A physical and functional map of the human TNF-α/NF-κB signal transduction pathway

Tewis Bouwmeester, Angela Bauch, Heinz Ruffner, Pierre Olivier Angrand, Giovanna Bergamini, Karen Croughton, Cristina Cruciat, Dirk Eberhard, Julien Gagneur, Sonja Ghidelli, Carsten Hopf, Bettina Huhse, Raffaella Mangano, Anne Marie Michon, Markus Schirle, Judith Schlegl, Markus Schwab, Martin A. Stein, Andreas Bauer, Georg CasariGerard Drewes, Anne Claude Gavin, David B. Jackson, Gerard Joberty, Gitte Neubauer, Jens Rick, Bernhard Kuster, Giulio Superti-Furga

Research output: Contribution to journalArticlepeer-review

901 Scopus citations

Abstract

Signal transduction pathways are modular composites of functionally interdependent sets of proteins that act in a coordinated fashion to transform environmental information into a phenotypic response. The pro-inflammatory cytokine tumour necrosis factor (TNF -α triggers a signalling cascade, converging on the activation of the transcription factor NF-κB, which forms the basis for numerous physiological and pathological processes. Here we report the mapping of a protein interaction network around 32 known and candidate TNF-α/NF-κB pathway components by using an integrated approach comprising tandem affinity purification, liquid-chromatography tandem mass spectrometry, network analysis and directed functional perturbation studies using RNA interference. We identified 221 molecular associations and 80 previously unknown interactors, including 10 new functional modulators of the pathway. This systems approach provides significant insight into the logic of the TNF-α/NF-κB pathway and is generally applicable to other pathways relevant to human disease.

Original languageEnglish
Pages (from-to)97-105
Number of pages9
JournalNature Cell Biology
Volume6
Issue number2
DOIs
StatePublished - Feb 2004
Externally publishedYes

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