Gene interactions and pathways from curated databases and text-mining
Nature 2003, PMID: 12917691

The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination.

Kovalenko, Andrew; Chable-Bessia, Christine; Cantarella, Giuseppina; Israël, Alain; Wallach, David; Courtois, Gilles

NF-kappaB transcription factors have key roles in inflammation, immune response, oncogenesis and protection against apoptosis. In most cells, these factors are kept inactive in the cytoplasm through association with IkappaB inhibitors. After stimulation by various reagents, IkappaB is phosphorylated by the IkappaB kinase (IKK) complex and degraded by the proteasome, allowing NF-kappaB to translocate to the nucleus and activate its target genes. Here we report that CYLD, a tumour suppressor that is mutated in familial cylindromatosis, interacts with NEMO, the regulatory subunit of IKK. CYLD also interacts directly with tumour-necrosis factor receptor (TNFR)-associated factor 2 (TRAF2), an adaptor molecule involved in signalling by members of the family of TNF/nerve growth factor receptors. CYLD has deubiquitinating activity that is directed towards non-K48-linked polyubiquitin chains, and negatively modulates TRAF-mediated activation of IKK, strengthening the notion that ubiquitination is involved in IKK activation by TRAFs and suggesting that CYLD functions in this process. Truncations of CYLD found in cylindromatosis result in reduced enzymatic activity, indicating a link between impaired deubiquitination of CYLD substrates and human pathophysiology.

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Text Mining Data

NF-kappaB → CYLD: " The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination "

IKK → TRAF: " CYLD has deubiquitinating activity that is directed towards non-K48 linked polyubiquitin chains, and negatively modulates TRAF mediated activation of IKK , strengthening the notion that ubiquitination is involved in IKK activation by TRAFs and suggesting that CYLD functions in this process "

Manually curated Databases

  • IRef Bind Interaction: IKBKG — CYLD
  • IRef Bind Interaction: TRAF2 — CYLD
  • IRef Bind_translation Interaction: IKBKG — CYLD (two hybrid)
  • IRef Bind_translation Interaction: IKBKG — CYLD (coimmunoprecipitation)
  • IRef Bind_translation Interaction: TRAF2 — CYLD (two hybrid)
  • IRef Bind_translation Interaction: TRAF2 — CYLD (coimmunoprecipitation)
  • IRef Biogrid Interaction: CYLD — IKBKG (direct interaction, two hybrid)
  • IRef Biogrid Interaction: CYLD — IKBKG (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CYLD — IKBKG (direct interaction, enzymatic study)
  • IRef Biogrid Interaction: TRAF2 — CYLD (direct interaction, two hybrid)
  • IRef Biogrid Interaction: TRAF2 — CYLD (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: TRAF2 — CYLD (direct interaction, enzymatic study)
  • IRef Biogrid Interaction: CYLD — TRAF6 (direct interaction, enzymatic study)
  • IRef Hprd Interaction: TRAF2 — CYLD (in vitro)
  • IRef Hprd Interaction: CYLD — TRAF6 (in vitro)
  • IRef Hprd Interaction: CYLD — TRAF6 (in vivo)
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD/RIP/TRAF2 complex (TNFRSF1A-TRADD-RIPK1-TRAF2-TNF) → sTNF-alpha/TNFR1A/TRADD complex (TNFRSF1A-TRADD-TNF) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD/RIP/TRAF2 complex (TNFRSF1A-TRADD-RIPK1-TRAF2-TNF) → sTNF-alpha/TNFR1A/TRADD/STAT1 (dimer) complex (TNFRSF1A-TRADD-STAT1-TNF) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD/RIP/TRAF2 complex (TNFRSF1A-TRADD-RIPK1-TRAF2-TNF) → STAT1 (STAT1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD/RIP/TRAF2 complex (TNFRSF1A-TRADD-RIPK1-TRAF2-TNF) → RIP (RIPK1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD/RIP/TRAF2 complex (TNFRSF1A-TRADD-RIPK1-TRAF2-TNF) → TRAF2 (TRAF2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD complex (TNFRSF1A-TRADD-TNF) → sTNF-alpha/TNFR1A/TRADD/STAT1 (dimer) complex (TNFRSF1A-TRADD-STAT1-TNF) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD complex (TNFRSF1A-TRADD-TNF) → STAT1 (STAT1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD complex (TNFRSF1A-TRADD-TNF) → CYLD (CYLD) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD complex (TNFRSF1A-TRADD-TNF) → RIP (RIPK1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD complex (TNFRSF1A-TRADD-TNF) → TRAF2 (TRAF2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD/STAT1 (dimer) complex (TNFRSF1A-TRADD-STAT1-TNF) → STAT1 (STAT1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD/STAT1 (dimer) complex (TNFRSF1A-TRADD-STAT1-TNF) → RIP (RIPK1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/TRADD/STAT1 (dimer) complex (TNFRSF1A-TRADD-STAT1-TNF) → TRAF2 (TRAF2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : STAT1 (STAT1) → CYLD (CYLD) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : STAT1 (STAT1) → RIP (RIPK1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : STAT1 (STAT1) → TRAF2 (TRAF2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : CYLD (CYLD) → RIP (RIPK1) (modification, inhibits)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : CYLD (CYLD) → TRAF2 (TRAF2) (modification, inhibits)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : RIP (RIPK1) → TRAF2 (TRAF2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database Canonical NF-kappaB pathway: CYLD (CYLD) → NEMO (IKBKG) (modification, activates)
    Evidence: assay, physical interaction
  • Reactome Reaction: RIPK2 → CYLD (reaction)
  • Reactome Reaction: IKBKG → CYLD (reaction)
  • Reactome Reaction: NOD2 → CYLD (reaction)
  • Reactome Reaction: NOD1 → CYLD (reaction)
In total, 32 gene pairs are associated to this article in curated databases