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.
Bouwmeester
Tewis
T
Cellzome AG, Meyerhofstrasse 1, 69117 Heidelberg, Germany. tewis.bouwmeester@cellzome.com
Bauch
Angela
A
Ruffner
Heinz
H
Angrand
Pierre-Olivier
PO
Bergamini
Giovanna
G
Croughton
Karen
K
Cruciat
Cristina
C
Eberhard
Dirk
D
Gagneur
Julien
J
Ghidelli
Sonja
S
Hopf
Carsten
C
Huhse
Bettina
B
Mangano
Raffaella
R
Michon
Anne-Marie
AM
Schirle
Markus
M
Schlegl
Judith
J
Schwab
Markus
M
Stein
Martin A
MA
Bauer
Andreas
A
Casari
Georg
G
Drewes
Gerard
G
Gavin
Anne-Claude
AC
Jackson
David B
DB
Joberty
Gerard
G
Neubauer
Gitte
G
Rick
Jens
J
Kuster
Bernhard
B
Superti-Furga
Giulio
G
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
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