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

  • Bouwmeester T
  • Bauch A
  • Ruffner H
 et al. 
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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)-alpha triggers a signalling cascade, converging on the activation of the transcription factor NF- kappaB, 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-kappaB 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-kappaB pathway and is generally applicable to other pathways relevant to human disease.

Author-supplied keywords

  • ACTIVATION
  • Affinity
  • Affinity: methods
  • Animals
  • Biological
  • Carrier Proteins
  • Carrier Proteins: genetics
  • Carrier Proteins: metabolism
  • Cell Cycle Proteins
  • Cell Cycle Proteins: genetics
  • Cell Cycle Proteins: metabolism
  • Cell Line
  • Chaperonins
  • Chromatography
  • Drosophila Proteins
  • Enzyme Activation
  • GENERATION
  • HSP90
  • HSP90 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins: genetics
  • HSP90 Heat-Shock Proteins: metabolism
  • Humans
  • I-kappa B Proteins
  • I-kappa B Proteins: isolation & purification
  • I-kappa B Proteins: metabolism
  • IKK
  • KINASE
  • MAP Kinase Kinase Kinase 3
  • MAP Kinase Kinase Kinases
  • MAP Kinase Kinase Kinases: genetics
  • MAP Kinase Kinase Kinases: metabolism
  • MECHANISM
  • Macromolecular Substances
  • Mass Spectrometry
  • Mass Spectrometry: methods
  • Models
  • Molecular Chaperones
  • Molecular Chaperones: genetics
  • Molecular Chaperones: metabolism
  • NF-KAPPA-B2/P100
  • NF-kappa B
  • NF-kappa B: genetics
  • NF-kappa B: isolation & purification
  • NF-kappa B: metabolism
  • P52
  • PROTEIN
  • Proteome
  • Proteome: analysis
  • RNA Interference
  • Receptors
  • SCALE DATA
  • Signal Transduction
  • Signal Transduction: physiology
  • Tacrolimus Binding Proteins
  • Tacrolimus Binding Proteins: genetics
  • Tacrolimus Binding Proteins: metabolism
  • Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factor-alpha: genetics
  • Tumor Necrosis Factor-alpha: isolation & purificat
  • Tumor Necrosis Factor-alpha: metabolism
  • Tumor Necrosis Factor: metabolism
  • Tumor Suppressor Proteins
  • Tumor Suppressor Proteins: genetics
  • Tumor Suppressor Proteins: metabolism

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Authors

  • Tewis Bouwmeester

  • Angela Bauch

  • Heinz Ruffner

  • Pierre-Olivier O Angrand

  • Giovanna Bergamini

  • Karen Croughton

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