title: A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.
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-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.
authors.affiliation: Cellzome AG, Meyerhofstrasse 1, 69117 Heidelberg, Germany. tewis.bouwmeester@cellzome.com
authors.forename: Tewis
authors.initials: T
authors.lastname: Bouwmeester
authors.forename: Angela
authors.initials: A
authors.lastname: Bauch
authors.forename: Heinz
authors.initials: H
authors.lastname: Ruffner
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Angrand
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bergamini
authors.forename: Karen
authors.initials: K
authors.lastname: Croughton
authors.forename: Cristina
authors.initials: C
authors.lastname: Cruciat
authors.forename: Dirk
authors.initials: D
authors.lastname: Eberhard
authors.forename: Julien
authors.initials: J
authors.lastname: Gagneur
authors.forename: Sonja
authors.initials: S
authors.lastname: Ghidelli
authors.forename: Carsten
authors.initials: C
authors.lastname: Hopf
authors.forename: Bettina
authors.initials: B
authors.lastname: Huhse
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mangano
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Michon
authors.forename: Markus
authors.initials: M
authors.lastname: Schirle
authors.forename: Judith
authors.initials: J
authors.lastname: Schlegl
authors.forename: Markus
authors.initials: M
authors.lastname: Schwab
authors.forename: Martin A
authors.initials: MA
authors.lastname: Stein
authors.forename: Andreas
authors.initials: A
authors.lastname: Bauer
authors.forename: Georg
authors.initials: G
authors.lastname: Casari
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gavin
authors.forename: David B
authors.initials: DB
authors.lastname: Jackson
authors.forename: Gerard
authors.initials: G
authors.lastname: Joberty
authors.forename: Gitte
authors.initials: G
authors.lastname: Neubauer
authors.forename: Jens
authors.initials: J
authors.lastname: Rick
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kuster
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018833:Chaperonins; D002846:Chromatography, Affinity / Q000379:methods; D029721:Drosophila Proteins; D004789:Enzyme Activation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000302:isolation & purification / Q000378:metabolism; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D046911:Macromolecular Substances; D013058:Mass Spectrometry / Q000379:methods; D008954:Models, Biological; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D020543:Proteome / Q000032:analysis; D034622:RNA Interference; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018833:Chaperonins; D029721:Drosophila Proteins; D018841:HSP90 Heat-Shock Proteins; D020672:I-kappa B Proteins; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D016328:NF-kappa B; D020543:Proteome; D018124:Receptors, Tumor Necrosis Factor; D022021:Tacrolimus Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D000099159:Tacrolimus Binding Protein 5; C498362:CDC37 protein, human; C067857:MCC protein, human; C482625:MAP3K3 protein, human