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.
Adam-Klages
S
S
Institut für Immunologie, Christian-Albrechts-Universität Kiel, Federal Republic of Germany.
Adam
D
D
Wiegmann
K
K
Struve
S
S
Kolanus
W
W
Schneider-Mergener
J
J
Krönke
M
M
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010449:Peptide Mapping; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*
D015703:Antigens, CD; D047908:Intracellular Signaling Peptides and Proteins; C102036:NSMAF protein, human; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D013108:Sphingomyelin Phosphodiesterase