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Review
. 2016 Jul 15;17(7):1144.
doi: 10.3390/ijms17071144.

Signaling Pathways in Melanogenesis

Stacey A N D'Mello  1 , Graeme J Finlay  2   3 , Bruce C Baguley  4 , Marjan E Askarian-Amiri  5   6
Affiliations
Review

Signaling Pathways in Melanogenesis

Stacey A N D'Mello et al. Int J Mol Sci. .

Abstract

Melanocytes are melanin-producing cells found in skin, hair follicles, eyes, inner ear, bones, heart and brain of humans. They arise from pluripotent neural crest cells and differentiate in response to a complex network of interacting regulatory pathways. Melanins are pigment molecules that are endogenously synthesized by melanocytes. The light absorption of melanin in skin and hair leads to photoreceptor shielding, thermoregulation, photoprotection, camouflage and display coloring. Melanins are also powerful cation chelators and may act as free radical sinks. Melanin formation is a product of complex biochemical events that starts from amino acid tyrosine and its metabolite, dopa. The types and amounts of melanin produced by melanocytes are determined genetically and are influenced by a variety of extrinsic and intrinsic factors such as hormonal changes, inflammation, age and exposure to UV light. These stimuli affect the different pathways in melanogenesis. In this review we will discuss the regulatory mechanisms involved in melanogenesis and explain how intrinsic and extrinsic factors regulate melanin production. We will also explain the regulatory roles of different proteins involved in melanogenesis.

Keywords: MITF; melanogenesis; signaling pathways in melanogenesis; tyrosinase.

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Figures

Figure 1
Figure 1
Association of keratinocytes and melanocytes. The dendritic melanocyte is located in the basal layer of skin and produces melanin. Melanin pigments in melanosomes are transferred to keratinocytes.
Figure 2
Figure 2
Eumelanin and pheomelanin are synthesized within melanosomes of melanocytes by a series of reactions that are catalyzed by specific melanogenic enzymes (black). Production of these enzymes is driven by the MITF transcription factor whose activity is regulated by a number of signaling pathways including PKC (brown), cAMP (blue), MEK (purple), and WNT (orange). These signaling pathways are activated upstream by receptors such as KIT (ligand: SCF) and MC1R (ligands: α-MSH, ACTH and ASP). The MITF transcription factor drives the expression of a number of genes including SOX10 and PAX3. Protein kinase C (PKC); cyclic AMP (cAMP); MAPK/ERK Kinase (MEK); Wingless-related integration site (WNT); Stem Cell Factor (SCF); Melanocyte-specific melanocortin-1 receptor (MC1R); α-melanocyte-stimulating hormone (α-MSH); adrenocorticotropic hormone (ACTH); agonist stimulating protein (ASP).
Figure 3
Figure 3
Genes activated by MITF. The transcription of multiple genes is regulated by MITF. This in turn regulates multiple cellular processes including differentiation, proliferation, survival and motility. MITF binds to specific sequences that are classifiable as members of the widely distributed E-(enhancer)-box family of regulatory motifs [52].
Figure 4
Figure 4
Upregulation of melanogenesis by SOX9. cAMP is elevated following UVB radiation and expression of α-MSH. α-MSH activates the PKA pathway to phosphorylate CREB and upregulate SOX9. Activated CREB and SOX9 induce MITF gene expression. MITF upregulation induces TYR expression leading to induction of melanogenesis. UVB irradiation upregulates SOX9 and activates the MITF promoter followed by TYRP2 induction.
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