Nature Cell Biology
6, 97 - 105 (2004)
Published online: 25 January 2004; | doi:10.1038/ncb1086
There is an Erratum (May 2004) associated with this Article.
A physical and functional map of the human TNF- /NF- B signal transduction pathwayTewis 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 Casari, Gerard Drewes, Anne-Claude Gavin, David B. Jackson, Gerard Joberty, Gitte Neubauer, Jens Rick, Bernhard Kuster
& Giulio Superti-Furga
Cellzome AG, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Correspondence should be addressed to Tewis Bouwmeester tewis.bouwmeester@cellzome.com or Giulio Superti-Furga giulio.superti-furga@cellzome.comSignal 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)- triggers a signalling cascade, converging on the activation of the transcription factor NF- B, 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-/NF-B 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-/NF-B pathway and is generally applicable to other pathways relevant to human disease.
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