Impaired neutral sphingomyelinase activation and cutaneous barrier repair in FAN-deficient mice.
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.
Kreder
D
D
Institute of Immunology, University of Kiel, Brunswiker Strasse 4, 24105 Kiel, Germany.
Krut
O
O
Adam-Klages
S
S
Wiegmann
K
K
Scherer
G
G
Plitz
T
T
Jensen
J M
JM
Proksch
E
E
Steinmann
J
J
Pfeffer
K
K
Krönke
M
M
D000595:Amino Acid Sequence; D000818:Animals; D003602:Cytotoxicity, Immunologic; D004789:Enzyme Activation / Q000187:drug effects; D004817:Epidermis / Q000293:injuries / Q000502:physiology*; D018390:Gene Targeting; D006706:Homeostasis; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural; D051379:Mice; D008817:Mice, Mutant Strains; D010539:Permeability; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D033921:Vesicular Transport Proteins; D014945:Wound Healing
D047908:Intracellular Signaling Peptides and Proteins; C491133:Lyst protein, mouse; C491112:Nsmaf protein, mouse; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D033921:Vesicular Transport Proteins; D013108:Sphingomyelin Phosphodiesterase