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A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.

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)-alpha triggers a signalling cascade, converging on the activation of the transcription factor NF-kappa 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-alpha/NF-kappa 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-alpha/NF-kappa B pathway and is generally applicable to other pathways relevant to human disease.

Pubmed ID: 14743216


  • Bouwmeester T
  • Bauch A
  • Ruffner H
  • Angrand PO
  • Bergamini G
  • Croughton K
  • Cruciat C
  • Eberhard D
  • Gagneur J
  • Ghidelli S
  • Hopf C
  • Huhse B
  • Mangano R
  • Michon AM
  • Schirle M
  • Schlegl J
  • Schwab M
  • Stein MA
  • Bauer A
  • Casari G
  • Drewes G
  • Gavin AC
  • Jackson DB
  • Joberty G
  • Neubauer G
  • Rick J
  • Kuster B
  • Superti-Furga G


Nature cell biology

Publication Data

February 2, 2004

Associated Grants


Mesh Terms

  • Animals
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cell Line
  • Chaperonins
  • Chromatography, Affinity
  • Drosophila Proteins
  • Enzyme Activation
  • HSP90 Heat-Shock Proteins
  • Humans
  • I-kappa B Proteins
  • MAP Kinase Kinase Kinase 3
  • MAP Kinase Kinase Kinases
  • Macromolecular Substances
  • Mass Spectrometry
  • Models, Biological
  • Molecular Chaperones
  • NF-kappa B
  • Proteome
  • RNA Interference
  • Receptors, Tumor Necrosis Factor
  • Signal Transduction
  • Tacrolimus Binding Proteins
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins