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FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase.

The initiation of intracellular signaling events through the 55 kDa tumor necrosis factor-receptor (TNF-R55) appears to depend on protein intermediates that interact with specific cytoplasmic domains of TNF-R55. By combined use of the yeast interaction trap system and a peptide scanning library, the novel WD-repeat protein FAN has been identified, which specifically binds to a cytoplasmic nine amino acid binding motif of TNF-R55. This region has been previously recognized as a distinct functional domain that is both required and sufficient for the activation of neutral sphingomyelinase (N-SMase). Overexpression of full-length FAN enhanced N-SMase activity in TNF-treated cells, while truncated mutants of FAN produced dominant negative effects. The data suggest that FAN regulates ceramide production by N-SMase, which is a crucial step in TNF signaling.

Pubmed ID: 8808629


  • Adam-Klages S
  • Adam D
  • Wiegmann K
  • Struve S
  • Kolanus W
  • Schneider-Mergener J
  • Krönke M



Publication Data

September 20, 1996

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Antigens, CD
  • Binding Sites
  • COS Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Jurkat Cells
  • Molecular Sequence Data
  • Molecular Structure
  • Peptide Mapping
  • Proteins
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Saccharomyces cerevisiae
  • Sequence Deletion
  • Signal Transduction
  • Sphingomyelin Phosphodiesterase