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. 1999 May 4;18(9):2472–2479. doi: 10.1093/emboj/18.9.2472

Impaired neutral sphingomyelinase activation and cutaneous barrier repair in FAN-deficient mice.

D Kreder 1, O Krut 1, S Adam-Klages 1, K Wiegmann 1, G Scherer 1, T Plitz 1, J M Jensen 1, E Proksch 1, J Steinmann 1, K Pfeffer 1, M Krönke 1
PMCID: PMC1171329  PMID: 10228161

Abstract

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.

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