Abstract
Wnt/β-catenin signaling is essential for melanogenesis in melanocytes. Neurokinin-1 receptor (NK-1R) has recently been demonstrated to be involved in melanin production. However, the cross talk between NK-1R and Wnt/β-catenin is poorly understood. Here, [Sar9, Met(O2)11] substance P (SMSP) was used to activate NK-1R, while L-733060 was used to inhibit it. The effects of NK-1R activation and inhibition on Wnt and its inhibitors were analyzed using western blot and real-time quantitative PCR. The results showed that SMSP positively regulated Wnt/β-catenin signaling by increasing the expression of β-catenin and p-GSK3β protein, which resulted from the weakened expression of the Wnt inhibitor Dickkopf-1 (DKK1). On the contrary, L-733060 lowered the expression of β-catenin and p-GSK3β protein through the up-regulation of DKK1 expression. Furthermore, in L-733060-treated mice, it was found that the pigmentation level as well as the melanogenic proteins and β-catenin protein expression were down-regulated, while the expression of DKK1 was up-regulated. These results showed the interaction between NK-1R and Wnt in human melanocytes in vitro and C57BL/6J mice in vivo, indicating that NK-1R may positively regulate melanogenesis through Wnt/β-catenin signaling pathway.
Highlights
Melanocytes are located in the basal layer of the epidermis and are responsible for producing melanin, a substance that gives skin and hair their pigments [1]
To analyze the relevance between Neurokinin-1 receptor (NK-1R) and Wnt/ β-catenin in melanogenesis, we examined whether NK-1R directly regulates the expression of β-catenin and GSK3β, the key genes and proteins implicated in the Wnt/β-catenin signaling pathway
These findings indicate that NK-1R is a positive regulator of Wnt/β-catenin signaling pathway in melanocytes
Summary
Melanocytes are located in the basal layer of the epidermis and are responsible for producing melanin, a substance that gives skin and hair their pigments [1]. Melanogenesis is promoted by various stimulators such as UV irradiation, cytokines, growth factors, and hormones [2]. In the absence of Wnt, β-catenin is degraded by a multiprotein complex containing Disheveled (Dvl), GSK-3β, Axin, adenomatous polyposis coli (APC), and casein kinase1α (CK1α), which phosphorylates β-catenin and leads to its ubiquitination and proteasomal degradation [11, 12]. In the presence of Wnt, GSK-3β-dependent phosphorylation of β-catenin is blocked and β-catenin is translocated into the nucleus [13], which upregulates the expression of the microphtalmia-associated transcription factor (MITF) and recruits the complex of β-catenin and TCF/LEF to the binding sites of the MITF promoter [14]. The expression of Dickkopf-1 (DKK1) as an inhibitor of canonical Wnt/β-catenin signaling is responsible for pigmentation inhibition of melanocytes through suppression of β-catenin and MITF expression [15, 16]
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