF-kappa B-dependent gene expression and cell proliferation, which correlate with cancer patient survival in vivo.
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