id: P01189
gene_symbol: POMC
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >
  Pro-opiomelanocortin is a paradigm for post-translational polyprotein processing.
  A single
  267 AA precursor is proteolytically cleaved by prohormone convertases (PC1/3, PC2)
  into
  multiple bioactive peptides with distinct and sometimes ANTAGONISTIC functions.
  Key products
  include ACTH (stimulates cortisol release from adrenal cortex), alpha-MSH (anorexigenic,
  increases pigmentation via MC1R), beta-endorphin (orexigenic opiate), and met-enkephalin.
  Critically, tissue-specific processing produces different peptide combinations:
  anterior
  pituitary corticotrophs produce mainly ACTH; hypothalamic neurons produce both alpha-MSH
  (appetite suppression) and beta-endorphin (appetite stimulation). GO annotations
  at the
  gene level conflate functions that are peptide-specific - ideally annotations should
  use
  PRO ontology IDs for peptide-specific functions. POMC mutations cause obesity with
  adrenal
  insufficiency and red hair (PMID:9620771).
functional_isoforms:
- id: POMC_ACTH
  name: ACTH (Corticotropin)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids: [PRO_0000024969]
    residues: "138-176"
  description: >
    Adrenocorticotropic hormone. Primary product in anterior pituitary corticotrophs.
    Stimulates the adrenal cortex to release cortisol (glucocorticoids). ACTH binds
    MC2R (melanocortin receptor 2), which is exclusively expressed in adrenal cortex.
    This is the primary endpoint of the HPA axis. ACTH itself contains alpha-MSH
    sequence (residues 1-13 of ACTH = alpha-MSH) but ACTH is NOT further processed
    in anterior pituitary - only in intermediate pituitary is ACTH cleaved to alpha-MSH.
  isoform_specific_terms:
  - id: GO:0031780
    label: corticotropin hormone receptor binding
  - id: GO:2000851
    label: positive regulation of glucocorticoid secretion

- id: POMC_ALPHA_MSH
  name: Alpha-MSH (Melanotropin alpha)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids: [PRO_0000024970]
    residues: "138-150"
  description: >
    ANOREXIGENIC peptide - suppresses appetite. Produced in hypothalamic arcuate
    nucleus
    (POMC neurons) and intermediate pituitary. Signals through MC4R in hypothalamus
    to
    reduce food intake and increase energy expenditure. Also increases pigmentation
    via
    MC1R in melanocytes (hence red hair in POMC-deficient patients). Alpha-MSH has
    OPPOSITE effects to beta-endorphin on appetite - both are produced in the same
    hypothalamic neurons but stored in separate granules with distinct release mechanisms.
  isoform_specific_terms:
  - id: GO:0032099
    label: negative regulation of appetite
  - id: GO:0033059
    label: cellular pigmentation
  - id: GO:0070996
    label: type 1 melanocortin receptor binding
  - id: GO:0031782
    label: type 4 melanocortin receptor binding

- id: POMC_BETA_ENDORPHIN
  name: Beta-endorphin
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids: [PRO_0000024975]
    residues: "237-267"
  description: >
    OREXIGENIC opiate - STIMULATES appetite. This is the OPPOSITE effect to alpha-MSH!
    Endogenous opioid peptide that binds mu-opioid receptors (OPRM1). Produced in
    hypothalamic POMC neurons (same cells as alpha-MSH) and pituitary. Functions
    in
    pain modulation, stress response, and reward. The beta-endorphin/alpha-MSH balance
    in hypothalamus affects feeding behavior - both peptides are from the same precursor
    but have antagonistic effects on appetite.
  isoform_specific_terms:
  - id: GO:0032100
    label: positive regulation of appetite
  - id: GO:0019233
    label: sensory perception of pain

- id: POMC_BETA_MSH
  name: Beta-MSH (Melanotropin beta)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids: [PRO_0000024974]
    residues: "217-234"
  description: >
    Melanocyte-stimulating hormone. Increases pigmentation via MC1R binding.
    Less well characterized than alpha-MSH. Produced primarily in intermediate
    pituitary (minimal in adult humans). May also have effects on appetite
    regulation via MC4R, similar to alpha-MSH.
  isoform_specific_terms:
  - id: GO:0033059
    label: cellular pigmentation

- id: POMC_GAMMA_MSH
  name: Gamma-MSH (Melanotropin gamma)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids: [PRO_0000024967]
    residues: "77-87"
  description: >
    Part of the N-terminal peptide (NPP) region. Less characterized than alpha/beta-MSH.
    May have cardiovascular effects and adrenal functions distinct from other MSH
    peptides.
    Binds MC3R. The gamma-MSH-containing fragment (NPP) may have aldosterone-stimulating
    activity.
  isoform_specific_terms:
  - id: GO:0031781
    label: type 3 melanocortin receptor binding
existing_annotations:
# =====================================================================
# MOLECULAR FUNCTION ANNOTATIONS
# =====================================================================
- term:
    id: GO:0001664
    label: G protein-coupled receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >
      POMC-derived peptides (ACTH, alpha-MSH, beta-MSH, gamma-MSH) are well-established
      ligands for melanocortin GPCRs (MC1R-MC5R). This is a core molecular function
      of
      the POMC gene products. The IBA phylogenetic inference is sound.
    action: ACCEPT
    reason: >
      Multiple POMC cleavage products are endogenous ligands for melanocortin receptors
      (GPCRs). ACTH binds MC2R, alpha-MSH binds MC1R/MC3R/MC4R/MC5R. Well-supported
      by
      extensive literature and confirmed by direct binding studies (PMID:19743876).
    supported_by:
    - reference_id: PMID:19743876
      supporting_text: "Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R."

- term:
    id: GO:0005179
    label: hormone activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "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."

- term:
    id: GO:0005179
    label: hormone activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      Duplicate annotation with IEA above, ISS inference from orthologs is appropriate.
    action: ACCEPT
    reason: >
      Hormone activity is conserved across mammals. ISS annotation is appropriate
      and
      consistent with experimental evidence.

- term:
    id: GO:0005179
    label: hormone activity
  evidence_type: IMP
  original_reference_id: PMID:9620771
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    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.
    action: REMOVE
    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.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: "HuRI is estimated to represent 2-11% of the binary protein interactome"

- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IMP
  original_reference_id: PMID:9620771
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "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)"

- term:
    id: GO:0070996
    label: type 1 melanocortin receptor binding
  evidence_type: IPI
  original_reference_id: PMID:19743876
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:19743876
      supporting_text: "Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R."

- term:
    id: GO:0070996
    label: type 1 melanocortin receptor binding
  evidence_type: IDA
  original_reference_id: PMID:18292087
  review:
    summary: >
      Smith et al. 2008 studied MC1R signaling using alpha-MSH agonists. Confirms
      MC1R binding by melanocortin peptides.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:18292087
      supporting_text: "the potent MC1R agonist (Nle4,D-Phe7)-alpha-melanocyte-stimulating hormone"

- term:
    id: GO:0031781
    label: type 3 melanocortin receptor binding
  evidence_type: IPI
  original_reference_id: PMID:19743876
  review:
    summary: >
      Yang et al. 2009 demonstrated ACTH and alpha-MSH binding to MC3R through
      receptor binding and activation studies.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:19743876
      supporting_text: "Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R"

- term:
    id: GO:0031782
    label: type 4 melanocortin receptor binding
  evidence_type: IPI
  original_reference_id: PMID:19743876
  review:
    summary: >
      MC4R binding is critical for appetite regulation by alpha-MSH. This is the
      key receptor mediating anorexigenic effects of alpha-MSH in hypothalamus.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:19743876
      supporting_text: "Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R"
    - reference_id: PMID:9620771
      supporting_text: "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)"

- term:
    id: GO:0001664
    label: G protein-coupled receptor binding
  evidence_type: IDA
  original_reference_id: PMID:19452503
  review:
    summary: >
      Sanchez-Laorden et al. 2009 studied MC1R trafficking and activation, demonstrating
      ligand (alpha-MSH/ACTH) binding to this GPCR.
    action: ACCEPT
    reason: >
      Paper confirms GPCR (MC1R) binding by melanocortin peptides. GPCR binding
      is
      the mechanism of action for POMC-derived peptides.
    supported_by:
    - reference_id: PMID:19452503
      supporting_text: "The melanocortin 1 receptor (MC1R), a Gs protein-coupled receptor (GPCR) expressed in melanocytes"

# =====================================================================
# CELLULAR COMPONENT ANNOTATIONS
# =====================================================================
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >
      POMC-derived peptides are secreted hormones that function in the extracellular
      space. IBA phylogenetic inference is appropriate.
    action: ACCEPT
    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.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >
      Extracellular region is the broader parent term. POMC products are secreted
      and act extracellularly.
    action: ACCEPT
    reason: >
      Consistent with secreted hormone function. Appropriate IEA inference.

- term:
    id: GO:0030141
    label: secretory granule
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >
      POMC is stored in and processed within secretory granules in pituitary and
      hypothalamic neurons before release. IBA is appropriate.
    action: ACCEPT
    reason: >
      UniProt notes that alpha-MSH and beta-endorphin are stored in separate granules
      in hypothalamic POMC neurons. Secretory granule localization is well-established.
    supported_by:
    - reference_id: UniProtKB:P01189
      supporting_text: "Melanocyte-stimulating hormone alpha and beta-endorphin are stored in separate granules in hypothalamic POMC neurons"

- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >
      Duplicate of IBA annotation above. Extracellular space is correct for secreted
      peptide hormones.
    action: ACCEPT
    reason: >
      IEA inference consistent with experimental evidence for secreted localization.

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >
      POMC transits through cytoplasm during biosynthesis but this is not its
      functional location. This is over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    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.

- term:
    id: GO:0030141
    label: secretory granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >
      Duplicate of IBA annotation. Secretory granule localization is correct.
    action: ACCEPT
    reason: >
      IEA inference consistent with IBA and experimental evidence.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-379044
  review:
    summary: >
      Reactome pathway annotation for GPCR signaling. Extracellular region is where
      ligands interact with receptors.
    action: ACCEPT
    reason: >
      Appropriate localization for secreted hormone peptides.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-388596
  review:
    summary: >
      Reactome annotation for melanocortin receptor binding. Multiple Reactome
      TAS annotations to same GO term represent different pathway contexts.
    action: ACCEPT
    reason: >
      Valid annotation - POMC peptides bind melanocortin receptors extracellularly.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-744886
  review:
    summary: >
      Reactome annotation for GPCR:Gs complex dissociation pathway.
    action: ACCEPT
    reason: >
      Valid - ligands act extracellularly to activate GPCRs.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-744887
  review:
    summary: >
      Reactome annotation for liganded Gs-activating GPCRs.
    action: ACCEPT
    reason: >
      Valid - melanocortins bind Gs-coupled MCRs extracellularly.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5603251
  review:
    summary: >
      Reactome annotation for defective ACTH not binding MC2R.
    action: ACCEPT
    reason: >
      Valid pathway annotation - ACTH acts extracellularly on MC2R.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-112042
  review:
    summary: >
      Reactome annotation for opioid binding to MOR (mu opioid receptor).
      Beta-endorphin is the POMC product that binds opioid receptors.
    action: ACCEPT
    reason: >
      Beta-endorphin (POMC 237-267) binds mu-opioid receptor extracellularly.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-112271
  review:
    summary: >
      Reactome annotation for receptor:G-protein complex dissociation in opioid
      signaling.
    action: ACCEPT
    reason: >
      Valid pathway annotation for beta-endorphin function.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-167408
  review:
    summary: >
      Reactome annotation for high affinity receptor:G-protein binding.
    action: ACCEPT
    reason: >
      Valid - POMC peptides act as extracellular ligands for GPCRs.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-167419
  review:
    summary: >
      Reactome annotation for GDP release from receptor:G-protein complex.
    action: ACCEPT
    reason: >
      Valid pathway annotation.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-167427
  review:
    summary: >
      Reactome annotation for opioid dissociation from MOR.
    action: ACCEPT
    reason: >
      Valid - beta-endorphin binds MOR extracellularly.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-167429
  review:
    summary: >
      Reactome annotation for GTP binding to receptor:G-protein complex.
    action: ACCEPT
    reason: >
      Valid pathway annotation.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-374298
  review:
    summary: >
      Reactome annotation for opioid receptors binding opioid peptides.
    action: ACCEPT
    reason: >
      Beta-endorphin and met-enkephalin from POMC bind opioid receptors extracellularly.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-380073
  review:
    summary: >
      Reactome annotation for Gi-coupled GPCR activation (opioid signaling).
    action: ACCEPT
    reason: >
      Valid - opioid receptors are Gi-coupled, beta-endorphin acts extracellularly.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-388605
  review:
    summary: >
      Reactome annotation specifically for ACTH (POMC 138-176) binding MC2R.
    action: ACCEPT
    reason: >
      Core function - ACTH binds MC2R extracellularly to stimulate cortisol release.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6789615
  review:
    summary: >
      Reactome annotation for STAT3-upregulated extracellular proteins.
    action: ACCEPT
    reason: >
      Valid - POMC products are extracellular.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-749454
  review:
    summary: >
      Reactome annotation for Gi complex dissociation.
    action: ACCEPT
    reason: >
      Valid pathway annotation for opioid signaling.

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-749456
  review:
    summary: >
      Reactome annotation for Gi-coupled GPCR binding.
    action: ACCEPT
    reason: >
      Valid - opioid peptides act extracellularly.

- term:
    id: GO:0034774
    label: secretory granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-265301
  review:
    summary: >
      Reactome annotation for corticotropin cleavage from POMC. Processing occurs
      in secretory granule lumen.
    action: ACCEPT
    reason: >
      POMC processing by prohormone convertases (PC1/3, PC2) occurs in the lumen
      of secretory granules. This is where the mature peptides are generated.

- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IDA
  original_reference_id: PMID:20810565
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:20810565
      supporting_text: "In contrast to the peptide hormones beta-LPH and beta-endorphin, which are derived from the C terminus of POMC, the N-terminal peptides ACTH, alpha-MSH, and gamma-MSH were never detected in peroxisomes."

- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:9620771
  review:
    summary: >
      The Krude paper describes POMC mutation phenotypes but does not directly
      demonstrate extracellular localization. However, the inferred hormonal function
      implies extracellular action.
    action: ACCEPT
    reason: >
      While not directly demonstrated in this paper, POMC products function as
      circulating hormones, which by definition are extracellular.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: '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'

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      ISS annotation for cytoplasm. Like the IEA annotation, this is technically
      true but functionally misleading.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      Cytoplasm is not a meaningful functional location for POMC. The protein
      enters the secretory pathway and functions extracellularly.

- term:
    id: GO:0030141
    label: secretory granule
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      ISS annotation consistent with IBA and IEA annotations. Secretory granule
      is a valid localization.
    action: ACCEPT
    reason: >
      Secretory granule storage and processing is conserved across POMC orthologs.

# =====================================================================
# BIOLOGICAL PROCESS ANNOTATIONS
# =====================================================================
- term:
    id: GO:2000852
    label: regulation of corticosterone secretion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "adrenocorticotrophin (ACTH)... isolated ACTH deficiency"

- term:
    id: GO:0007218
    label: neuropeptide signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >
      POMC produces multiple neuropeptides (alpha-MSH, beta-endorphin) that function
      in hypothalamic signaling. UniProt keyword mapping is appropriate.
    action: ACCEPT
    reason: >
      Alpha-MSH and beta-endorphin are classical neuropeptides produced in
      hypothalamic POMC neurons. Neuropeptide signaling is a core function.

- term:
    id: GO:0106071
    label: positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >
      Melanocortin receptors (MC1R-MC5R) are Gs-coupled GPCRs that activate
      adenylate cyclase. POMC peptides as ligands positively regulate this pathway.
    action: ACCEPT
    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.

- term:
    id: GO:0140668
    label: positive regulation of oxytocin production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >
      Some evidence suggests melanocortins affect oxytocin release, but this is
      not a well-established core function of POMC.
    action: MARK_AS_OVER_ANNOTATED
    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.

- term:
    id: GO:1990680
    label: response to melanocyte-stimulating hormone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >
      This annotation is problematic - POMC PRODUCES melanocyte-stimulating hormone,
      it does not respond to it. This appears to be an erroneous annotation.
    action: REMOVE
    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."

- term:
    id: GO:0106071
    label: positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      Duplicate of IEA annotation. ISS is appropriate as melanocortin receptor
      signaling mechanism is conserved.
    action: ACCEPT
    reason: >
      Conserved function - melanocortin receptors couple to Gs and activate AC.

- term:
    id: GO:0019722
    label: calcium-mediated signaling
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      Some melanocortin receptors can couple to calcium signaling, but this is
      not the primary signaling mechanism for most MCRs.
    action: KEEP_AS_NON_CORE
    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.

- term:
    id: GO:1990680
    label: response to melanocyte-stimulating hormone
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      Same issue as IEA annotation - POMC produces MSH, it does not respond to it.
    action: REMOVE
    reason: >
      POMC is the source of MSH, not a responder. This annotation is erroneous.

- term:
    id: GO:0006091
    label: generation of precursor metabolites and energy
  evidence_type: IMP
  original_reference_id: PMID:9620771
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "early-onset obesity, adrenal insufficiency and red hair pigmentation"

- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IMP
  original_reference_id: PMID:9620771
  review:
    summary: >
      POMC-derived peptides are signaling molecules that activate receptor signaling.
      This is correct but very general.
    action: ACCEPT
    reason: >
      All POMC peptide hormones function by activating signal transduction cascades
      through their receptors. This is a valid high-level annotation.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: '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'

- term:
    id: GO:0007267
    label: cell-cell signaling
  evidence_type: IMP
  original_reference_id: PMID:9620771
  review:
    summary: >
      POMC-derived peptides mediate cell-cell signaling between endocrine cells
      and target tissues. This is a core function.
    action: ACCEPT
    reason: >
      ACTH signals from pituitary to adrenal cortex, alpha-MSH signals between
      hypothalamic neurons and melanocytes/hypothalamic circuits. Classical
      cell-cell signaling function.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: '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'

- term:
    id: GO:0008217
    label: regulation of blood pressure
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >
      Blood pressure regulation is an indirect effect of POMC peptides, primarily
      through ACTH-stimulated glucocorticoid release. Not a core direct function.

- term:
    id: GO:0032098
    label: regulation of appetite
  evidence_type: IMP
  original_reference_id: PMID:9620771
  review:
    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).
    action: MODIFY
    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_replacement_terms:
    - id: GO:0032099
      label: negative regulation of appetite
    - id: GO:0032100
      label: positive regulation of appetite
    additional_reference_ids:
    - UniProtKB:P01189
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor"
    - reference_id: UniProtKB:P01189
      supporting_text: "-!- FUNCTION: [Beta-endorphin]: Endogenous orexigenic opiate."

- term:
    id: GO:0033059
    label: cellular pigmentation
  evidence_type: IMP
  original_reference_id: PMID:9620771
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "red hair pigmentation caused by POMC mutations"
    - reference_id: UniProtKB:P01189
      supporting_text: "[Melanocyte-stimulating hormone alpha]: Increases the pigmentation of skin by increasing melanin production in melanocytes."

- term:
    id: GO:0032720
    label: negative regulation of tumor necrosis factor production
  evidence_type: IDA
  original_reference_id: PMID:10233018
  review:
    summary: >
      Taherzadeh et al. 1999 demonstrated alpha-MSH inhibits TNF-alpha production
      in macrophages. This is an anti-inflammatory function of alpha-MSH.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:10233018
      supporting_text: "The inflammatory cytokine tumor necrosis factor (TNF)-alpha was inhibited in relation to alpha-MSH concentration."

- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:18292087
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:18292087
      supporting_text: "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"

# =====================================================================
# CORE FUNCTIONS
# =====================================================================
# IMPORTANT: POMC is a POLYPROTEIN precursor - a single gene product that is
# proteolytically cleaved into multiple bioactive peptides with DISTINCT
# and sometimes ANTAGONISTIC functions. The core functions below describe
# the gene's role through its various cleavage products. Ideally, peptide-
# specific functions would be annotated at the PRO level (e.g., PRO:0000024969
# for ACTH), but GO annotations are typically made at the gene level.

- term:
    id: GO:0016486
    label: peptide hormone processing
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "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."
    - reference_id: UniProtKB:P01189
      supporting_text: "Specific enzymatic cleavages at paired basic residues yield the different active peptides."

# ---------------------------------------------------------------------
# Core Function 2: HPA Axis Regulation via ACTH
# ---------------------------------------------------------------------
# ACTH (residues 138-176) is the primary product in anterior pituitary
# corticotrophs. ACTH binds MC2R on adrenal cortex cells to stimulate
# glucocorticoid (cortisol) release. This is the endpoint of the HPA axis.
- term:
    id: GO:0031780
    label: corticotropin hormone receptor binding
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "adrenal insufficiency... isolated ACTH deficiency"
    - reference_id: Reactome:R-HSA-388605
      supporting_text: "POMC(138-176) binds MC2R"

# ---------------------------------------------------------------------
# Core Function 3: Appetite Suppression via Alpha-MSH
# ---------------------------------------------------------------------
# Alpha-MSH (residues 138-150, contained within ACTH) is released by
# hypothalamic POMC neurons. It binds MC4R to suppress appetite and
# increase energy expenditure. This is the ANOREXIGENIC function.
- term:
    id: GO:2000851
    label: positive regulation of glucocorticoid secretion
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "adrenal insufficiency... isolated ACTH deficiency"
    - reference_id: Reactome:R-HSA-388605
      supporting_text: "POMC(138-176) binds MC2R"

# ---------------------------------------------------------------------
# Core Function 3: Appetite Suppression via Alpha-MSH
# ---------------------------------------------------------------------
# Alpha-MSH (residues 138-150, contained within ACTH) is released by
# hypothalamic POMC neurons. It binds MC4R to suppress appetite and
# increase energy expenditure. This is the ANOREXIGENIC function.
- term:
    id: GO:0051464
    label: positive regulation of cortisol secretion
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "adrenal insufficiency... isolated ACTH deficiency"
    - reference_id: Reactome:R-HSA-388605
      supporting_text: "POMC(138-176) binds MC2R"

# ---------------------------------------------------------------------
# Core Function 3: Appetite Suppression via Alpha-MSH
# ---------------------------------------------------------------------
# Alpha-MSH (residues 138-150, contained within ACTH) is released by
# hypothalamic POMC neurons. It binds MC4R to suppress appetite and
# increase energy expenditure. This is the ANOREXIGENIC function.
- term:
    id: GO:0097009
    label: energy homeostasis
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "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)"
    - reference_id: PMID:19743876
      supporting_text: "Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R."

# ---------------------------------------------------------------------
# Core Function 4: Skin Pigmentation via MSH Peptides
# ---------------------------------------------------------------------
# Alpha-MSH and beta-MSH bind MC1R on melanocytes to stimulate melanin
# production. Loss of POMC results in fair skin and red hair due to
# absence of MC1R stimulation.
- term:
    id: GO:0042438
    label: melanin biosynthetic process
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:9620771
      supporting_text: "red hair pigmentation caused by POMC mutations"
    - reference_id: UniProtKB:P01189
      supporting_text: "[Melanocyte-stimulating hormone alpha]: Increases the pigmentation of skin by increasing melanin production in melanocytes."
    - reference_id: PMID:18292087
      supporting_text: "MC1R signaling in B16 mouse melanoma cells and primary human melanocytes"

# ---------------------------------------------------------------------
# Core Function 5: Opioid Signaling and Appetite Stimulation via Beta-Endorphin
# ---------------------------------------------------------------------
# Beta-endorphin (residues 237-267) is an endogenous opioid peptide that
# binds mu-opioid receptor. It is OREXIGENIC (stimulates appetite), which
# is ANTAGONISTIC to alpha-MSH's anorexigenic effect. Both are produced
# from the same precursor in hypothalamic neurons.
- term:
    id: GO:0001515
    label: opioid peptide activity
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: UniProtKB:P01189
      supporting_text: "-!- FUNCTION: [Beta-endorphin]: Endogenous orexigenic opiate."
    - reference_id: Reactome:R-HSA-374298
      supporting_text: "Opioid receptors bind opioid peptides"

- term:
    id: GO:0048265
    label: response to pain
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: UniProtKB:P01189
      supporting_text: "-!- FUNCTION: [Beta-endorphin]: Endogenous orexigenic opiate."
    - reference_id: Reactome:R-HSA-374298
      supporting_text: "Opioid receptors bind opioid peptides"

core_functions:
# ---------------------------------------------------------------------
# Core Function 1: Neuropeptide Hormone Precursor
# ---------------------------------------------------------------------
# This is the PRIMARY function of POMC - serving as a precursor for multiple
# bioactive peptides. The precursor itself has no activity; the function
# emerges through post-translational processing by PC1/3 and PC2.
- description: >
    Serves as a polyprotein precursor that is proteolytically processed by
    prohormone convertases (PC1/PC3, PC2) in a tissue-specific manner to
    generate multiple bioactive neuropeptide hormones including ACTH,
    melanocyte-stimulating hormones (alpha-, beta-, gamma-MSH), beta-endorphin,
    and beta-lipotropin. Processing occurs in secretory granules within
    neuroendocrine cells of the pituitary and hypothalamus.
  molecular_function:
    id: GO:0005179
    label: hormone activity
  directly_involved_in:
  - id: GO:0007218
    label: neuropeptide signaling pathway
  - id: GO:0016486
    label: peptide hormone processing
  locations:
  - id: GO:0034774
    label: secretory granule lumen
  - id: GO:0030141
    label: secretory granule
  - id: GO:0005615
    label: extracellular space
  anatomical_locations:
  - id: UBERON:0002196
    label: adenohypophysis
  - id: UBERON:0001898
    label: hypothalamus
  supported_by:
  - reference_id: PMID:9620771
    supporting_text: "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."
  - reference_id: UniProtKB:P01189
    supporting_text: "This is a prohormone that is cleaved to give multiple peptide hormones."

# ---------------------------------------------------------------------
# Core Function 2: HPA Axis Regulation via ACTH
# ---------------------------------------------------------------------
# ACTH (residues 138-176) is the primary product in anterior pituitary
# corticotrophs. ACTH binds MC2R on adrenal cortex cells to stimulate
# glucocorticoid (cortisol) release. This is the endpoint of the HPA axis.
- description: >
    Regulates the hypothalamic-pituitary-adrenal (HPA) axis via the cleavage
    product ACTH (corticotropin, residues 138-176). ACTH binds MC2R
    (corticotropin receptor) on adrenal cortex cells to stimulate
    glucocorticoid (cortisol in humans) secretion. Loss of POMC causes
    isolated ACTH deficiency with secondary adrenal insufficiency.
  molecular_function:
    id: GO:0031780
    label: corticotropin hormone receptor binding
  directly_involved_in:
  - id: GO:2000851
    label: positive regulation of glucocorticoid secretion
  - id: GO:0051464
    label: positive regulation of cortisol secretion
  - id: GO:0007267
    label: cell-cell signaling
  locations:
  - id: GO:0005615
    label: extracellular space
  anatomical_locations:
  - id: UBERON:0002196
    label: adenohypophysis
  - id: UBERON:0001235
    label: adrenal cortex
  supported_by:
  - reference_id: PMID:9620771
    supporting_text: "adrenal insufficiency... isolated ACTH deficiency"
  - reference_id: Reactome:R-HSA-388605
    supporting_text: "POMC(138-176) binds MC2R"

# ---------------------------------------------------------------------
# Core Function 3: Appetite Suppression via Alpha-MSH
# ---------------------------------------------------------------------
# Alpha-MSH (residues 138-150, contained within ACTH) is released by
# hypothalamic POMC neurons. It binds MC4R to suppress appetite and
# increase energy expenditure. This is the ANOREXIGENIC function.
- description: >
    Suppresses appetite and promotes negative energy balance via the cleavage
    product alpha-MSH (melanotropin alpha, residues 138-150). In hypothalamic
    arcuate nucleus POMC neurons, alpha-MSH is released and binds MC4R to
    reduce food intake and increase energy expenditure. Loss of POMC causes
    severe early-onset obesity due to absence of this anorexigenic signal.
    Note: This is ANTAGONISTIC to beta-endorphin's orexigenic function.
  molecular_function:
    id: GO:0031782
    label: type 4 melanocortin receptor binding
  directly_involved_in:
  - id: GO:0032099
    label: negative regulation of appetite
  - id: GO:0097009
    label: energy homeostasis
  locations:
  - id: GO:0005615
    label: extracellular space
  anatomical_locations:
  - id: UBERON:0001898
    label: hypothalamus
  supported_by:
  - reference_id: PMID:9620771
    supporting_text: "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)"
  - reference_id: PMID:19743876
    supporting_text: "Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R."

# ---------------------------------------------------------------------
# Core Function 4: Skin Pigmentation via MSH Peptides
# ---------------------------------------------------------------------
# Alpha-MSH and beta-MSH bind MC1R on melanocytes to stimulate melanin
# production. Loss of POMC results in fair skin and red hair due to
# absence of MC1R stimulation.
- description: >
    Stimulates melanin production and skin/hair pigmentation via the cleavage
    products alpha-MSH (138-150) and beta-MSH (217-234). These melanocortins
    bind MC1R on melanocytes to activate cAMP signaling and induce
    eumelanin synthesis. Loss of POMC causes red hair pigmentation and
    fair skin phenotype due to absence of MC1R agonism.
  molecular_function:
    id: GO:0070996
    label: type 1 melanocortin receptor binding
  directly_involved_in:
  - id: GO:0033059
    label: cellular pigmentation
  - id: GO:0042438
    label: melanin biosynthetic process
  locations:
  - id: GO:0005615
    label: extracellular space
  anatomical_locations:
  - id: UBERON:0001416
    label: skin of body
  supported_by:
  - reference_id: PMID:9620771
    supporting_text: "red hair pigmentation caused by POMC mutations"
  - reference_id: UniProtKB:P01189
    supporting_text: "[Melanocyte-stimulating hormone alpha]: Increases the pigmentation of skin by increasing melanin production in melanocytes."
  - reference_id: PMID:18292087
    supporting_text: "MC1R signaling in B16 mouse melanoma cells and primary human melanocytes"

# ---------------------------------------------------------------------
# Core Function 5: Opioid Signaling and Appetite Stimulation via Beta-Endorphin
# ---------------------------------------------------------------------
# Beta-endorphin (residues 237-267) is an endogenous opioid peptide that
# binds mu-opioid receptor. It is OREXIGENIC (stimulates appetite), which
# is ANTAGONISTIC to alpha-MSH's anorexigenic effect. Both are produced
# from the same precursor in hypothalamic neurons.
- description: >
    Functions as an endogenous opioid via the cleavage product beta-endorphin
    (residues 237-267). Beta-endorphin binds mu-opioid receptor (OPRM1) to
    modulate pain perception, stress response, and reward. Critically,
    beta-endorphin is OREXIGENIC (appetite-stimulating), which is
    ANTAGONISTIC to alpha-MSH's anorexigenic function. Both peptides are
    released from the same hypothalamic POMC neurons but stored in separate
    granules with distinct release mechanisms.
  molecular_function:
    id: GO:0001515
    label: opioid peptide activity
  directly_involved_in:
  - id: GO:0032100
    label: positive regulation of appetite
  - id: GO:0048265
    label: response to pain
  locations:
  - id: GO:0005615
    label: extracellular space
  anatomical_locations:
  - id: UBERON:0001898
    label: hypothalamus
  - id: UBERON:0002196
    label: adenohypophysis
  supported_by:
  - reference_id: UniProtKB:P01189
    supporting_text: "-!- FUNCTION: [Beta-endorphin]: Endogenous orexigenic opiate."
  - reference_id: Reactome:R-HSA-374298
    supporting_text: "Opioid receptors bind opioid peptides"

references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10233018
  title: alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages.
  findings: []
- id: PMID:18292087
  title: Melanocortin-1 receptor signaling markedly induces the expression of the NR4A nuclear receptor subgroup in melanocytic cells.
  findings: []
- id: PMID:19452503
  title: 'Aberrant trafficking of human melanocortin 1 receptor variants associated with red hair and skin cancer: Steady-state retention of mutant forms in the proximal golgi.'
  findings: []
- id: PMID:19743876
  title: Novel binding motif of ACTH analogues at the melanocortin receptors.
  findings: []
- id: PMID:20810565
  title: Peroxisomal localization of the proopiomelanocortin-derived peptides beta-lipotropin and beta-endorphin.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:9620771
  title: Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans.
  findings: []
- id: Reactome:R-HSA-112042
  title: Opioid binds MOR
  findings: []
- id: Reactome:R-HSA-112271
  title: The receptor:G-protein complex dissociates
  findings: []
- id: Reactome:R-HSA-167408
  title: The high affinity receptor complex binds to G-protein
  findings: []
- id: Reactome:R-HSA-167419
  title: The receptor:G-protein complex releases GDP
  findings: []
- id: Reactome:R-HSA-167427
  title: Opioid dissociates from MOR
  findings: []
- id: Reactome:R-HSA-167429
  title: The receptor:G-protein complex  binds GTP
  findings: []
- id: Reactome:R-HSA-265301
  title: Corticotropin cleavage from POMC
  findings: []
- id: Reactome:R-HSA-374298
  title: Opioid receptors bind opioid peptides
  findings: []
- id: Reactome:R-HSA-379044
  title: Liganded Gs-activating GPCR acts as a GEF for Gs
  findings: []
- id: Reactome:R-HSA-380073
  title: Liganded Gi-activating GPCR acts as a GEF for Gi
  findings: []
- id: Reactome:R-HSA-388596
  title: Melanocortin receptors bind melanocortins
  findings: []
- id: Reactome:R-HSA-388605
  title: POMC(138-176) binds MC2R
  findings: []
- id: Reactome:R-HSA-5603251
  title: Defective ACTH does not bind MCR2
  findings: []
- id: Reactome:R-HSA-6789615
  title: Expression of STAT3-upregulated extracellular proteins
  findings: []
- id: Reactome:R-HSA-744886
  title: The Ligand:GPCR:Gs complex dissociates
  findings: []
- id: Reactome:R-HSA-744887
  title: Liganded Gs-activating GPCRs bind inactive heterotrimeric Gs
  findings: []
- id: Reactome:R-HSA-749454
  title: The Ligand:GPCR:Gi complex dissociates
  findings: []
- id: Reactome:R-HSA-749456
  title: Liganded Gi-activating GPCRs bind inactive heterotrimeric G-protein Gi
  findings: []