Ribosomal S6 kinase 2-forkhead box protein O4 signaling pathway plays an essential role in melanogenesisopen access
- Authors
- Jeung, Dohyun; Lee, Ga-Eun; Chen, Weidong; Byun, Jiin; Nam, Soo-Bin; Park, You-Min; Lee, Hye Suk; Kang, Han Chang; Lee, Joo Young; Kim, Kwang Dong; Hong, Young-Soo; Lee, Cheol-Jung; Kim, Dae Joon; Cho, Yong-Yeon
- Issue Date
- Dec-2024
- Publisher
- Nature Research
- Keywords
- FOXO4; FOXO4 activity; Melanogenesis; RSK2; Signaling pathway
- Citation
- Scientific Reports, v.14, no.1
- Indexed
- SCIE
SCOPUS
- Journal Title
- Scientific Reports
- Volume
- 14
- Number
- 1
- URI
- https://scholarworks.gnu.ac.kr/handle/sw.gnu/70481
- DOI
- 10.1038/s41598-024-60165-9
- ISSN
- 2045-2322
- Abstract
- Although previous studies have examined the signaling pathway involved in melanogenesis through which ultraviolet (UV) or α-melanocyte-stimulating hormones (α-MSH) stimuli act as key inducers to produce melanin at the stratum basal layer of the epidermis, the signaling pathway regulating melanogenesis is still controversial. This study reports that α-MSH, not UVA and UVB, acted as a major stimulus of melanogenesis in B16F10 melanoma cells. Signaling pathway analysis using gene knockdown technology and chemical inhibitors, the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)/p90 ribosomal S6 kinase 2 (RSK2) played an important role in melanogenesis. Unexpectedly, LY294002, a PI3K inhibitor, increased melanogenesis without UV or α-MSH stimulation, suggesting that the PI3K/AKT signaling pathway may not be a major signaling pathway for melanogenesis. Chemical inhibition of the MEKs/ERKs/RSK2 signaling pathway using U0126 or BI-D1870 suppressed melanogenesis by stimulation of UVA or α-MSH stimulation, or both. In particular, the genetic depletion of RSK2 or constitutive active (CA)-RSK2 overexpression showed that RSK2 plays a key role in melanogenesis. Interestingly, forkhead box protein O4 (FOXO4) was phosphorylated by RSK2, resulting in the increase of FOXO4’s transactivation activity. Notably, the FOXO4 mutant harboring serine-to-alanine replacement at the phosphorylation sites totally abrogated the transactivation activity and reduced melanin production, indicating that RSK2-mediated FOXO4 activity plays a key role in melanogenesis. Furthermore, kaempferol, a flavonoid inhibiting the RSK2 activity, suppressed melanogenesis. In addition, FOXO4-wt overexpression showed that FOXO4 enhance melanin synthesis. Overall, the RSK2-FOXO4 signaling pathway plays a key role in modulating melanogenesis. © The Author(s) 2024.
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