Melanocyte development and pigmentation
Melanocytes are cells located in the epidermis that are responsible for producing
melanin. This process is known as melanogenesis.
There are 3 main pathways regulating melanogenesis: via cyclic adenosine monophosphate
(cAMP), via Protein kinase C, beta
(PKC-beta) and via Nitric oxide
cAMP plays a key role in the control of pigmentation.
Pigmentation in mammals is stimulated mainly by Alpha-melanocyte stimulating hormone
(alpha-MSH) and Adrenocorticotropic hormone
(ACTH). Both of them can bind to the Melanocortin 1 receptor
(MC1R), which is coupled to G-protein
alpha-s and stimulates Adenylate cyclase,
resulting in cAMP production and cAMP-dependent protein
kinase (PKA) activation .
PKA, in turn, phosphorylates and activates cAMP response
element-binding protein 1 (CREB1). Phosphorylated
CREB1 interacts with CREB binding protein
(CBP) to activate the expression of
microphthalmia-associated transcription factor (MITF)
throughout the CRE in the promoter region of the gene , .
MITF, in turn, regulates transcription of genes coding MRPs
through interactions with M- and E-boxes present in the promoter regions of Tyrosinase
(TYRO), Tyrosinase-related protein 1
(TYRP1), and Tyrosinase-related protein 2
(TYRP2). Taken together, these complex molecular processes
finally allow a fine tuning of melanocyte differentiation leading to melanin synthesis
The transcription factors Paired box 3 P (PAX3) and SRY
(sex determining region Y)-box 10 (SOX10) transactivate the
MITF gene promoter and regulate the
TYRP1 and TYRP2 respectively.
Additionally, SOX10 directly binds to
TYRP2 promoter and enhances its expression , .
WNT signaling pathway plays a critical role in melanocyte development.
Wingless-related MMTV integration site 3A (WNT3A) binds to
the members of the seven transmembrane receptor Frizzled
(Frizzled) and activates the canonical WNT
pathway, which results in Catenin beta 1
(Beta-catenin) translocation to the nucleus.
Beta-catenin and Lymphoid enhancer-binding factor 1
(Lef-1) are recruited to the
MITF gene promoter and up-regulate MITF
expression, which in turn leads to pigment cell differentiation . In addition, Beta-catenin associates
with MITF and activates transcription of MITF
target genes .
MITF regulates not only the expression of enzymes
involved in melanin synthesis, but also the expression of
MC1R that can initiate melanogenesis via
cAMP pathway .
cAMP can regulate another signaling pathways that are
also involved in the control of melanogenesis. cAMP inhibits
Phosphatidylinositol 3-kinase (PI3K) and v-akt murine
thymoma viral oncogene homolog (AKT(PKB)) and promotes an
activation of Glycogen synthase kinase 3 beta (GSK3 beta).
GSK3 beta, by phosphorylation of
MITF on serine 298, increases its binding to the M-box of
the TYRO promoter, leading to stimulation of tyrosinase
Additionally, cAMP stimulates v-Ha-ras Harvey rat sarcoma viral oncogene homolog
(H-Ras)/ Mitogen-activated protein kinases 1 and 3
(ERK1/2) pathway. In this pathway, cAMP activates the
H-Ras/ v-Raf murine sarcoma viral oncogene homolog B1
(B-Raf)/ Mitogen-activated protein kinase kinase 1
(MEK1 (MAP2K1))/ ERK1/2/
Ribosomal protein S6 kinase, 90kDa, polypeptide 1 (p90RSK1)
cascade. Phosphorylation of MITF on serine by
p90RSK1 promotes its degradation that prevents an excessive
production of melanin synthesis .
Kit ligand (MGF)/ v-kit Hardy-Zuckerman 4 feline sarcoma
viral oncogene homolog (c-Kit) signaling regulates
pigmentation in melanocytes by targeting MITF simultaneously
for activation and proteolytic degradation via 2 cascades: Growth factor receptor-bound
protein 2 (GRB2)/ : Son of sevenless
homolog (SOS)/ H-RAS/
B-Raf/ MEK1 (MAP2K1)/ ERK1/2/ p90RSK1
and PI3K/ AKT/ GSK3 beta , , .
Another signal transduction pathway important in the regulation of melanogenesis is
represented by PKC-beta . 1,2-Diacylglycerol
(DAG) stimulated by UV irradiation can activate this pathway
. Nucleotide binding protein, beta polypeptide 2-like 1
(RACK1), in turn, anchors activated
PKC-beta on the melanosome membrane, thus allowing
phosphorylate tyrosinase .
UV irradiation as well activates Guanylate cyclase
through stimulation of NO synthase, thus leading to increase cyclic
GMP. Cyclic GMP, in turn, activates
Protein kinase G1 and stimulates melanogenesis .
- Gantz I, Fong TM
The melanocortin system.
American journal of physiology. Endocrinology and metabolism 2003 Mar;284(3):E468-74
- Sato S, Roberts K, Gambino G, Cook A, Kouzarides T, Goding CR
CBP/p300 as a co-factor for the Microphthalmia transcription factor.
Oncogene 1997 Jun 26;14(25):3083-92
- Bertolotto C, Abbe P, Hemesath TJ, Bille K, Fisher DE, Ortonne JP, Ballotti R
Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes.
The Journal of cell biology 1998 Aug 10;142(3):827-35
- Bertolotto C, Buscà R, Abbe P, Bille K, Aberdam E, Ortonne JP, Ballotti R
Different cis-acting elements are involved in the regulation of TRP1 and TRP2 promoter activities by cyclic AMP: pivotal role of M boxes (GTCATGTGCT) and of microphthalmia.
Molecular and cellular biology 1998 Feb;18(2):694-702
- Bondurand N, Pingault V, Goerich DE, Lemort N, Sock E, Le Caignec C, Wegner M, Goossens M
Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.
Human molecular genetics 2000 Aug 12;9(13):1907-17
- Ludwig A, Rehberg S, Wegner M
Melanocyte-specific expression of dopachrome tautomerase is dependent on synergistic gene activation by the Sox10 and Mitf transcription factors.
FEBS letters 2004 Jan 2;556(1-3):236-44
- Takeda K, Yasumoto K, Takada R, Takada S, Watanabe K, Udono T, Saito H, Takahashi K, Shibahara S
Induction of melanocyte-specific microphthalmia-associated transcription factor by Wnt-3a.
The Journal of biological chemistry 2000 May 12;275(19):14013-6
- Schepsky A, Bruser K, Gunnarsson GJ, Goodall J, Hallsson JH, Goding CR, Steingrimsson E, Hecht A
The microphthalmia-associated transcription factor Mitf interacts with beta-catenin to determine target gene expression.
Molecular and cellular biology 2006 Dec;26(23):8914-27
- Aoki H, Moro O
Involvement of microphthalmia-associated transcription factor (MITF) in expression of human melanocortin-1 receptor (MC1R).
Life sciences 2002 Sep 20;71(18):2171-9
- Khaled M, Larribere L, Bille K, Aberdam E, Ortonne JP, Ballotti R, Bertolotto C
Glycogen synthase kinase 3beta is activated by cAMP and plays an active role in the regulation of melanogenesis.
The Journal of biological chemistry 2002 Sep 13;277(37):33690-7
- Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher DE
MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes.
Nature 1998 Jan 15;391(6664):298-301
- Price ER, Ding HF, Badalian T, Bhattacharya S, Takemoto C, Yao TP, Hemesath TJ, Fisher DE
Lineage-specific signaling in melanocytes. C-kit stimulation recruits p300/CBP to microphthalmia.
The Journal of biological chemistry 1998 Jul 17;273(29):17983-6
- Widlund HR, Fisher DE
Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival.
Oncogene 2003 May 19;22(20):3035-41
- Park HY, Wu H, Killoran CE, Gilchrest BA
The receptor for activated C-kinase-I (RACK-I) anchors activated PKC-beta on melanosomes.
Journal of cell science 2004 Jul 15;117(Pt 16):3659-68
- Gilchrest BA, Park HY, Eller MS, Yaar M
Mechanisms of ultraviolet light-induced pigmentation.
Photochemistry and photobiology 1996 Jan;63(1):1-10
- Roméro-Graillet C, Aberdam E, Biagoli N, Massabni W, Ortonne JP, Ballotti R
Ultraviolet B radiation acts through the nitric oxide and cGMP signal transduction pathway to stimulate melanogenesis in human melanocytes.
The Journal of biological chemistry 1996 Nov 8;271(45):28052-6