POMC

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0001664 G protein-coupled receptor binding	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: POMC-derived peptides (ACTH, alpha-MSH, beta-MSH, gamma-MSH) are well-established ligands for melanocortin receptors, but GO:0001664 is a generic parent that is less informative than the accepted specific melanocortin receptor binding terms. Reason: The underlying biology is correct, but POMC curation should prefer specific melanocortin receptor binding terms over generic GPCR binding. ACTH binds MC2R and alpha-MSH binds MC1R/MC3R/MC4R/MC5R; the specific accepted terms in this review capture those activities more cleanly. Supporting Evidence: PMID:19743876 Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R. file:human/POMC/POMC-deep-research-falcon.md Melanocortin receptor binding vs generic GPCR binding: Prefer melanocortin receptor binding terms, with MC2R specificity for ACTH explicitly supported; do not use generic “GPCR binding” for POMC gene product as a catch-all.
GO:0005179 hormone activity	IEA GO_REF:0000120	ACCEPT	Summary: POMC gives rise to multiple peptide hormones including ACTH, MSH peptides, and beta-endorphin. Hormone activity is a core function. IEA is consistent with extensive experimental evidence. Reason: This is the defining function of POMC - it is a prohormone that produces multiple bioactive peptide hormones. UniProt classifies it under "Hormone" keywords, and PMID:9620771 demonstrates hormonal functions through mutation phenotypes. Supporting Evidence: PMID:9620771 Sequential cleavage of the precursor protein pre-pro-opiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) alpha, beta and gamma as well as the opioid-receptor ligand beta-endorphin. file:human/POMC/POMC-deep-research-falcon.md Pro-opiomelanocortin (POMC) is best curated in GO as a secreted prohormone precursor that is sorted to regulated secretory granules and proteolytically processed in a tissue-specific manner to yield multiple bioactive peptides (ACTH, α/β/γ-MSH, β-endorphin; enkephalin motifs embedded in the β-LPH/β-endorphin region).
GO:0005179 hormone activity	ISS GO_REF:0000024	ACCEPT	Summary: Duplicate annotation with IEA above, ISS inference from orthologs is appropriate. Reason: Hormone activity is conserved across mammals. ISS annotation is appropriate and consistent with experimental evidence.
GO:0005179 hormone activity	IMP PMID:9620771 Severe early-onset obesity, adrenal insufficiency and red ha...	ACCEPT	Summary: The Krude et al. 1998 paper describes POMC-null patients with adrenal insufficiency (loss of ACTH hormone function) and obesity (loss of alpha-MSH hormone function). IMP from mutant phenotype is well-justified. Reason: Loss of POMC function results in loss of hormonal activity - ACTH deficiency causes secondary hypocortisolism, alpha-MSH deficiency causes obesity and red hair. This directly demonstrates hormone activity through loss-of-function. Supporting Evidence: PMID:9620771 early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput Y2H interactome study (HuRI) identified POMC interactors. However, 'protein binding' is uninformative for a secreted prohormone. The actual function is GPCR binding, which is separately annotated. Reason: 'Protein binding' is too vague and uninformative for a prohormone. The meaningful interactions are with melanocortin receptors and opioid receptors, which are captured by more specific MF terms. HuRI Y2H interactions for a secreted/processed prohormone are likely not physiologically relevant - POMC is processed in the secretory pathway and its products function extracellularly. Supporting Evidence: PMID:32296183 HuRI is estimated to represent 2–11% of the binary protein interactome file:human/POMC/POMC-deep-research-falcon.md Generic protein binding / identical protein binding: Do not annotate generic binding (including “identical protein binding”) unless there is direct biochemical interaction evidence for the relevant molecular entity (precursor vs peptide).
GO:0005102 signaling receptor binding	IMP PMID:9620771 Severe early-onset obesity, adrenal insufficiency and red ha...	ACCEPT	Summary: Loss of POMC function causes phenotypes consistent with loss of signaling through melanocortin receptors (MC1R for pigmentation, MC4R for appetite, MC2R for ACTH). This is a valid parent term for the more specific MCR binding terms. Reason: POMC-derived peptides bind melanocortin receptors (signaling receptors). This is correctly inferred from mutant phenotype - loss of receptor activation. More specific terms (MC1R/MC3R/MC4R binding) provide additional detail. Supporting Evidence: PMID:9620771 Recent studies in animal models elucidated a central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor (MC4-R; refs 3-5)
GO:0070996 type 1 melanocortin receptor binding	IPI PMID:19743876 Novel binding motif of ACTH analogues at the melanocortin re...	ACCEPT	Summary: Yang et al. 2009 directly tested ACTH and MSH peptide binding to melanocortin receptors. ACTH and alpha-MSH bind MC1R. This is a core molecular function. Reason: Direct binding studies demonstrate alpha-MSH and ACTH bind MC1R. This receptor mediates pigmentation effects of MSH peptides. MC1R binding is a core function of alpha-MSH (POMC 138-150). Supporting Evidence: PMID:19743876 Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R.
GO:0070996 type 1 melanocortin receptor binding	IDA PMID:18292087 Melanocortin-1 receptor signaling markedly induces the expre...	ACCEPT	Summary: Smith et al. 2008 studied MC1R signaling using alpha-MSH agonists. Confirms MC1R binding by melanocortin peptides. Reason: The study uses MC1R agonist (NDP-alpha-MSH) and wild-type alpha-MSH to study MC1R signaling in melanocytes, confirming MC1R binding as a core function. Supporting Evidence: PMID:18292087 the potent MC1R agonist (Nle4,D-Phe7)-alpha-melanocyte-stimulating hormone
GO:0031781 type 3 melanocortin receptor binding	IPI PMID:19743876 Novel binding motif of ACTH analogues at the melanocortin re...	ACCEPT	Summary: Yang et al. 2009 demonstrated ACTH and alpha-MSH binding to MC3R through receptor binding and activation studies. Reason: MC3R is a target of alpha-MSH and ACTH peptides. The paper directly demonstrates receptor binding and activation at hMC3R. Gamma-MSH from POMC preferentially binds MC3R. Supporting Evidence: PMID:19743876 Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R
GO:0031782 type 4 melanocortin receptor binding	IPI PMID:19743876 Novel binding motif of ACTH analogues at the melanocortin re...	ACCEPT	Summary: MC4R binding is critical for appetite regulation by alpha-MSH. This is the key receptor mediating anorexigenic effects of alpha-MSH in hypothalamus. Reason: MC4R binding by alpha-MSH is the molecular basis of POMC's role in appetite suppression. Loss of this interaction explains obesity in POMC-null patients. Core molecular function. Supporting Evidence: PMID:19743876 Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R PMID:9620771 Recent studies in animal models elucidated a central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor (MC4-R; refs 3-5)
GO:0001664 G protein-coupled receptor binding	IDA PMID:19452503 Aberrant trafficking of human melanocortin 1 receptor varian...	MARK AS OVER ANNOTATED	Summary: Sanchez-Laorden et al. 2009 studied MC1R trafficking and activation, demonstrating melanocortin ligand biology, but the GO annotation uses a generic GPCR binding parent. Reason: The paper supports MC1R pathway biology, but specific melanocortin receptor binding terms are already present and more informative. GO:0001664 should not be retained as a core generic catch-all for POMC-derived peptide receptor binding. Supporting Evidence: PMID:19452503 The melanocortin 1 receptor (MC1R), a Gs protein-coupled receptor (GPCR) expressed in melanocytes file:human/POMC/POMC-deep-research-falcon.md Melanocortin receptor binding vs generic GPCR binding: Prefer melanocortin receptor binding terms, with MC2R specificity for ACTH explicitly supported; do not use generic “GPCR binding” for POMC gene product as a catch-all.
GO:0005615 extracellular space	IBA GO_REF:0000033	ACCEPT	Summary: POMC-derived peptides are secreted hormones that function in the extracellular space. IBA phylogenetic inference is appropriate. Reason: All POMC-derived bioactive peptides (ACTH, MSH, beta-endorphin) are secreted and function extracellularly to bind receptors on target cells. UniProt notes "Secreted" for subcellular location.
GO:0005576 extracellular region	IEA GO_REF:0000120	ACCEPT	Summary: Extracellular region is the broader parent term. POMC products are secreted and act extracellularly. Reason: Consistent with secreted hormone function. Appropriate IEA inference.
GO:0030141 secretory granule	IBA GO_REF:0000033	ACCEPT	Summary: POMC is stored in and processed within secretory granules in pituitary and hypothalamic neurons before release. IBA is appropriate. Reason: UniProt notes that alpha-MSH and beta-endorphin are stored in separate granules in hypothalamic POMC neurons. Secretory granule localization is well-established. Supporting Evidence: UniProtKB:P01189 Melanocyte-stimulating hormone alpha and beta-endorphin are stored in separate granules in hypothalamic POMC neurons
GO:0005615 extracellular space	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate of IBA annotation above. Extracellular space is correct for secreted peptide hormones. Reason: IEA inference consistent with experimental evidence for secreted localization.
GO:0005737 cytoplasm	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: POMC transits through cytoplasm during biosynthesis but this is not its functional location. This is over-annotation. Reason: While POMC precursor passes through the cytoplasm during synthesis, this is not meaningful for function. POMC enters the secretory pathway via signal peptide and is processed in ER/Golgi/secretory granules. Cytoplasm annotation is technically true but functionally misleading.
GO:0030141 secretory granule	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate of IBA annotation. Secretory granule localization is correct. Reason: IEA inference consistent with IBA and experimental evidence.
GO:0005576 extracellular region	TAS Reactome:R-HSA-379044	ACCEPT	Summary: Reactome pathway annotation for GPCR signaling. Extracellular region is where ligands interact with receptors. Reason: Appropriate localization for secreted hormone peptides.
GO:0005576 extracellular region	TAS Reactome:R-HSA-388596	ACCEPT	Summary: Reactome annotation for melanocortin receptor binding. Multiple Reactome TAS annotations to same GO term represent different pathway contexts. Reason: Valid annotation - POMC peptides bind melanocortin receptors extracellularly.
GO:0005576 extracellular region	TAS Reactome:R-HSA-744886	ACCEPT	Summary: Reactome annotation for GPCR:Gs complex dissociation pathway. Reason: Valid - ligands act extracellularly to activate GPCRs.
GO:0005576 extracellular region	TAS Reactome:R-HSA-744887	ACCEPT	Summary: Reactome annotation for liganded Gs-activating GPCRs. Reason: Valid - melanocortins bind Gs-coupled MCRs extracellularly.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5603251	ACCEPT	Summary: Reactome annotation for defective ACTH not binding MC2R. Reason: Valid pathway annotation - ACTH acts extracellularly on MC2R.
GO:0005576 extracellular region	TAS Reactome:R-HSA-112042	ACCEPT	Summary: Reactome annotation for opioid binding to MOR (mu opioid receptor). Beta-endorphin is the POMC product that binds opioid receptors. Reason: Beta-endorphin (POMC 237-267) binds mu-opioid receptor extracellularly.
GO:0005576 extracellular region	TAS Reactome:R-HSA-112271	ACCEPT	Summary: Reactome annotation for receptor:G-protein complex dissociation in opioid signaling. Reason: Valid pathway annotation for beta-endorphin function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-167408	ACCEPT	Summary: Reactome annotation for high affinity receptor:G-protein binding. Reason: Valid - POMC peptides act as extracellular ligands for GPCRs.
GO:0005576 extracellular region	TAS Reactome:R-HSA-167419	ACCEPT	Summary: Reactome annotation for GDP release from receptor:G-protein complex. Reason: Valid pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-167427	ACCEPT	Summary: Reactome annotation for opioid dissociation from MOR. Reason: Valid - beta-endorphin binds MOR extracellularly.
GO:0005576 extracellular region	TAS Reactome:R-HSA-167429	ACCEPT	Summary: Reactome annotation for GTP binding to receptor:G-protein complex. Reason: Valid pathway annotation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-374298	ACCEPT	Summary: Reactome annotation for opioid receptors binding opioid peptides. Reason: Beta-endorphin and met-enkephalin from POMC bind opioid receptors extracellularly.
GO:0005576 extracellular region	TAS Reactome:R-HSA-380073	ACCEPT	Summary: Reactome annotation for Gi-coupled GPCR activation (opioid signaling). Reason: Valid - opioid receptors are Gi-coupled, beta-endorphin acts extracellularly.
GO:0005576 extracellular region	TAS Reactome:R-HSA-388605	ACCEPT	Summary: Reactome annotation specifically for ACTH (POMC 138-176) binding MC2R. Reason: Core function - ACTH binds MC2R extracellularly to stimulate cortisol release.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6789615	ACCEPT	Summary: Reactome annotation for STAT3-upregulated extracellular proteins. Reason: Valid - POMC products are extracellular.
GO:0005576 extracellular region	TAS Reactome:R-HSA-749454	ACCEPT	Summary: Reactome annotation for Gi complex dissociation. Reason: Valid pathway annotation for opioid signaling.
GO:0005576 extracellular region	TAS Reactome:R-HSA-749456	ACCEPT	Summary: Reactome annotation for Gi-coupled GPCR binding. Reason: Valid - opioid peptides act extracellularly.
GO:0034774 secretory granule lumen	TAS Reactome:R-HSA-265301	ACCEPT	Summary: Reactome annotation for corticotropin cleavage from POMC. Processing occurs in secretory granule lumen. Reason: POMC processing by prohormone convertases (PC1/3, PC2) occurs in the lumen of secretory granules. This is where the mature peptides are generated.
GO:0005782 peroxisomal matrix	IDA PMID:20810565 Peroxisomal localization of the proopiomelanocortin-derived ...	KEEP AS NON CORE	Summary: Hoftberger et al. 2010 report surprising peroxisomal localization of beta-LPH and beta-endorphin in cells expressing ALDP. This is tissue-specific and applies only to the C-terminal POMC products. Reason: The paper demonstrates peroxisomal localization specifically for beta-LPH and beta-endorphin (C-terminal POMC products) in cells expressing ALDP. However, N-terminal peptides (ACTH, alpha-MSH, gamma-MSH) were NOT found in peroxisomes. This is a specialized localization, not a core function. Supporting Evidence: PMID:20810565 In contrast to the peptide hormones β-LPH and β-endorphin, which are derived from the C terminus of POMC, the N-terminal peptides ACTH, α-MSH, and γ-MSH were never detected in peroxisomes.
GO:0005615 extracellular space	IDA PMID:9620771 Severe early-onset obesity, adrenal insufficiency and red ha...	ACCEPT	Summary: The Krude paper describes POMC mutation phenotypes but does not directly demonstrate extracellular localization. However, the inferred hormonal function implies extracellular action. Reason: While not directly demonstrated in this paper, POMC products function as circulating hormones, which by definition are extracellular. Supporting Evidence: PMID:9620771 Sequential cleavage of the precursor protein pre-pro-opiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) alpha, beta and gamma as well as the opioid-receptor ligand beta-endorphin
GO:0005737 cytoplasm	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS annotation for cytoplasm. Like the IEA annotation, this is technically true but functionally misleading. Reason: Cytoplasm is not a meaningful functional location for POMC. The protein enters the secretory pathway and functions extracellularly.
GO:0030141 secretory granule	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation consistent with IBA and IEA annotations. Secretory granule is a valid localization. Reason: Secretory granule storage and processing is conserved across POMC orthologs.
GO:2000852 regulation of corticosterone secretion	IBA GO_REF:0000033	ACCEPT	Summary: ACTH (POMC 138-176) stimulates adrenal cortex to release glucocorticoids. In rodents, this is corticosterone; in humans, cortisol. IBA annotation is appropriate for the conserved function. Reason: ACTH regulation of adrenal glucocorticoid secretion is the primary function of the HPA axis. This is conserved across mammals - the specific glucocorticoid varies but the mechanism is the same. Supporting Evidence: PMID:9620771 While a few cases of isolated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far.
GO:0007218 neuropeptide signaling pathway	IEA GO_REF:0000043	ACCEPT	Summary: POMC produces multiple neuropeptides (alpha-MSH, beta-endorphin) that function in hypothalamic signaling. UniProt keyword mapping is appropriate. Reason: Alpha-MSH and beta-endorphin are classical neuropeptides produced in hypothalamic POMC neurons. Neuropeptide signaling is a core function.
GO:0106071 positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	IEA GO_REF:0000107	ACCEPT	Summary: Melanocortin receptors (MC1R-MC5R) are Gs-coupled GPCRs that activate adenylate cyclase. POMC peptides as ligands positively regulate this pathway. Reason: MC1R, MC2R, MC3R, MC4R, and MC5R are all coupled to Gs and activate adenylate cyclase upon binding melanocortin peptides. This is the signaling mechanism.
GO:0140668 positive regulation of oxytocin production	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Some evidence suggests melanocortins affect oxytocin release, but this is not a well-established core function of POMC. Reason: While there may be some regulatory effects of melanocortins on oxytocin, this is not a direct or primary function of POMC. The evidence base is limited and this appears to be an over-extension of IEA transfer.
GO:1990680 response to melanocyte-stimulating hormone	IEA GO_REF:0000107	REMOVE	Summary: This annotation is problematic - POMC PRODUCES melanocyte-stimulating hormone, it does not respond to it. This appears to be an erroneous annotation. Reason: POMC is the precursor that produces MSH peptides. It does not respond to MSH. This annotation appears to confuse POMC with MSH receptors or downstream targets. POMC-expressing cells may respond to feedback, but the gene product itself does not "respond to MSH."
GO:0106071 positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: Duplicate of IEA annotation. ISS is appropriate as melanocortin receptor signaling mechanism is conserved. Reason: Conserved function - melanocortin receptors couple to Gs and activate AC.
GO:0019722 calcium-mediated signaling	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Some melanocortin receptors can couple to calcium signaling, but this is not the primary signaling mechanism for most MCRs. Reason: While MC1R and other MCRs can activate calcium signaling in some contexts, the primary signaling mechanism is cAMP/PKA via Gs coupling. Calcium signaling is a secondary effect, not a core function.
GO:1990680 response to melanocyte-stimulating hormone	ISS GO_REF:0000024	REMOVE	Summary: Same issue as IEA annotation - POMC produces MSH, it does not respond to it. Reason: POMC is the source of MSH, not a responder. This annotation is erroneous.
GO:0006091 generation of precursor metabolites and energy	IMP PMID:9620771 Severe early-onset obesity, adrenal insufficiency and red ha...	MARK AS OVER ANNOTATED	Summary: POMC-null patients have metabolic abnormalities, but this is an indirect effect of hormone loss, not a direct molecular function. This term is too general. Reason: While POMC loss affects metabolism (obesity, adrenal insufficiency), this is an indirect consequence of loss of hormonal regulation, not a direct role in energy generation pathways. This annotation is over-interpretation of phenotype data. Supporting Evidence: PMID:9620771 early-onset obesity, adrenal insufficiency and red hair pigmentation
GO:0007165 signal transduction	IMP PMID:9620771 Severe early-onset obesity, adrenal insufficiency and red ha...	ACCEPT	Summary: POMC-derived peptides are signaling molecules that activate receptor signaling. This is correct but very general. Reason: All POMC peptide hormones function by activating signal transduction cascades through their receptors. This is a valid high-level annotation. Supporting Evidence: PMID:9620771 Recent studies in animal models elucidated a central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor (MC4-R; refs 3-5) and the linkage of human obesity to chromosome 2 in close proximity to the POMC locus, led to the proposal of an association of POMC with human obesity
GO:0007267 cell-cell signaling	IMP PMID:9620771 Severe early-onset obesity, adrenal insufficiency and red ha...	ACCEPT	Summary: POMC-derived peptides mediate cell-cell signaling between endocrine cells and target tissues. This is a core function. Reason: ACTH signals from pituitary to adrenal cortex, alpha-MSH signals between hypothalamic neurons and melanocytes/hypothalamic circuits. Classical cell-cell signaling function. Supporting Evidence: PMID:9620771 Sequential cleavage of the precursor protein pre-pro-opiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) alpha, beta and gamma as well as the opioid-receptor ligand beta-endorphin
GO:0008217 regulation of blood pressure	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ACTH affects blood pressure through cortisol release; alpha-MSH may have direct cardiovascular effects via MC3R/MC4R. However, this is not a primary function of POMC. Reason: Blood pressure regulation is an indirect effect of POMC peptides, primarily through ACTH-stimulated glucocorticoid release. Not a core direct function.
GO:0032098 regulation of appetite	IMP PMID:9620771 Severe early-onset obesity, adrenal insufficiency and red ha...	MODIFY	Summary: POMC-null patients have severe obesity due to hyperphagia, demonstrating POMC role in appetite regulation. HOWEVER, this annotation conflates antagonistic functions: alpha-MSH suppresses appetite (anorexigenic) while beta-endorphin stimulates appetite (orexigenic). Reason: The term "regulation of appetite" is appropriate at the gene level because POMC produces BOTH appetite-suppressing (alpha-MSH via MC4R) AND appetite- stimulating (beta-endorphin via opioid receptors) peptides. The net effect in POMC-null patients is obesity because alpha-MSH loss predominates. However, ideally this should be annotated at the peptide level with specific terms (GO:0032099 negative regulation of appetite for alpha-MSH; GO:0032100 positive regulation of appetite for beta-endorphin). Proposed replacements: negative regulation of appetite positive regulation of appetite Supporting Evidence: PMID:9620771 alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor UniProtKB:P01189 -!- FUNCTION: [Beta-endorphin]: Endogenous orexigenic opiate. file:human/POMC/POMC-deep-research-falcon.md Appetite and stress are supported mechanistically through defined endocrine/neuropeptide pathways (α-MSH → MC3R/MC4R; ACTH → MC2R). Prefer pathway-grounded BP terms (e.g., regulation of food intake; regulation of glucocorticoid secretion) over very broad behavior/development annotations.
GO:0033059 cellular pigmentation	IMP PMID:9620771 Severe early-onset obesity, adrenal insufficiency and red ha...	ACCEPT	Summary: POMC-null patients have red hair and fair skin, demonstrating alpha-MSH role in pigmentation via MC1R. This is a core function of alpha-MSH. Reason: Alpha-MSH binding to MC1R in melanocytes stimulates melanin production. Loss of alpha-MSH (POMC mutation) causes red hair/fair skin phenotype. Core function. Supporting Evidence: PMID:9620771 red hair pigmentation caused by POMC mutations UniProtKB:P01189 [Melanocyte-stimulating hormone alpha]: Increases the pigmentation of skin by increasing melanin production in melanocytes.
GO:0032720 negative regulation of tumor necrosis factor production	IDA PMID:10233018 alpha-MSH and its receptors in regulation of tumor necrosis ...	KEEP AS NON CORE	Summary: Taherzadeh et al. 1999 demonstrated alpha-MSH inhibits TNF-alpha production in macrophages. This is an anti-inflammatory function of alpha-MSH. Reason: The paper demonstrates alpha-MSH suppresses TNF-alpha in LPS-stimulated macrophages via MC1R. This is a validated function but represents the immunomodulatory role of alpha-MSH, which is secondary to its pigmentation and appetite regulation functions. Supporting Evidence: PMID:10233018 The inflammatory cytokine tumor necrosis factor (TNF)-alpha was inhibited in relation to alpha-MSH concentration.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:18292087 Melanocortin-1 receptor signaling markedly induces the expre...	MARK AS OVER ANNOTATED	Summary: Smith et al. 2008 showed MC1R signaling (via alpha-MSH) induces transcription of NR4A nuclear receptors in melanocytes. This is downstream of receptor activation, not a direct function of POMC. Reason: This annotation conflates ligand function with downstream transcriptional effects. Alpha-MSH binding to MC1R activates cAMP/PKA which then activates transcription factors. POMC peptides do not directly regulate transcription; they bind extracellular receptors. This is over-annotation. Supporting Evidence: PMID:18292087 Here we show that 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:0016486 peptide hormone processing	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:9620771 Sequential cleavage of the precursor protein pre-pro-opiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) alpha, beta and gamma as well as the opioid-receptor ligand beta-endorphin. UniProtKB:P01189 Specific enzymatic cleavages at paired basic residues yield the different active peptides. file:human/POMC/POMC-deep-research-falcon.md Canonical regulated-secretory-pathway processing of POMC uses PCSK1/PC1-3 and PCSK2/PC2 endoproteolysis, followed by exopeptidase trimming (e.g., CPE) and additional modifications that can alter activity (e.g., acetylation affecting β-endorphin opioid activity).
GO:0031780 corticotropin hormone receptor binding	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:9620771 While a few cases of isolated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far. Reactome:R-HSA-388605 POMC(138-176) binds MC2R file:human/POMC/POMC-deep-research-falcon.md MC2R (ACTH receptor) is uniquely selective: MC2R binds a single endogenous ligand, ACTH—important for GO term choice (melanocortin receptor binding rather than generic GPCR binding).
GO:2000851 positive regulation of glucocorticoid secretion	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: Reactome:R-HSA-388605 POMC(138-176) binds MC2R
GO:0051464 positive regulation of cortisol secretion	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:9620771 early-onset obesity, adrenal insufficiency and red hair pigmentation Reactome:R-HSA-388605 POMC(138-176) binds MC2R
GO:0097009 energy homeostasis	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:9620771 Recent studies in animal models elucidated a central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor (MC4-R; refs 3-5) PMID:19743876 Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R.
GO:0042438 melanin biosynthetic process	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:9620771 red hair pigmentation caused by POMC mutations UniProtKB:P01189 [Melanocyte-stimulating hormone alpha]: Increases the pigmentation of skin by increasing melanin production in melanocytes. PMID:18292087 MC1R signaling in B16 mouse melanoma cells and primary human melanocytes
GO:0001515 opioid peptide activity	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: UniProtKB:P01189 -!- FUNCTION: [Beta-endorphin]: Endogenous orexigenic opiate. Reactome:R-HSA-374298 Opioid receptors bind opioid peptides file:human/POMC/POMC-deep-research-falcon.md β-endorphin is described as a POMC-derived peptide that binds opioid receptors (μ/δ/κ) with agonist activity for major forms.
GO:0051930 regulation of sensory perception of pain	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: UniProtKB:P01189 -!- FUNCTION: [Beta-endorphin]: Endogenous orexigenic opiate. Reactome:R-HSA-374298 Opioid receptors bind opioid peptides

Gene Description

Functional Isoforms

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

📚 Additional Documentation

Notes

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