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Impaired neutral sphingomyelinase activation and cutaneous barrier repair in FAN‐deficient mice
Author(s) -
Kreder Dirk,
Krut Oleg,
AdamKlages Sabine,
Wiegmann Katja,
Scherer Gudrun,
Plitz Tom,
Jensen JensMichael,
Proksch Ehrhardt,
Steinmann Jörg,
Pfeffer Klaus,
Krönke Martin
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.9.2472
Subject(s) - biology , sphingomyelin , microbiology and biotechnology , anatomy , genetics , membrane
The WD‐40 repeat protein FAN binds to a distinct domain of the p55 receptor for tumor necrosis factor (TNF) and signals the activation of neutral sphingomyelinase (N‐SMase). To analyze the physiological role of FAN in vivo , we generated FAN‐deficient mice by targeted gene disruption. Mice lacking a functional FAN protein do not show any overt phenotypic abnormalities; in particular, the architecture and cellular composition of lymphoid organs appeared to be unaltered. An essential role of FAN in the TNF‐induced activation of N‐SMase was demonstrated using thymocytes from FAN knockout mice. Activation of extracellular signal‐regulated kinases in response to TNF treatment, however, was not impaired by the absence of the FAN protein. FAN‐deficient mice show delayed kinetics of recovery after cutaneous barrier disruption suggesting a physiological role of FAN in epidermal barrier repair. Although FAN exhibits striking structural homologies with the CHS/Beige proteins, FAN‐deficient mice did not reproduce the phenotype of beige mice.