MC1R (melanocortin 1 receptor) is a class A seven-transmembrane G protein-coupled receptor of the plasma membrane, expressed mainly in epidermal melanocytes and also in some immune cells. It binds the POMC-derived peptides alpha-, beta- and gamma-MSH and ACTH, couples to Gs to activate adenylate cyclase and cAMP/PKA signalling, and thereby drives melanogenesis and the switch from red/yellow pheomelanin to photoprotective black/brown eumelanin. Its signalling is antagonised by agouti signalling protein and modulated by MRAP/MRAP2, OPN3 and MGRN1. MC1R is highly polymorphic; loss-of-function variants that impair ligand coupling or cell-surface trafficking cause red hair, fair skin, poor tanning and increased melanoma and skin cancer risk, and MC1R signalling also enhances UV DNA damage repair.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro GPCR family mapping. Reason: Correct but general; MC1R is specifically a melanocortin (MSH/ACTH) receptor, a descendant term already carried by the gene. Proposed replacements: melanocyte-stimulating hormone receptor activity Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH PMID:9571181 The Arg151Cys variant of MC1R binds to radio-labelled analogue of alpha-MSH with identical affinity as wild type MC1R but can not be stimulated to produce cyclic AMP (cAMP). |
| GO:0004977 melanocortin receptor activity | IEA GO_REF:0000120 | MODIFY | Summary: Combined automated melanocortin receptor activity. Reason: Correct; the more precise melanocyte-stimulating hormone receptor activity (descendant, already annotated by IBA/IDA) is supported. Proposed replacements: melanocyte-stimulating hormone receptor activity Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH |
| GO:0004977 melanocortin receptor activity | TAS PMID:9571181 Human pigmentation phenotype: a point mutation generates non... | MODIFY | Summary: Melanocortin receptor activity traced to the R151C variant paper. Reason: The paper shows wild-type MC1R binds an alpha-MSH analogue and signals to cAMP; the descendant MSH receptor term is more precise. Proposed replacements: melanocyte-stimulating hormone receptor activity Supporting Evidence: PMID:9571181 The Arg151Cys variant of MC1R binds to radio-labelled analogue of alpha-MSH with identical affinity as wild type MC1R but can not be stimulated to produce cyclic AMP (cAMP). |
| GO:0004978 corticotropin receptor activity | IDA PMID:8463333 Molecular cloning of a novel melanocortin receptor. | KEEP AS NON CORE | Summary: MC1R responds to ACTH as well as MSH peptides. Reason: MC1R binds ACTH with high affinity (UniProt, multiple experimental references), so ACTH-receptor activity is genuine, but the physiological corticotropin receptor is MC2R; for MC1R, ACTH is a secondary ligand to alpha-MSH. The cited cloning paper characterised the melanocortin receptor subgroup pharmacology; curator judgement retained. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH |
| GO:0004980 melanocyte-stimulating hormone receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: MSH receptor activity inherited at the MC1R clade node. Reason: Core activity of MC1R, consistent with direct ligand-binding and cAMP signalling data. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH PMID:9571181 The Arg151Cys variant of MC1R binds to radio-labelled analogue of alpha-MSH with identical affinity as wild type MC1R but can not be stimulated to produce cyclic AMP (cAMP). |
| GO:0004980 melanocyte-stimulating hormone receptor activity | IDA PMID:8463333 Molecular cloning of a novel melanocortin receptor. | ACCEPT | Summary: MSH receptor pharmacology for the heptapeptide core of MSH/ACTH. Reason: Core activity; MC1R binds alpha-, beta-, gamma-MSH and ACTH and signals via Gs. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH |
| GO:0004980 melanocyte-stimulating hormone receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated MSH receptor activity. Reason: Consistent with the core activity. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH |
| GO:0004980 melanocyte-stimulating hormone receptor activity | IPI PMID:19743876 Novel binding motif of ACTH analogues at the melanocortin re... | ACCEPT | Summary: Binding and signalling of ACTH analogues at hMC1R. Reason: The study measured binding and cAMP signalling of POMC-derived peptides at hMC1R; MSH receptor activity is the correct informative term. Supporting Evidence: PMID:19743876 Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R. |
| GO:0005515 protein binding | IPI PMID:19329486 MRAP and MRAP2 are bidirectional regulators of the melanocor... | REMOVE | Summary: MC1R interacts with the accessory protein MRAP. Reason: Bare protein binding is uninformative; the MRAP interaction reduces MC1R responsiveness but no specific MC1R molecular function follows. Removal does not dispute the interaction. Supporting Evidence: PMID:19329486 We report that MRAP and MRAP2 can interact with all 5 MCRs. |
| GO:0005515 protein binding | IPI PMID:19329486 MRAP and MRAP2 are bidirectional regulators of the melanocor... | REMOVE | Summary: MC1R interacts with MRAP2. Reason: Bare protein binding is uninformative under the protein-binding policy. Supporting Evidence: PMID:19329486 We report that MRAP and MRAP2 can interact with all 5 MCRs. |
| GO:0005515 protein binding | IPI PMID:19743876 Novel binding motif of ACTH analogues at the melanocortin re... | MODIFY | Summary: MC1R binds POMC-derived ACTH peptides. Reason: The interaction is receptor-ligand binding; the informative term is MSH receptor activity (already annotated from the same paper). Proposed replacements: melanocyte-stimulating hormone receptor activity Supporting Evidence: PMID:19743876 Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R. |
| GO:0005515 protein binding | IPI PMID:31097585 Human nonvisual opsin 3 regulates pigmentation of epidermal ... | MODIFY | Summary: MC1R forms a complex with the GPCR OPN3 in melanocytes. Reason: The partner is itself a GPCR and the two receptors form a heteromeric complex that modulates MC1R cAMP output; G protein-coupled receptor binding is more informative than bare protein binding. Proposed replacements: G protein-coupled receptor binding Supporting Evidence: PMID:31097585 OPN3 and MC1R colocalize at both the plasma membrane and in intracellular structures, and can form a physical complex |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Cytoplasm propagated from a broad GPCR node. Reason: MC1R is a multi-pass plasma membrane receptor. Intracellular pools exist (biosynthetic ER/Golgi transit and endosomes; ER-retained loss-of-function variants), but these are membrane-bound compartments, not the cytoplasm, so this annotation misrepresents the functional location. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN002733616 UNRESOLVED Broad GPCR ancestral node carrying a cytoplasm IBD seeded by receptors with intracellular pools; for MC1R the intracellular pools are membrane-bound (ER/Golgi/endosome), not cytosolic. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:31097585}; Multi-pass membrane protein {ECO:0000255}. PMID:19452503 Three highly penetrant RHC variants, R151C, R160W, and D294H are loss-of-function MC1R mutants with altered cell surface expression. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane inherited across the melanocortin/GPCR node. Reason: MC1R is a 7-TM receptor active at the cell surface. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:31097585}; Multi-pass membrane protein {ECO:0000255}. PMID:31097585 OPN3 and MC1R colocalize at both the plasma membrane and in intracellular structures, and can form a physical complex |
| GO:0005886 plasma membrane | IDA PMID:19452503 Aberrant trafficking of human melanocortin 1 receptor varian... | ACCEPT | Summary: Cell-surface trafficking of wild-type versus RHC variant MC1R. Reason: Direct trafficking assays show wild-type MC1R at the cell surface and variants retained in ER or cis-Golgi. Supporting Evidence: PMID:19452503 Three highly penetrant RHC variants, R151C, R160W, and D294H are loss-of-function MC1R mutants with altered cell surface expression. |
| GO:0005886 plasma membrane | IDA PMID:31097585 Human nonvisual opsin 3 regulates pigmentation of epidermal ... | ACCEPT | Summary: MC1R colocalizes with OPN3 at the plasma membrane in melanocytes. Reason: Direct evidence in human epidermal melanocytes. Supporting Evidence: PMID:31097585 OPN3 and MC1R colocalize at both the plasma membrane and in intracellular structures, and can form a physical complex |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping. Reason: Correct. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:31097585}; Multi-pass membrane protein {ECO:0000255}. |
| GO:0005886 plasma membrane | TAS PMID:9571181 Human pigmentation phenotype: a point mutation generates non... | ACCEPT | Summary: Plasma membrane receptor in the R151C study. Reason: Radioligand binding on intact cells implies surface receptor. Supporting Evidence: PMID:9571181 The Arg151Cys variant of MC1R binds to radio-labelled analogue of alpha-MSH with identical affinity as wild type MC1R but can not be stimulated to produce cyclic AMP (cAMP). file:human/MC1R/MC1R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:31097585}; Multi-pass membrane protein {ECO:0000255}. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-379044 | ACCEPT | Summary: Reactome places liganded MC1R at the plasma membrane in melanocortin/Gs reactions. Reason: Consistent with direct evidence. Supporting Evidence: Reactome:R-HSA-379044 file:human/MC1R/MC1R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:31097585}; Multi-pass membrane protein {ECO:0000255}. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-388596 | ACCEPT | Summary: Reactome places liganded MC1R at the plasma membrane in melanocortin/Gs reactions. Reason: Consistent with direct evidence. Supporting Evidence: Reactome:R-HSA-388596 file:human/MC1R/MC1R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:31097585}; Multi-pass membrane protein {ECO:0000255}. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-744886 | ACCEPT | Summary: Reactome places liganded MC1R at the plasma membrane in melanocortin/Gs reactions. Reason: Consistent with direct evidence. Supporting Evidence: Reactome:R-HSA-744886 file:human/MC1R/MC1R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:31097585}; Multi-pass membrane protein {ECO:0000255}. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-744887 | ACCEPT | Summary: Reactome places liganded MC1R at the plasma membrane in melanocortin/Gs reactions. Reason: Consistent with direct evidence. Supporting Evidence: Reactome:R-HSA-744887 file:human/MC1R/MC1R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:31097585}; Multi-pass membrane protein {ECO:0000255}. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: InterPro GPCR signaling mapping. Reason: Correct but general; MC1R signals through Gs to adenylate cyclase. Proposed replacements: adenylate cyclase-activating G protein-coupled receptor signaling pathway Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt Upon activation, MC1R couples with the G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway. |
| GO:0007187 G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger | TAS PMID:9571181 Human pigmentation phenotype: a point mutation generates non... | MODIFY | Summary: Cyclic nucleotide second messenger coupling. Reason: Correct in essence; MC1R specifically activates adenylate cyclase via Gs. Proposed replacements: adenylate cyclase-activating G protein-coupled receptor signaling pathway Supporting Evidence: PMID:9571181 The Arg151Cys variant of MC1R binds to radio-labelled analogue of alpha-MSH with identical affinity as wild type MC1R but can not be stimulated to produce cyclic AMP (cAMP). file:human/MC1R/MC1R-uniprot.txt Upon activation, MC1R couples with the G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway. |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Gs-coupled adenylate cyclase activation inherited. Reason: Core pathway. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt Upon activation, MC1R couples with the G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway. PMID:9571181 The Arg151Cys variant of MC1R binds to radio-labelled analogue of alpha-MSH with identical affinity as wild type MC1R but can not be stimulated to produce cyclic AMP (cAMP). |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA PMID:19329486 MRAP and MRAP2 are bidirectional regulators of the melanocor... | ACCEPT | Summary: NDP-MSH-induced cAMP responses of MC1R modulated by MRAP/MRAP2. Reason: Core pathway. Supporting Evidence: PMID:19329486 MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA PMID:19743876 Novel binding motif of ACTH analogues at the melanocortin re... | ACCEPT | Summary: cAMP signalling by ACTH analogues at hMC1R. Reason: Core pathway. Supporting Evidence: PMID:19743876 we examined the role of Phe(7) in ACTH on human (h) MC1R, MC3R, and MC4R binding and signaling |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA PMID:8463333 Molecular cloning of a novel melanocortin receptor. | ACCEPT | Summary: Pharmacological characterization of melanocortin receptor cAMP responses. Reason: Core pathway, consistent with UniProt curated function. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt Upon activation, MC1R couples with the G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway. |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction of adenylate cyclase-activating GPCR pathway. Reason: Consistent with core pathway supported experimentally. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt Upon activation, MC1R couples with the G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway. |
| GO:0007200 phospholipase C-activating G protein-coupled receptor signaling pathway | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: PLC-activating GPCR signalling transferred from mouse. Reason: MC1R is canonically a Gs/cAMP receptor; PLC coupling is not established for human MC1R in the cited or cached literature. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt Upon activation, MC1R couples with the G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway. |
| GO:0007200 phospholipase C-activating G protein-coupled receptor signaling pathway | ISS PMID:18292087 Melanocortin-1 receptor signaling markedly induces the expre... | MARK AS OVER ANNOTATED | Summary: PLC-activating GPCR signalling by similarity to mouse, citing the NR4A paper. Reason: The cited paper concerns cAMP-driven NR4A induction, not PLC signalling; the canonical pathway is Gs/adenylate cyclase. Supporting Evidence: PMID:18292087 MC1R signaling in B16 mouse melanoma cells and primary human melanocytes rapidly, and transiently, induces the transcription of the NR4A subfamily of orphan nuclear receptors. file:human/MC1R/MC1R-uniprot.txt Upon activation, MC1R couples with the G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway. |
| GO:0007218 neuropeptide signaling pathway | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Neuropeptide signaling pathway inferred from corticotropin receptor activity. Reason: Melanocortins are neuropeptide hormones, so the logical inference is valid, but MC1R acts mainly in melanocytes and immune cells, so this is peripheral. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH |
| GO:0008528 G protein-coupled peptide receptor activity | TAS PMID:18292087 Melanocortin-1 receptor signaling markedly induces the expre... | MODIFY | Summary: Peptide GPCR activity. Reason: Correct but general; MSH receptor activity is the precise descendant. Proposed replacements: melanocyte-stimulating hormone receptor activity Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH |
| GO:0009650 UV protection | TAS PMID:7581459 Variants of the melanocyte-stimulating hormone receptor gene... | KEEP AS NON CORE | Summary: MC1R variants associated with red hair and poor tanning. Reason: MC1R promotes photoprotective eumelanin synthesis, so loss-of-function variants reduce UV protection; this organism-level outcome is downstream of the core receptor function. Supporting Evidence: PMID:7581459 variations in this protein are associated with a poor tanning response |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA prediction of regulation of gene expression. Reason: Very general, indirect consequence of cAMP signalling (e.g. MITF and NR4A induction); not an activity of the receptor itself. Supporting Evidence: PMID:18292087 MC1R signaling in B16 mouse melanoma cells and primary human melanocytes rapidly, and transiently, induces the transcription of the NR4A subfamily of orphan nuclear receptors. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Generic membrane from InterPro. Reason: Correct but general; plasma membrane is supported and already annotated. Proposed replacements: plasma membrane Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:31097585}; Multi-pass membrane protein {ECO:0000255}. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:19737927 Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase inhibits... | KEEP AS NON CORE | Summary: MC1R co-immunoprecipitates with the E3 ligase MGRN1, which competes with Gs. Reason: The interaction is documented, but MC1R is not ubiquitinated by MGRN1; the binding is a regulatory interaction rather than a core activity. Supporting Evidence: PMID:19737927 MGRN1 co-immunoprecipitated with MCRs, suggesting a physical interaction of the proteins. |
| GO:0032720 negative regulation of tumor necrosis factor production | IMP PMID:10233018 alpha-MSH and its receptors in regulation of tumor necrosis ... | KEEP AS NON CORE | Summary: Blocking MC1R antibody increases TNF production by THP-1 macrophages. Reason: Supports an anti-inflammatory role of melanocortin signalling via MC1R in monocytes; peripheral to pigmentation. Supporting Evidence: PMID:10233018 Incubation of resting macrophages with antibody to hMC-1R increased TNF-alpha concentration |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000107 | MODIFY | Summary: Intracellular signal transduction transferred from mouse. Reason: MC1R is the receptor upstream of the cAMP/PKA cassette rather than an intracellular transducer; positive regulation of cAMP/PKA signal transduction (already carried) describes its role. Proposed replacements: positive regulation of cAMP/PKA signal transduction Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt Upon activation, MC1R couples with the G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway. |
| GO:0035556 intracellular signal transduction | ISS PMID:18292087 Melanocortin-1 receptor signaling markedly induces the expre... | MODIFY | Summary: Intracellular signal transduction by similarity. Reason: As above. Proposed replacements: positive regulation of cAMP/PKA signal transduction Supporting Evidence: PMID:18292087 MC1R signaling in B16 mouse melanoma cells and primary human melanocytes rapidly, and transiently, induces the transcription of the NR4A subfamily of orphan nuclear receptors. file:human/MC1R/MC1R-uniprot.txt Upon activation, MC1R couples with the G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway. |
| GO:0042438 melanin biosynthetic process | IBA GO_REF:0000033 | MODIFY | Summary: Melanin biosynthetic process inherited at MC1R node. Reason: MC1R does not catalyse melanin synthesis; it regulates melanogenesis by raising cAMP. The correct term is positive regulation of melanin biosynthetic process (already annotated by IMP). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002733711 SUPPORTS SOURCE BUT NOT TARGET MC1R clade node; the process assertion is biologically grounded in mouse Mc1r pigmentation phenotypes, but the receptor regulates rather than performs melanin biosynthesis. Proposed replacements: positive regulation of melanin biosynthetic process Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt This activation promotes melanogenesis, resulting in the production of eumelanin (black/brown) and pheomelanin (red/yellow) in melanocytes |
| GO:0042562 hormone binding | IEA GO_REF:0000107 | MODIFY | Summary: Hormone binding transferred from rat. Reason: True but general; MC1R binds peptide hormones (MSH, ACTH). Proposed replacements: peptide hormone binding Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH |
| GO:0043473 pigmentation | TAS PMID:18292087 Melanocortin-1 receptor signaling markedly induces the expre... | ACCEPT | Summary: MC1R regulates pigmentation. Reason: MC1R is a principal genetic determinant of human pigmentation phenotype. Supporting Evidence: PMID:7581459 the MC1R is a control point in the regulation of pigmentation phenotype |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of Pol II transcription transferred from mouse. Reason: Transcriptional induction (MITF, NR4A) is an indirect downstream consequence of cAMP/CREB signalling; MC1R is not a transcriptional regulator. Supporting Evidence: PMID:18292087 MC1R signaling in B16 mouse melanoma cells and primary human melanocytes rapidly, and transiently, induces the transcription of the NR4A subfamily of orphan nuclear receptors. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS PMID:18292087 Melanocortin-1 receptor signaling markedly induces the expre... | MARK AS OVER ANNOTATED | Summary: Positive regulation of Pol II transcription by similarity (NR4A induction). Reason: Indirect consequence of receptor-initiated cAMP signalling. Supporting Evidence: PMID:18292087 MC1R signaling in B16 mouse melanoma cells and primary human melanocytes rapidly, and transiently, induces the transcription of the NR4A subfamily of orphan nuclear receptors. |
| GO:0048023 positive regulation of melanin biosynthetic process | IMP PMID:19338054 Identification and functional analysis of novel variants of ... | ACCEPT | Summary: Loss-of-function MC1R variants reduce cAMP coupling and melanogenic signalling. Reason: Core physiological output of MC1R. Supporting Evidence: PMID:19338054 The other mutations are associated with varying degrees of loss of function (LOF), from moderate decreases in coupling to the cAMP pathway file:human/MC1R/MC1R-uniprot.txt This activation promotes melanogenesis, resulting in the production of eumelanin (black/brown) and pheomelanin (red/yellow) in melanocytes |
| GO:0060259 regulation of feeding behavior | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Regulation of feeding behavior transferred from rat. Reason: Melanocortin control of feeding is mediated by MC4R/MC3R in the hypothalamus; there is no human MC1R evidence for a feeding role. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH |
| GO:0070914 UV-damage excision repair | IDA PMID:18292087 Melanocortin-1 receptor signaling markedly induces the expre... | MODIFY | Summary: MC1R signalling enhances removal of UV-induced pyrimidine dimers via NR4A factors. Reason: MC1R does not participate in the excision repair machinery; its signalling promotes repair indirectly. Positive regulation of DNA repair captures the claim more accurately. Proposed replacements: positive regulation of DNA repair Supporting Evidence: PMID:18292087 These data identify the NR4A receptor family as potential mediators of an MC1R-coordinated DNA damage response to UV exposure in melanocytic cells. |
| GO:0141163 positive regulation of cAMP/PKA signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: Positive regulation of cAMP/PKA signalling inherited. Reason: MC1R activation via Gs raises cAMP and activates PKA. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt Upon activation, MC1R couples with the G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway. |
| GO:0141163 positive regulation of cAMP/PKA signal transduction | IEA GO_REF:0000107 | ACCEPT | Summary: Positive regulation of cAMP/PKA signalling transferred from mouse. Reason: Consistent with core function. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt Upon activation, MC1R couples with the G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway. |
| GO:0141163 positive regulation of cAMP/PKA signal transduction | ISS PMID:18292087 Melanocortin-1 receptor signaling markedly induces the expre... | ACCEPT | Summary: Positive regulation of cAMP/PKA signalling by similarity. Reason: Consistent with core function. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt Upon activation, MC1R couples with the G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway. PMID:18292087 MC1R signaling in B16 mouse melanoma cells and primary human melanocytes rapidly, and transiently, induces the transcription of the NR4A subfamily of orphan nuclear receptors. |
| GO:2000253 positive regulation of feeding behavior | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of feeding behavior transferred from rat. Reason: As for regulation of feeding behavior; feeding control is attributed to MC4R/MC3R. Supporting Evidence: file:human/MC1R/MC1R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH |
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Download this section (compressed HTML)Q: What fraction of wild-type MC1R resides intracellularly versus at the cell surface in human melanocytes, and is OPN3 heterodimerization regulated by this partitioning?
Q: Does MC1R signal via non-cAMP effectors (e.g. PLC, PI3K/AKT) in human melanocytes in a physiologically meaningful way?
Experiment: Quantify surface versus total MC1R with extracellular-epitope antibodies and surface biotinylation in primary human melanocytes expressing wild-type and RHC variants, combined with BRET-based Gs and Gq activation assays.
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