Gene interactions and pathways from curated databases and text-mining
J Immunol 2002, PMID: 12391233

Interaction with factor associated with neutral sphingomyelinase activation, a WD motif-containing protein, identifies receptor for activated C-kinase 1 as a novel component of the signaling pathways of the p55 TNF receptor.

Tcherkasowa, Anna Ewgenjewna; Adam-Klages, Sabine; Kruse, Marie-Luise; Wiegmann, Katja; Mathieu, Sabine; Kolanus, Waldemar; Krönke, Martin; Adam, Dieter

Factor associated with neutral sphingomyelinase activation (FAN) represents a p55 TNFR (TNF-R55)-associated protein essential for the activation of neutral sphingomyelinase. By means of the yeast interaction trap system, we have identified the scaffolding protein receptor for activated C-kinase (RACK)1 as an interaction partner of FAN. Mapping studies in yeast revealed that RACK1 is recruited to the C-terminal WD-repeat region of FAN and binds to FAN through a domain located within WD repeats V to VII of RACK1. Our data indicate that binding of both proteins is not mediated by linear motifs but requires folding into a secondary structure, such as the multibladed propeller characteristic of WD-repeat proteins. The interaction of FAN and RACK1 was verified in vitro by glutathione S-transferase-based coprecipitation assays as well as in eukaryotic cells by coimmunoprecipitation experiments. Colocalization studies in transfected cells suggest that TNF-R55 forms a complex with FAN and that this complex recruits RACK1 to the plasma membrane. Furthermore, activation of N-SMase by TNF was strongly enhanced when RACK1, FAN, and a noncytotoxic TNF-R55 mutant were expressed concurrently, suggesting RACK1 as a modulator of N-SMase activation. Together, these findings implicate RACK1 as a novel component of the signaling pathways of TNF-R55.

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Text Mining Data

N-SMase → TNF: " Furthermore, activation of N-SMase by TNF was strongly enhanced when RACK1, FAN, and a noncytotoxic TNF-R55 mutant were expressed concurrently, suggesting RACK1 as a modulator of N-SMase activation "

N-SMase → RACK1: " Furthermore, activation of N-SMase by TNF was strongly enhanced when RACK1 , FAN, and a noncytotoxic TNF-R55 mutant were expressed concurrently, suggesting RACK1 as a modulator of N-SMase activation "

TNF → RACK1: " Furthermore, activation of N-SMase by TNF was strongly enhanced when RACK1 , FAN, and a noncytotoxic TNF-R55 mutant were expressed concurrently, suggesting RACK1 as a modulator of N-SMase activation "

Manually curated Databases

  • IRef Bind Interaction: TNFRSF1A — NSMAF
  • IRef Bind Interaction: TNFRSF1A — GNB2L1
  • IRef Bind Interaction: GNB2L1 — NSMAF
  • IRef Bind_translation Interaction: TNFRSF1A — NSMAF (coimmunoprecipitation)
  • IRef Bind_translation Interaction: TNFRSF1A — GNB2L1 (coimmunoprecipitation)
  • IRef Bind_translation Interaction: GNB2L1 — NSMAF (coimmunoprecipitation)
  • IRef Bind_translation Interaction: GNB2L1 — NSMAF (affinity chromatography technology)
  • IRef Bind_translation Interaction: GNB2L1 — NSMAF (two hybrid)
  • IRef Biogrid Interaction: GNB2L1 — NSMAF (direct interaction, two hybrid)
  • IRef Biogrid Interaction: GNB2L1 — NSMAF (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: GNB2L1 — NSMAF (direct interaction, pull down)
  • IRef Hprd Interaction: TNFRSF1A — GNB2L1 (in vitro)
  • IRef Hprd Interaction: GNB2L1 — NSMAF (in vitro)
  • IRef Hprd Interaction: GNB2L1 — NSMAF (in vivo)
  • IRef Hprd Interaction: GNB2L1 — NSMAF (two hybrid)
  • IRef Ophid Interaction: TNFRSF1A — GNB2L1 (aggregation, confirmational text mining)
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/FAN/NSMASE complex (TNFRSF1A-NSMAF-SMPD2-TNF) → RACK1 (GNB2L1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : sTNF-alpha/TNFR1A/FAN/NSMASE complex (TNFRSF1A-NSMAF-SMPD2-TNF) → sTNF-alpha/TNFR1A/FAN/NSMASE/RACK1 complex (TNFRSF1A-NSMAF-SMPD2-GNB2L1-TNF) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database TNF receptor signaling pathway : RACK1 (GNB2L1) → sTNF-alpha/TNFR1A/FAN/NSMASE/RACK1 complex (TNFRSF1A-NSMAF-SMPD2-GNB2L1-TNF) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
In total, 15 gene pairs are associated to this article in curated databases