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FLASH GENE

Symbol

MC1R

contributors: mct - updated : 03-02-2016

HGNC name	melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor)
HGNC id	6929

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	anonymous DNA segment
SPECIAL FEATURE	arranged in tandem
STRUCTURE	3.09 kb     1 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter (TATA box)
	cytosine-phosphate-guanine/HTF
	Binding site
text structure	AP1 and AP2 binding sites
	two TATA box, several E-boxes
	UBE3A is able to induce MC1R promoter activity

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text	has an inefficient poly(A) site allowing intergenic splicing with its downstream neighbour TUBB3 (PMID: 26657157)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002386 1 - 3115 NP_002377 - 317 - 2001 11707265 65 C terminal extra Aas - - splicing 1270 - 385 - 2001 11707265 65 C terminal extra Aas MC1R mutant I40T - - 954 - 317 - 2001 11707265 MC1R variant F45L - - 954 - 317 - 2001 11707265 MC1R variant S83L - - 954 - 317 - 2001 11707265 MC1R mutant V122M - - 954 - 317 - 2001 11707265

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive intestine small intestine     highly   liver       highly Endocrine adrenal gland cortex         pancreas       highly Urinary kidney       moderately Visual eye       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial barrier lining retinal pigment epithelium (RPE)     Homo sapiens Epithelial secretory glandular endocrine

cells

System Cell Pubmed Species Stage Rna symbol Skin/Tegument melanocyte Homo sapiens

cell lineage	cells of melanocytic origin
cell lines
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	seven transmembrane segments (7TM) receptor
	two intracellular loops, the second may be involved in GPCR recycling

mono polymer

homomer , heteromer , dimer

HOMOLOGY

interspecies	homolog to murine extension (Ext)
	homolog to C.elegans Y62E10A.4

Homologene

FAMILY

G protein coupled receptor superfamily

CATEGORY

regulatory , signaling hormone , receptor membrane G

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,cytoskeleton,microtubule
text	melanosomes, at the cell surface

basic FUNCTION	melanocortin receptor 1 or melanocyte stimulating hormone (alpha MSH) receptor, heptahelical G protein-coupled receptor
	regulator of eumelanin and phaeomelanin production
	regulator of pigmentation phenotype
	sex-specific role for MC1R in acute noxious thermal responses and pain of inflammatory origin
	DEFB103B may be a novel MC1R agonist involved in regulating melanocyte responses in humans
	MC1R and cAMP signaling can directly inhibit melanoma growth through regulation of the G2/M checkpoint (pMID: 23908401)
	MC1R-signaling stimulates black eumelanin production through a cAMP-dependent pathway

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

development

text	epidermal development and maintenance UV protection

PATHWAY

metabolism

signaling

hormonal , signal transduction

activation of the MC1R/POMC signaling pathway has been implicated in the regulation of both inflammation and extracellular matrix homeostasis

a component	constitutive dimer when expressed alone and constitutive heterodimer when co-expressed with variant alleles
	homodimerization most likely results from formation of four disulfide bonds as well as non-covalent interactions of domain-swapping type
	MC1R-PTEN axis is a central regulator for melanocytes response to UVB exposure revealing the molecular basis underlying the association between MC1R variants and melanomagenesis

INTERACTION

DNA

RNA

small molecule

protein	OCA2
	CNR1 activation did not engage the key regulator of skin pigmentation, cyclic AMP, showing a major difference compared with the regulation of melanogenesis by POMC through MC1R
	MC1R regulates melanoma cell migration via inhibition of SDC2 expression
	TP53 is an important target of the downstream MC1R signaling that reduces oxidative stress and possibly malignant transformation of melanocytes
	melanin-independent interaction between MC1R and MET signaling pathways is required for HGF-dependent melanoma and this pathway is likely involved in human melanoma

cell & other

REGULATION

activated by

POMC stimulating eumelanin synthesis and enhancing repair of ultraviolet radiation (UV)-induced DNA damage

ASSOCIATED DISORDERS

corresponding disease(s)

HCL4

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional       loss of function compromises the DNA damage response (DDR) and genomic stability of melanocytes constitutional     --low   by human dermal fibroblasts contributes to excess collagen synthesis in keloid scars

Susceptibility

ephelides in childhood and solar lentigines red hair and fair skin cutaneous malignant melanoma (germline variants confer risk for BRAF-mutant melanoma) to facial pigmented spots during aging

Variant & Polymorphism other	Arg151-Cys/Arg160-TRP/ASP294HIS strong associated with melanoma
	variants altering melanoma cell growth and adhesion to extracellular matrix
	variant R151C, R160W, and D294H strongly associated with red hair (decreasing MC1R cell surface expression)
	variant RHC alleles associated with red hair, poor tanning ability, and increased skin cancer risk are partial loss-of-function forms
	genetic variations in MC1R contribute to the acquired amount of facial pigmented spots during aging, through pathways independent of the basal melanin production
	polymorphisms being a predisposing factor of melanoma in a southern European population with a relatively low incidence of the disease

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

Mc1r is down-regulated in the skin of the Ube3a(-/-) mice