The regulatory mechanism of melanogenesis by FTY720, a sphingolipid analogue.

We previously reported that sphingosine-1-phosphate (S1P) decreases melanin synthesis via extracellular signal-regulated protein kinase (ERK) activation and microphthalmia-associated transcription factor (MITF) degradation. Although FTY720 is an S1P structural analogue, the effects of FTY720 on melanogenesis are not completely understood. Thus, we investigated the influence of FTY720 on melanin synthesis in a spontaneously immortalized mouse melanocyte cell line (Mel-Ab). FTY720 inhibited melanin synthesis in a concentration-dependent manner. Further, FTY720 has a different signal transduction mechanism to regulate melanogenesis from the S1P-induced signalling pathway. Our results showed that FTY720 down-regulated MITF and tyrosinase expression without ERK activation. MITF, the master regulator of pigmentation, is a target for the Wnt signalling pathway, including glycogen synthase kinase 3β (GSK3β) and β-catenin. Thus, the influence of FTY720 on GSK3β and β-catenin was further investigated. Decreased MITF and tyrosinase were associated with a reduction of β-catenin protein and mRNA levels. Decreased β-catenin expression by FTY720 may down-regulate expression of MITF, which finally reduces melanin synthesis.