GCG

UniProt ID: P01275
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

GCG encodes proglucagon, a 180-residue secreted polyprotein precursor that is proteolytically processed in a tissue-specific manner by prohormone convertases to yield several distinct bioactive peptide hormones, each acting through its own class B G protein-coupled receptor. In pancreatic islet alpha-cells, PCSK2/PC2 liberates glucagon, the principal counter-regulatory hormone of insulin, which binds the glucagon receptor (GCGR) on hepatocytes and raises blood glucose by stimulating gluconeogenesis and glycogenolysis while suppressing glycolysis. In intestinal enteroendocrine L-cells and selected brainstem and hypothalamic neurons, PCSK1/PC1 liberates glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, and glicentin. GLP-1 is an incretin that potentiates glucose-dependent insulin secretion, slows gastric emptying, and promotes satiety and beta-cell survival, acting via GLP1R. GLP-2 is intestinotrophic, stimulating crypt cell proliferation and villus growth via GLP2R. Oxyntomodulin reduces food intake and gastric emptying. All mature peptides are secreted hormones; the precursor itself has no intrinsic activity, and its biology is distributed across its cleavage products. The peptides signal predominantly through Gs to activate adenylyl cyclase and elevate intracellular cAMP in their respective target cells.

Functional Isoforms

Curated functional classes representing distinct biological activities. These may be splice variants, cleavage products, or other forms with different functions.

Glucagon CLEAVAGE PRODUCT
ID: GCG_GLUCAGON
UNIPROT CHAIN: PRO_0000011256 (residues 53-81)
29-residue peptide, the major bioactive product of proglucagon processing in pancreatic islet alpha-cells (PCSK2/PC2). Binds and activates the glucagon receptor GCGR on hepatocytes (Gs-coupled), elevating cAMP and raising blood glucose by increasing gluconeogenesis and glycogenolysis and decreasing glycolysis. The principal counter-regulatory hormone of insulin; secreted in response to hypoglycemia. Glucagon is a substrate of insulin-degrading enzyme (IDE) and can self-assemble into amyloid fibrils in vitro. Receptor-binding/glucose-mobilizing functions belong to THIS peptide, not to the GLP-1/GLP-2 products.
Isoform-specific terms: glucagon receptor binding positive regulation of gluconeogenesis
Glucagon-like peptide 1 (GLP-1) CLEAVAGE PRODUCT
ID: GCG_GLP1
UNIPROT CHAIN: PRO_0000011258, PRO_0000011259, PRO_0000011260 (residues 92-128 / 98-128 / 98-127)
Incretin hormone produced mainly in intestinal L-cells (and pancreatic alpha-cells and some neurons) by PCSK1/PC1, then N-terminally truncated to the active GLP-1(7-37) and GLP-1(7-36)amide forms. Acts through GLP1R (Gs) to potently stimulate glucose-dependent insulin secretion, slow gastric emptying, suppress glucagon, promote satiety, and enhance beta-cell mass/survival. Rapidly inactivated by DPP4 (and slowly by FAP). The insulin-secretion, incretin, satiety and anti-apoptotic functions belong to THIS peptide.
Isoform-specific terms: positive regulation of insulin secretion involved in cellular response to glucose stimulus feeding behavior negative regulation of apoptotic process
Glucagon-like peptide 2 (GLP-2) CLEAVAGE PRODUCT
ID: GCG_GLP2
UNIPROT CHAIN: PRO_0000011262 (residues 146-178)
33-residue intestinotrophic peptide produced in intestinal L-cells by PCSK1/PC1. Acts through its own receptor GLP2R (Gs), expressed in the gut, to stimulate intestinal growth, increase villus height and crypt cell proliferation, decrease enterocyte apoptosis, and enhance nutrient assimilation. The intestinal-growth functions belong to THIS peptide and signal through a distinct receptor from glucagon and GLP-1.
Isoform-specific terms: signaling receptor binding
Oxyntomodulin CLEAVAGE PRODUCT
ID: GCG_OXYNTOMODULIN
UNIPROT CHAIN: PRO_0000011255 (residues 53-89)
Intestinal L-cell peptide (glucagon plus C-terminal extension). Reduces food intake and inhibits gastric emptying; a dual weak agonist of GCGR and GLP1R. Anorectic effects are attributed to THIS peptide.
Glicentin CLEAVAGE PRODUCT
ID: GCG_GLICENTIN
UNIPROT CHAIN: PRO_0000011253 (residues 21-89)
N-terminal proglucagon product from intestinal L-cells. Proposed to modulate gastric acid secretion and gastro-pyloro-duodenal activity and to support intestinal mucosal growth early in life; functions are weakly supported (ECO:0000303).
Glicentin-related polypeptide (GRPP) CLEAVAGE PRODUCT
ID: GCG_GRPP
UNIPROT CHAIN: PRO_0000011254 (residues 21-50)
N-terminal fragment of glicentin released during processing; no well-defined function established.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005576 extracellular region
IBA
GO_REF:0000033 		ACCEPT
Summary: All mature proglucagon-derived peptides are secreted hormones that act in the extracellular space. Correct cellular location.
Supporting Evidence:
UniProtKB:P01275
Secreted in the A cells of the islets of Langerhans
GO:0001678 intracellular glucose homeostasis
IBA
GO_REF:0000033 		MODIFY
Summary: Glucagon regulates whole-organism/blood glucose, not cell-autonomous intracellular glucose homeostasis. The IBA propagated a too-specific sibling term; the systemic term glucose homeostasis is the correct fit.
Reason: "intracellular glucose homeostasis" denotes maintenance of glucose levels within a cell, whereas glucagon's role is in systemic blood-glucose homeostasis. Replace with the general glucose homeostasis term, which is also independently annotated to this gene.
Proposed replacements: glucose homeostasis
GO:0005179 hormone activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Core molecular function. The proglucagon-derived peptides are bona fide secreted peptide hormones acting on cognate receptors.
Supporting Evidence:
UniProtKB:P01275
the major bioactive hormone is glucagon cleaved by PCSK2/PC2
GO:0007188 adenylate cyclase-modulating G protein-coupled receptor signaling pathway
IBA
GO_REF:0000033 		ACCEPT
Summary: Glucagon, GLP-1 and GLP-2 all act through class B GPCRs (GCGR, GLP1R, GLP2R) coupled to Gs, elevating cAMP. Correct, though the activating child term GO:0007189 is more precise.
Supporting Evidence:
UniProtKB:P01275
couples to the G(s) G protein and elevates intracellular cAMP
GO:0031769 glucagon receptor binding
IBA
GO_REF:0000033 		ACCEPT
Summary: Specific, informative molecular function for the glucagon peptide chain (binds GCGR). Core function.
Supporting Evidence:
UniProtKB:P01275
Binds to and activates the glucagon receptor GCGR
GO:0035774 positive regulation of insulin secretion involved in cellular response to glucose stimulus
IBA
GO_REF:0000033 		ACCEPT
Summary: Captures the GLP-1 incretin effect, including its hallmark glucose-dependence. Best available term for this function. Core (GLP-1 chain).
Supporting Evidence:
UniProtKB:P01275
Potent stimulator of glucose-dependent insulin release
GO:0045722 positive regulation of gluconeogenesis
IBA
GO_REF:0000033 		ACCEPT
Summary: Glucagon raises blood glucose by stimulating hepatic gluconeogenesis. Core function (glucagon chain).
Supporting Evidence:
UniProtKB:P01275
Regulates blood glucose by increasing gluconeogenesis and decreasing glycolysis
GO:0005102 signaling receptor binding
IEA
GO_REF:0000117 		ACCEPT
Summary: Correct but general. The peptides bind their cognate signaling receptors; more specific descendants (glucagon receptor binding, receptor ligand activity) are also annotated and are preferable as the core MF.
GO:0005179 hormone activity
IEA
GO_REF:0000002 		ACCEPT
Summary: Redundant with the IBA hormone activity annotation; correct core molecular function.
GO:0005576 extracellular region
IEA
GO_REF:0000120 		ACCEPT
Summary: Secreted hormone; correct location. Redundant with other extracellular region annotations.
GO:0005515 protein binding
IPI
PMID:17051221
Structures of human insulin-degrading enzyme reveal a new su... 		KEEP AS NON CORE
Summary: Records glucagon as a substrate captured in the insulin-degrading enzyme (IDE) structure. A real binary interaction but uninformative as a molecular function and not a core activity (this is hormone clearance/degradation).
Reason: "protein binding" (GO:0005515) conveys no functional specificity; the interaction reflects glucagon being degraded by IDE rather than a function glucagon enables.
Supporting Evidence:
PMID:17051221
structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta peptide (1-40), amylin and glucagon)
GO:0005515 protein binding
IPI
PMID:17715056
Crystal structure of the incretin-bound extracellular domain... 		KEEP AS NON CORE
Summary: Derives from a structural study of the GIP receptor extracellular domain bound to the incretin GIP; supports a peptide:receptor-ECD binary interaction logged for this entry. Uninformative generic MF; not a core function.
Reason: "protein binding" is non-specific. The paper structurally characterizes GIP (a paralogous incretin), and the interaction is recorded as a generic binary binding for the proglucagon entry rather than a distinct molecular activity.
Supporting Evidence:
PMID:17715056
the crystal structure of the complex of human GIP receptor extracellular domain (ECD) with its agonist, the incretin GIP(1-42)
GO:0005515 protein binding
IPI
PMID:21314817
Neuropeptide Y, B-type natriuretic peptide, substance P and ... 		KEEP AS NON CORE
Summary: Records GLP-1 as a (slow) substrate of fibroblast activation protein (FAP). Real protease:substrate interaction relevant to incretin clearance, but a generic and non-core molecular function.
Reason: Reflects degradation of GLP-1 by FAP, not an activity GLP-1 enables; "protein binding" is uninformative.
Supporting Evidence:
PMID:21314817
FAP slowly hydrolysed other hormone peptides, such as the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic peptide
GO:0005515 protein binding
IPI
PMID:21314817
Neuropeptide Y, B-type natriuretic peptide, substance P and ... 		KEEP AS NON CORE
Summary: Records GLP-1 as an efficient substrate of dipeptidyl peptidase 4 (DPP4, UniProt P27487). DPP4 is the primary enzyme responsible for GLP-1 inactivation in vivo (the pharmacological basis of gliptin-class antidiabetics). Real binary interaction but a generic, non-core molecular function.
Reason: Reflects degradation of GLP-1 by DPP4, not an activity GLP-1 enables; "protein binding" is uninformative.
Supporting Evidence:
PMID:21314817
the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are efficient DPP4 substrates
GO:0042802 identical protein binding
IPI
PMID:22212535
Mapping out the multistage fibrillation of glucagon. 		KEEP AS NON CORE
Summary: Reflects glucagon self-association into amyloid-like fibrils observed in vitro under acidic, concentrated conditions (relevant to pharmaceutical formulation). Not a physiological function of the secreted hormone.
Reason: Self-assembly into fibrils is an in-vitro biophysical property, not the in-vivo molecular function of glucagon; should not be treated as a core activity.
Supporting Evidence:
PMID:22212535
The 29-residue peptide hormone glucagon forms many different morphological types of amyloid-like fibrils
GO:0005737 cytoplasm
IEA
GO_REF:0000107 		REMOVE
Summary: Incorrect functional location for a secreted peptide hormone. Proglucagon transits the ER and secretory granules and is exported; it does not function in the cytoplasm. This is an over-broad electronic ortholog transfer.
Reason: Glucagon and the other products are secreted; "cytoplasm" (located_in) misrepresents their site of action and is not supported. The correct locations (extracellular region, ER lumen, secretory granule lumen) are separately annotated.
GO:0005886 plasma membrane
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: The secreted peptides engage receptors located in the target-cell plasma membrane from the extracellular side; the ligand itself is not "active in" the plasma membrane. Likely an Ensembl ortholog-transfer artifact.
Reason: "is_active_in plasma membrane" conflates the receptor's location with the ligand's; the hormone acts as an extracellular ligand, not as a plasma-membrane component.
GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway
IEA
GO_REF:0000107 		ACCEPT
Summary: Glucagon/GLP-1/GLP-2 all activate Gs-coupled receptors that stimulate adenylyl cyclase and raise cAMP. Correct and appropriately specific.
Supporting Evidence:
UniProtKB:P01275
couples to the G(s) G protein and elevates intracellular cAMP
GO:0014823 response to activity
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Weak, context-dependent term propagated by ortholog transfer. Glucagon participates in glucose mobilization during physical activity, but this is peripheral and not a core function.
GO:0035774 positive regulation of insulin secretion involved in cellular response to glucose stimulus
IEA
GO_REF:0000107 		ACCEPT
Summary: GLP-1 incretin effect; redundant with the IBA annotation of the same term. Core (GLP-1).
GO:0042593 glucose homeostasis
IEA
GO_REF:0000107 		ACCEPT
Summary: Central biological role: glucagon (and the incretins) regulate systemic glucose homeostasis. Correct, core.
Supporting Evidence:
UniProtKB:P01275
Plays a key role in glucose metabolism and homeostasis
GO:0043066 negative regulation of apoptotic process
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Reflects GLP-1's inhibition of pancreatic beta-cell apoptosis. Real but a general term and an indirect, downstream effect of GLP-1 receptor signaling; keep as non-core.
Supporting Evidence:
UniProtKB:P01275
Inhibits beta cell apoptosis
GO:0048018 receptor ligand activity
IEA
GO_REF:0000107 		ACCEPT
Summary: Accurate core molecular function: the proglucagon peptides are agonist ligands for their cognate GPCRs.
GO:0070374 positive regulation of ERK1 and ERK2 cascade
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Downstream intracellular consequence of GLP-1/glucagon receptor signaling in target cells (e.g., beta-cell proliferation). Indirect and several steps removed from the hormone's molecular function; non-core.
GO:0071377 cellular response to glucagon stimulus
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Semantically inverted for this gene. GCG is the SOURCE of the glucagon stimulus; this term describes the response program of glucagon-target cells, not a process the hormone is involved_in. Over-propagated electronic annotation.
Reason: "cellular response to glucagon stimulus" belongs to cells receiving glucagon, not to the glucagon-producing gene; annotating GCG as involved_in its own stimulus-response is not meaningful.
GO:0090280 positive regulation of calcium ion import
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: A downstream second-messenger effect of incretin/glucagon receptor signaling in target cells. Indirect; non-core.
GO:0032024 positive regulation of insulin secretion
TAS
Reactome:R-HSA-381676 		ACCEPT
Summary: GLP-1 stimulates insulin secretion (incretin effect). Correct; a more general parent of the glucose-dependent term GO:0035774 also annotated here. Core (GLP-1).
GO:0005576 extracellular region
EXP
PMID:22037645
Interleukin-6 enhances insulin secretion by increasing gluca... 		ACCEPT
Summary: Experimental support for secretion of GLP-1 (measured as a secreted/circulating hormone from L-cells and alpha-cells). Correct location.
Supporting Evidence:
PMID:22037645
increasing glucagon-like peptide-1
GO:0005576 extracellular region
EXP
PMID:40446798
A microbial amino-acid-conjugated bile acid, tryptophan-chol... 		ACCEPT
Summary: Secreted GLP-1 measured in a study of glucose homeostasis. Correct extracellular location for the secreted peptide.
GO:0048018 receptor ligand activity
TAS
Reactome:R-HSA-381612 		ACCEPT
Summary: GLP-1 acts as the agonist ligand of GLP1R (Reactome reaction "GLP1R binds GLP1"). Correct core molecular function.
GO:0005788 endoplasmic reticulum lumen
TAS
Reactome:R-HSA-381799 		ACCEPT
Summary: Correct biosynthetic transit location: preproglucagon is synthesized and folded in the ER lumen of L-cells. Appropriate as a pathway/location annotation.
GO:0005788 endoplasmic reticulum lumen
TAS
Reactome:R-HSA-421416 		ACCEPT
Summary: ER lumen transit during biosynthesis/trafficking. Redundant with the other ER-lumen annotation; correct.
GO:0034774 secretory granule lumen
TAS
Reactome:R-HSA-421416 		ACCEPT
Summary: Proglucagon and its products are stored in regulated secretory granules prior to exocytosis. Correct location.
GO:0005576 extracellular region
ISS
GO_REF:0000024 		ACCEPT
Summary: Secreted hormone; correct location. Redundant with other extracellular region annotations.
GO:0014823 response to activity
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Weak, context-dependent ortholog-transferred term; redundant with the IEA copy. Non-core.
GO:0042593 glucose homeostasis
ISS
GO_REF:0000024 		ACCEPT
Summary: Systemic glucose homeostasis; correct and central. Redundant with the IEA copy.
GO:0050796 regulation of insulin secretion
ISS
GO_REF:0000024 		ACCEPT
Summary: GLP-1 regulates insulin secretion (incretin). Correct; a general parent of the more specific positive-regulation terms also annotated. Core (GLP-1).
GO:0007186 G protein-coupled receptor signaling pathway
TAS
PMID:7929237
Synergistic activation of the type I adenylyl cyclase by Ca2... 		ACCEPT
Summary: Glucagon acts via a Gs-coupled GPCR; in this study glucagon was used as a Gs-coupled receptor agonist driving adenylyl cyclase. The GPCR-signaling annotation is correct, though general. The paper's focus is adenylyl cyclase regulation, with glucagon as a tool.
Supporting Evidence:
PMID:7929237
500 nM glucagon alone did not stimulate the enzyme but the combination of A23187 and glucagon activated the enzyme
GO:0005576 extracellular region
TAS
Reactome:R-HSA-163625 		ACCEPT
Summary: Correct location (glucagon binding GCGR occurs in the extracellular space). One of many redundant Reactome reaction-level extracellular-region annotations.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-379044 		ACCEPT
Summary: Correct but redundant Reactome extracellular-region annotation (Gs activation reaction).
GO:0005576 extracellular region
TAS
Reactome:R-HSA-379048 		ACCEPT
Summary: Correct but redundant Reactome extracellular-region annotation (Gq/11 activation reaction).
GO:0005576 extracellular region
TAS
Reactome:R-HSA-744886 		ACCEPT
Summary: Correct but redundant Reactome extracellular-region annotation (Ligand:GPCR:Gs dissociation).
GO:0005576 extracellular region
TAS
Reactome:R-HSA-744887 		ACCEPT
Summary: Correct but redundant Reactome extracellular-region annotation (Gs binding reaction).
GO:0005576 extracellular region
TAS
Reactome:R-HSA-749448 		ACCEPT
Summary: Correct but redundant Reactome extracellular-region annotation (Gq binding reaction).
GO:0005576 extracellular region
TAS
Reactome:R-HSA-749452 		ACCEPT
Summary: Correct but redundant Reactome extracellular-region annotation (Ligand:GPCR:Gq dissociation).
GO:0005576 extracellular region
TAS
Reactome:R-HSA-825631 		ACCEPT
Summary: Correct but redundant Reactome extracellular-region annotation (Glucagon:GCGR GTP-GDP exchange).
GO:0005576 extracellular region
TAS
Reactome:R-HSA-381612 		ACCEPT
Summary: Correct but redundant Reactome extracellular-region annotation (GLP1R binds GLP1).
GO:0005576 extracellular region
TAS
Reactome:R-HSA-383313 		ACCEPT
Summary: Correct location: GLP-1 is secreted from intestinal L-cells into the extracellular space. Redundant with other extracellular-region annotations.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-9023632 		ACCEPT
Summary: Correct but redundant Reactome extracellular-region annotation (DPP4 hydrolysis of GLP-1).
GO:0005576 extracellular region
TAS
Reactome:R-HSA-9023633 		ACCEPT
Summary: Correct but redundant Reactome extracellular-region annotation (DPP4 hydrolysis of GLP-1).
GO:0034774 secretory granule lumen
TAS
Reactome:R-HSA-383313 		ACCEPT
Summary: GLP-1 is packaged in secretory granules prior to release. Correct location; redundant with the other secretory-granule-lumen annotation.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-420123 		ACCEPT
Summary: Correct but redundant Reactome extracellular-region annotation (GLP2R binds GLP2).
GO:0005102 signaling receptor binding
TAS
PMID:9990065
Prototypic G protein-coupled receptor for the intestinotroph... 		ACCEPT
Summary: GLP-2 binds and activates its specific receptor GLP2R. Correct, informative molecular function for the GLP-2 chain.
Supporting Evidence:
PMID:9990065
GLP-2, like glucagon and GLP-1, exerts its actions through a distinct and specific novel receptor expressed in its principal target tissue
GO:0007186 G protein-coupled receptor signaling pathway
TAS
PMID:9990065
Prototypic G protein-coupled receptor for the intestinotroph... 		ACCEPT
Summary: GLP-2 signals through the Gs-coupled GLP2R (increased cAMP). Correct GPCR-signaling annotation for the GLP-2 chain.
Supporting Evidence:
PMID:9990065
Cells expressing the GLP-2R responded to GLP-2
GO:0007631 feeding behavior
TAS
PMID:8538742
A role for glucagon-like peptide-1 in the central regulation... 		ACCEPT
Summary: Central GLP-1 inhibits feeding and is a physiological mediator of satiety. Correct process annotation for the GLP-1 chain.
Supporting Evidence:
PMID:8538742
central GLP-1 is a new physiological mediator of satiety

Core Functions

Serves as a secreted polyprotein hormone precursor that is proteolytically processed in a tissue-specific manner (PCSK2/PC2 in pancreatic alpha-cells; PCSK1/PC1 in intestinal L-cells and neurons) to yield multiple distinct peptide hormones. The precursor is synthesized in the ER, stored in secretory granules, and secreted; its biology is realized through its cleavage products.

Molecular Function:
hormone activity
Cellular Locations:
endoplasmic reticulum lumen secretory granule lumen extracellular region
Supporting Evidence:
  • UniProtKB:P01275
    Proglucagon is post-translationally processed in a tissue-specific manner in pancreatic A cells and intestinal L cells

Via the glucagon peptide (residues 53-81, PRO_0000011256), binds and activates the glucagon receptor GCGR on hepatocytes, the principal counter-regulatory action to insulin: raises blood glucose by stimulating gluconeogenesis and glycogenolysis and decreasing glycolysis, signaling through Gs and elevating cAMP.

Molecular Function:
glucagon receptor binding
Directly Involved In:
positive regulation of gluconeogenesis glucose homeostasis adenylate cyclase-activating G protein-coupled receptor signaling pathway
Cellular Locations:
extracellular region
Supporting Evidence:
  • UniProtKB:P01275
    Regulates blood glucose by increasing gluconeogenesis and decreasing glycolysis
  • UniProtKB:P01275
    Binds to and activates the glucagon receptor GCGR

Via glucagon-like peptide 1 (GLP-1; residues 92-128 and the active 7-37/7-36amide forms), acts as an incretin agonist of GLP1R to potentiate glucose-dependent insulin secretion, promote satiety, and support beta-cell survival. Produced chiefly by intestinal L-cells and also pancreatic alpha-cells and neurons.

Molecular Function:
receptor ligand activity
Directly Involved In:
positive regulation of insulin secretion involved in cellular response to glucose stimulus feeding behavior
Cellular Locations:
extracellular region
Supporting Evidence:
  • UniProtKB:P01275
    Potent stimulator of glucose-dependent insulin release
  • PMID:8538742
    central GLP-1 is a new physiological mediator of satiety

Via glucagon-like peptide 2 (GLP-2; residues 146-178, PRO_0000011262), binds and activates the intestine-specific receptor GLP2R to stimulate intestinal growth: increased villus height and crypt cell proliferation with decreased enterocyte apoptosis, enhancing nutrient assimilation. A distinct receptor and function from glucagon and GLP-1.

Molecular Function:
signaling receptor binding
Directly Involved In:
G protein-coupled receptor signaling pathway
Cellular Locations:
extracellular region
Supporting Evidence:
  • PMID:9990065
    GLP-2 stimulates intestinal growth and up-regulates villus height in the small intestine, concomitant with increased crypt cell proliferation and decreased enterocyte apoptosis
  • PMID:9990065
    GLP-2, like glucagon and GLP-1, exerts its actions through a distinct and specific novel receptor expressed in its principal target tissue

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
UniProtKB:P01275
UniProtKB entry P01275 (GLUC_HUMAN), Pro-glucagon
  • Proglucagon is processed tissue-specifically; glucagon predominates in pancreatic A cells (PCSK2/PC2), while GLP-1, GLP-2, glicentin and oxyntomodulin are liberated in intestinal L cells (PCSK1/PC1).
    "Proglucagon is post-translationally processed in a tissue-specific manner in pancreatic A cells and intestinal L cells"
PMID:17051221
Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism.
  • Glucagon is one of four substrates co-crystallized with insulin-degrading enzyme (IDE), supporting glucagon as an IDE degradation substrate.
    "structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta peptide (1-40), amylin and glucagon)"
PMID:17715056
Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor.
  • Structural study of the GIP receptor extracellular domain bound to the incretin GIP; the structural principles are stated to be conserved among related class B hormone receptors such as GLP1R.
    "the crystal structure of the complex of human GIP receptor extracellular domain (ECD) with its agonist, the incretin GIP(1-42)"
PMID:21314817
Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-Ξ±.
  • GLP-1 is a (slow) substrate of fibroblast activation protein (FAP), in addition to being an efficient DPP4 substrate.
    "FAP slowly hydrolysed other hormone peptides, such as the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic peptide"
PMID:22037645
Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells.
  • IL-6 increases GLP-1 production from alpha cells by upregulating proglucagon (GCG) and prohormone convertase 1/3, enhancing insulin secretion.
    "IL-6 increased GLP-1 production from alpha cells through increased proglucagon (which is encoded by GCG) and prohormone convertase 1/3 expression"
  • GLP-1 is a hormone that induces insulin secretion (incretin).
    "Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin secretion"
PMID:22212535
Mapping out the multistage fibrillation of glucagon.
  • Glucagon self-assembles into multiple morphological types of amyloid-like fibrils in vitro, the basis of the identical protein binding annotation.
    "The 29-residue peptide hormone glucagon forms many different morphological types of amyloid-like fibrils"
PMID:40446798
A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves glucose homeostasis via the orphan receptor MRGPRE.
PMID:7929237
Synergistic activation of the type I adenylyl cyclase by Ca2+ and Gs-coupled receptors in vivo.
  • Glucagon, acting through its Gs-coupled receptor, synergizes with Ca2+ to activate type I adenylyl cyclase; used here as a Gs-coupled receptor agonist.
    "500 nM glucagon alone did not stimulate the enzyme but the combination of A23187 and glucagon activated the enzyme"
PMID:8538742
A role for glucagon-like peptide-1 in the central regulation of feeding.
  • Central (ICV) GLP-1 inhibits feeding and is a physiological mediator of satiety, establishing GLP-1's role in feeding behavior.
    "central GLP-1 is a new physiological mediator of satiety"
PMID:9990065
Prototypic G protein-coupled receptor for the intestinotrophic factor glucagon-like peptide 2.
  • GLP-2 is intestinotrophic and acts through its own distinct receptor (GLP2R), stimulating villus growth, crypt proliferation, and reduced enterocyte apoptosis.
    "GLP-2 stimulates intestinal growth and up-regulates villus height in the small intestine, concomitant with increased crypt cell proliferation and decreased enterocyte apoptosis"
  • GLP-2 exerts its actions through a distinct, specific receptor expressed in the gut, like glucagon and GLP-1 acting through their own receptors.
    "GLP-2, like glucagon and GLP-1, exerts its actions through a distinct and specific novel receptor expressed in its principal target tissue"
Reactome:R-HSA-163625
Glucagon binds to Glucagon receptor
Reactome:R-HSA-379044
Liganded Gs-activating GPCR acts as a GEF for Gs
Reactome:R-HSA-379048
Liganded Gq/11-activating GPCRs act as GEFs for Gq/11
Reactome:R-HSA-381612
GLP1R binds GLP1
Reactome:R-HSA-381676
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
Reactome:R-HSA-381799
Synthesis of Preproglucagon in intestinal L cells
Reactome:R-HSA-383313
Glucagon-like Peptide 1 is secreted from intestinal L cells
Reactome:R-HSA-420123
Glucagon-like receptor 2 binds GLP2
Reactome:R-HSA-421416
Proglucagon translocates from the ER Lumen to secretory granules
Reactome:R-HSA-744886
The Ligand:GPCR:Gs complex dissociates
Reactome:R-HSA-744887
Liganded Gs-activating GPCRs bind inactive heterotrimeric Gs
Reactome:R-HSA-749448
Liganded Gq-activating GPCRs bind inactive heterotrimeric Gq
Reactome:R-HSA-749452
The Ligand:GPCR:Gq complex dissociates
Reactome:R-HSA-825631
Glucagon:GCGR mediates GTP-GDP exchange
Reactome:R-HSA-9023632
DPP4(39-766) hydrolyzes Glucagon-like Peptide-1 (GLP-1)
Reactome:R-HSA-9023633
DPP4(1-766) hydrolyzes Glucagon-like Peptide-1 (GLP-1)

Suggested Questions for Experts

Q: Should GO annotations for proglucagon-derived functions be made at the level of the individual peptide chains (PRO ids) rather than the gene/precursor, to avoid conflating glucagon (GCGR), GLP-1 (GLP1R), and GLP-2 (GLP2R) functions that act through different receptors and in different tissues?

Q: For oxyntomodulin and glicentin, which functions are sufficiently well-supported to warrant dedicated GO annotations versus remaining as UniProt FUNCTION statements (currently ECO:0000303)?

Suggested Experiments

Experiment: Chain-resolved functional annotation: use tissue-specific (alpha-cell vs L-cell) secretomics/peptidomics to confirm which mature peptides are produced where, and pair with receptor-specific (GCGR/GLP1R/GLP2R) reporter assays to assign each downstream process (insulin secretion, gluconeogenesis, intestinal growth) to the correct peptide.

Experiment: Knock-in mouse models that selectively ablate processing to individual products (e.g., PC2-null pancreatic glucagon vs PC1/3-null intestinal GLP-1/GLP-2) to dissect which phenotypes (glucose mobilization, incretin/insulin secretion, intestinal trophic effects) depend on which proglucagon-derived peptide in vivo.

πŸ“š Additional Documentation

Notes

(GCG-notes.md)

GCG (Proglucagon) β€” review notes

UniProt: P01275 (GLUC_HUMAN), 180 aa precursor. HGNC:4191. Taxon 9606.

Core framing: one gene, many chains

GCG is the textbook example (alongside POMC) of a polyprotein precursor whose
biology lives in its cleavage products, not the precursor. Proglucagon is
processed tissue-specifically by prohormone convertases:

  • Pancreatic Ξ±-cells (islets of Langerhans): PCSK2/PC2 liberates glucagon
    as the major bioactive hormone.
  • Intestinal L-cells and selected brain neurons: PCSK1/PC1 liberates
    GLP-1, GLP-2, glicentin and oxyntomodulin.

[UniProt:P01275 PTM, "Proglucagon is post-translationally processed in a tissue-specific manner in pancreatic A cells and intestinal L cells. In pancreatic A cells, the major bioactive hormone is glucagon cleaved by PCSK2/PC2. In the intestinal L cells PCSK1/PC1 liberates GLP-1, GLP-2, glicentin and oxyntomodulin."]

The chains (UniProt feature table, PRO IDs)

Chain Residues PRO id Receptor Core role
Glicentin 21-89 PRO_0000011253 (unclear) gastric acid / mucosal growth (weak)
GRPP (glicentin-related polypeptide) 21-50 PRO_0000011254 β€” unknown
Oxyntomodulin 53-89 PRO_0000011255 GCGR/GLP1R (dual, weak) reduces food intake, inhibits gastric emptying
Glucagon 53-81 PRO_0000011256 GCGR raises blood glucose (gluconeogenesis↑, glycolysis↓); counter-regulatory to insulin
GLP-1 (and 7-37 / 7-36) 92-128 / 98-128 / 98-127 PRO_0000011258/9/60 GLP1R incretin: glucose-dependent insulin secretion; satiety; Ξ²-cell survival
GLP-2 146-178 PRO_0000011262 GLP2R intestinotrophic: villus growth, crypt proliferation, ↓enterocyte apoptosis

Critical consequence for GO curation: GO annotations are attached to the precursor
P01275 with no chain/PRO qualifier, so functions belonging to different
peptides with different receptors are conflated at the gene level. Ideally each
function would carry the PRO id of the responsible peptide. I capture this with the
functional_isoforms block (CLEAVAGE_PRODUCT, mapped to PRO ids) and attribute each
function in core_functions.

Per-chain function evidence (from UniProt FUNCTION blocks + literature)

Glucagon

  • "Plays a key role in glucose metabolism and homeostasis. Regulates blood glucose
    by increasing gluconeogenesis and decreasing glycolysis. A counterregulatory hormone
    of insulin... Binds to and activates the glucagon receptor GCGR, which couples to
    the G(s) G protein and elevates intracellular cAMP" [UniProt:P01275 FUNCTION Glucagon; ECO:0000269|PubMed:32193322].
  • Receptor binding: GO:0031769 glucagon receptor binding (IBA) is the specific MF.
  • Glucagon is an IDE substrate [PMID:17051221, structure of IDE with glucagon as one of four substrates: "structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta peptide (1-40), amylin and glucagon)"] β€” clearance, not a core function.
  • Glucagon self-assembles into amyloid fibrils in vitro PMID:22212535 β€” basis of GO:0042802 identical protein binding (IPI). In vitro / pharmaceutical-formulation behavior, not a physiological function.

GLP-1 (incretin)

  • "Potent stimulator of glucose-dependent insulin release" [UniProt:P01275 FUNCTION GLP-1; ECO:0000269|PubMed:22037645, PubMed:40446798]. Also gastric motility, suppression of glucagon, satiety, islet mass / Ξ²-cell proliferation, inhibits beta cell apoptosis.
  • IL-6 increases GLP-1 production from Ξ±-cells via ↑proglucagon + PC1/3 PMID:22037645.
  • Central satiety: ICV GLP-1 inhibits feeding; "central GLP-1 is a new physiological mediator of satiety" PMID:8538742. Basis of GO:0007631 feeding behavior (TAS).
  • GLP-1 is a DPP4 substrate (Reactome R-HSA-9023632/3) and a slow FAP substrate PMID:21314817 β€” degradation/clearance, not core.

GLP-2 (intestinotrophic)

  • "GLP-2 stimulates intestinal growth and up-regulates villus height in the small
    intestine, concomitant with increased crypt cell proliferation and decreased
    enterocyte apoptosis" PMID:9990065. Acts through its own receptor GLP-2R:
    "GLP-2, like glucagon and GLP-1, exerts its actions through a distinct and specific
    novel receptor" PMID:9990065. Basis of GO:0005102 signaling receptor binding (TAS) and GO:0007186 GPCR signaling (TAS) from this paper.

Oxyntomodulin / Glicentin

  • Oxyntomodulin: "Significantly reduces food intake. Inhibits gastric emptying"
    [UniProt:P01275 FUNCTION Oxyntomodulin]. Glicentin: gastric acid / mucosal growth (weak, ECO:0000303).

Annotation-by-annotation reasoning highlights

  • Hormone activity GO:0005179 (IBA/IEA), receptor ligand activity GO:0048018, glucagon
    receptor binding GO:0031769, signaling receptor binding GO:0005102    : all correct, core
    MF. These are the right way to describe the peptides' molecular function (agonist/ligand).
  • GPCR / adenylate cyclase-activating signaling (GO:0007188, GO:0007189, GO:0007186):
    all chains act through class B GPCRs (GCGR, GLP1R, GLP2R) β†’ Gs β†’ adenylyl cyclase β†’ cAMP.
    Correct.
  • Insulin secretion terms (GO:0035774, GO:0032024, GO:0050796): GLP-1 incretin effect.
    Correct, specific GO:0035774 (positive regulation of insulin secretion involved in
    cellular response to glucose stimulus) is the best term and captures glucose-dependence.
  • Gluconeogenesis GO:0045722, glucose homeostasis GO:0042593: glucagon. Correct, core.
  • GO:0001678 intracellular glucose homeostasis (IBA): questionable term choice β€”
    glucagon regulates systemic/blood glucose, not intracellular glucose homeostasis
    (cell-autonomous). The PANTHER family IBA propagated a sibling term; GO:0042593
    glucose homeostasis is the better fit. MODIFY.
  • GO:0005737 cytoplasm located_in (IEA, Ensembl): wrong for a secreted peptide hormone;
    proglucagon only transits cytoplasm-bounded compartments (ER β†’ granule). Misleading.
    REMOVE.
  • GO:0005886 plasma membrane is_active_in (IEA, Ensembl): the secreted ligand engages a
    PM receptor from the extracellular side; the peptide is not active in the PM. Over-annotation.
  • GO:0071377 cellular response to glucagon stimulus involved_in (IEA): semantically
    backwards β€” GCG is the source of the glucagon stimulus, not a cell responding to it.
    This is the response program of glucagon TARGET cells. Over-propagated IEA. MARK_AS_OVER_ANNOTATED.
  • GO:0070374 positive regulation of ERK1/2 cascade, GO:0090280 positive regulation of
    calcium ion import, GO:0043066 negative regulation of apoptotic process (all IEA Ensembl)    :
    real downstream effects of GLP-1/glucagon signaling in target cells but indirect, several
    steps removed from the hormone's molecular function; keep as non-core at most.
  • GO:0014823 response to activity (IEA/ISS): ortholog-transferred, weak/contextual; keep non-core.
  • GO:0005515 protein binding (IPI Γ—3) + GO:0042802 identical protein binding (IPI):
    real binary interactions (IDE substrate, FAP substrate, GIPR co-structure, self-fibrillation)
    but uninformative / non-physiological; KEEP_AS_NON_CORE (per guidance avoid "protein binding"
    as a core MF).
  • Locations: extracellular region GO:0005576 (secreted) = core; ER lumen GO:0005788 and
    secretory granule lumen GO:0034774 = correct biosynthetic/storage transit locations (ACCEPT).

References checked

All 9 PMIDs read at abstract level (only PMID:22037645 has full text in cache). Reference
correctness judgments recorded in reference_review. PMID:7929237 (type I adenylyl cyclase)
and PMID:17715056 (GIP receptor ECD) are tool/structure papers that use a GCG product or a
paralogous incretin peripherally β€” flagged LOW relevance.

πŸ“„ View Raw YAML

 
id: P01275
gene_symbol: GCG
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >
  GCG encodes proglucagon, a 180-residue secreted polyprotein precursor that is
  proteolytically processed in a tissue-specific manner by prohormone convertases to
  yield several distinct bioactive peptide hormones, each acting through its own class B
  G protein-coupled receptor. In pancreatic islet alpha-cells, PCSK2/PC2 liberates
  glucagon, the principal counter-regulatory hormone of insulin, which binds the glucagon
  receptor (GCGR) on hepatocytes and raises blood glucose by stimulating gluconeogenesis
  and glycogenolysis while suppressing glycolysis. In intestinal enteroendocrine L-cells
  and selected brainstem and hypothalamic neurons, PCSK1/PC1 liberates glucagon-like
  peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, and glicentin. GLP-1
  is an incretin that potentiates glucose-dependent insulin secretion, slows gastric
  emptying, and promotes satiety and beta-cell survival, acting via GLP1R. GLP-2 is
  intestinotrophic, stimulating crypt cell proliferation and villus growth via GLP2R.
  Oxyntomodulin reduces food intake and gastric emptying. All mature peptides are secreted
  hormones; the precursor itself has no intrinsic activity, and its biology is distributed
  across its cleavage products. The peptides signal predominantly through Gs to activate
  adenylyl cyclase and elevate intracellular cAMP in their respective target cells.

functional_isoforms:
- id: GCG_GLUCAGON
  name: Glucagon
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids: [PRO_0000011256]
    residues: "53-81"
  description: >
    29-residue peptide, the major bioactive product of proglucagon processing in pancreatic
    islet alpha-cells (PCSK2/PC2). Binds and activates the glucagon receptor GCGR on
    hepatocytes (Gs-coupled), elevating cAMP and raising blood glucose by increasing
    gluconeogenesis and glycogenolysis and decreasing glycolysis. The principal
    counter-regulatory hormone of insulin; secreted in response to hypoglycemia. Glucagon
    is a substrate of insulin-degrading enzyme (IDE) and can self-assemble into amyloid
    fibrils in vitro. Receptor-binding/glucose-mobilizing functions belong to THIS peptide,
    not to the GLP-1/GLP-2 products.
  isoform_specific_terms:
  - id: GO:0031769
    label: glucagon receptor binding
  - id: GO:0045722
    label: positive regulation of gluconeogenesis

- id: GCG_GLP1
  name: Glucagon-like peptide 1 (GLP-1)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids: [PRO_0000011258, PRO_0000011259, PRO_0000011260]
    residues: "92-128 / 98-128 / 98-127"
  description: >
    Incretin hormone produced mainly in intestinal L-cells (and pancreatic alpha-cells and
    some neurons) by PCSK1/PC1, then N-terminally truncated to the active GLP-1(7-37) and
    GLP-1(7-36)amide forms. Acts through GLP1R (Gs) to potently stimulate glucose-dependent
    insulin secretion, slow gastric emptying, suppress glucagon, promote satiety, and
    enhance beta-cell mass/survival. Rapidly inactivated by DPP4 (and slowly by FAP). The
    insulin-secretion, incretin, satiety and anti-apoptotic functions belong to THIS peptide.
  isoform_specific_terms:
  - id: GO:0035774
    label: positive regulation of insulin secretion involved in cellular response to glucose
      stimulus
  - id: GO:0007631
    label: feeding behavior
  - id: GO:0043066
    label: negative regulation of apoptotic process

- id: GCG_GLP2
  name: Glucagon-like peptide 2 (GLP-2)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids: [PRO_0000011262]
    residues: "146-178"
  description: >
    33-residue intestinotrophic peptide produced in intestinal L-cells by PCSK1/PC1. Acts
    through its own receptor GLP2R (Gs), expressed in the gut, to stimulate intestinal
    growth, increase villus height and crypt cell proliferation, decrease enterocyte
    apoptosis, and enhance nutrient assimilation. The intestinal-growth functions belong to
    THIS peptide and signal through a distinct receptor from glucagon and GLP-1.
  isoform_specific_terms:
  - id: GO:0005102
    label: signaling receptor binding

- id: GCG_OXYNTOMODULIN
  name: Oxyntomodulin
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids: [PRO_0000011255]
    residues: "53-89"
  description: >
    Intestinal L-cell peptide (glucagon plus C-terminal extension). Reduces food intake and
    inhibits gastric emptying; a dual weak agonist of GCGR and GLP1R. Anorectic effects are
    attributed to THIS peptide.

- id: GCG_GLICENTIN
  name: Glicentin
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids: [PRO_0000011253]
    residues: "21-89"
  description: >
    N-terminal proglucagon product from intestinal L-cells. Proposed to modulate gastric
    acid secretion and gastro-pyloro-duodenal activity and to support intestinal mucosal
    growth early in life; functions are weakly supported (ECO:0000303).

- id: GCG_GRPP
  name: Glicentin-related polypeptide (GRPP)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids: [PRO_0000011254]
    residues: "21-50"
  description: >
    N-terminal fragment of glicentin released during processing; no well-defined function
    established.

existing_annotations:
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      All mature proglucagon-derived peptides are secreted hormones that act in the
      extracellular space. Correct cellular location.
    action: ACCEPT
    supported_by:
    - reference_id: UniProtKB:P01275
      supporting_text: "Secreted in the A cells of the islets of Langerhans"
- term:
    id: GO:0001678
    label: intracellular glucose homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Glucagon regulates whole-organism/blood glucose, not cell-autonomous intracellular
      glucose homeostasis. The IBA propagated a too-specific sibling term; the systemic
      term glucose homeostasis is the correct fit.
    action: MODIFY
    reason: >-
      "intracellular glucose homeostasis" denotes maintenance of glucose levels within a
      cell, whereas glucagon's role is in systemic blood-glucose homeostasis. Replace with
      the general glucose homeostasis term, which is also independently annotated to this gene.
    proposed_replacement_terms:
    - id: GO:0042593
      label: glucose homeostasis
- term:
    id: GO:0005179
    label: hormone activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core molecular function. The proglucagon-derived peptides are bona fide secreted
      peptide hormones acting on cognate receptors.
    action: ACCEPT
    supported_by:
    - reference_id: UniProtKB:P01275
      supporting_text: "the major bioactive hormone is glucagon cleaved by PCSK2/PC2"
- term:
    id: GO:0007188
    label: adenylate cyclase-modulating G protein-coupled receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Glucagon, GLP-1 and GLP-2 all act through class B GPCRs (GCGR, GLP1R, GLP2R) coupled
      to Gs, elevating cAMP. Correct, though the activating child term GO:0007189 is more precise.
    action: ACCEPT
    supported_by:
    - reference_id: UniProtKB:P01275
      supporting_text: "couples to the G(s) G protein and elevates intracellular cAMP"
- term:
    id: GO:0031769
    label: glucagon receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Specific, informative molecular function for the glucagon peptide chain (binds GCGR).
      Core function.
    action: ACCEPT
    supported_by:
    - reference_id: UniProtKB:P01275
      supporting_text: "Binds to and activates the glucagon receptor GCGR"
- term:
    id: GO:0035774
    label: positive regulation of insulin secretion involved in cellular response to glucose
      stimulus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Captures the GLP-1 incretin effect, including its hallmark glucose-dependence. Best
      available term for this function. Core (GLP-1 chain).
    action: ACCEPT
    supported_by:
    - reference_id: UniProtKB:P01275
      supporting_text: "Potent stimulator of glucose-dependent insulin release"
- term:
    id: GO:0045722
    label: positive regulation of gluconeogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Glucagon raises blood glucose by stimulating hepatic gluconeogenesis. Core function
      (glucagon chain).
    action: ACCEPT
    supported_by:
    - reference_id: UniProtKB:P01275
      supporting_text: "Regulates blood glucose by increasing gluconeogenesis and decreasing
        glycolysis"
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      Correct but general. The peptides bind their cognate signaling receptors; more
      specific descendants (glucagon receptor binding, receptor ligand activity) are also
      annotated and are preferable as the core MF.
    action: ACCEPT
- term:
    id: GO:0005179
    label: hormone activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Redundant with the IBA hormone activity annotation; correct core molecular function.
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Secreted hormone; correct location. Redundant with other extracellular region annotations.
    action: ACCEPT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17051221
  qualifier: enables
  review:
    summary: >-
      Records glucagon as a substrate captured in the insulin-degrading enzyme (IDE)
      structure. A real binary interaction but uninformative as a molecular function and not
      a core activity (this is hormone clearance/degradation).
    action: KEEP_AS_NON_CORE
    reason: >-
      "protein binding" (GO:0005515) conveys no functional specificity; the interaction
      reflects glucagon being degraded by IDE rather than a function glucagon enables.
    supported_by:
    - reference_id: PMID:17051221
      supporting_text: "structures of human IDE in complex with four substrates (insulin B
        chain, amyloid-beta peptide (1-40), amylin and glucagon)"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17715056
  qualifier: enables
  review:
    summary: >-
      Derives from a structural study of the GIP receptor extracellular domain bound to the
      incretin GIP; supports a peptide:receptor-ECD binary interaction logged for this entry.
      Uninformative generic MF; not a core function.
    action: KEEP_AS_NON_CORE
    reason: >-
      "protein binding" is non-specific. The paper structurally characterizes GIP (a
      paralogous incretin), and the interaction is recorded as a generic binary binding for
      the proglucagon entry rather than a distinct molecular activity.
    supported_by:
    - reference_id: PMID:17715056
      supporting_text: "the crystal structure of the complex of human GIP receptor
        extracellular domain (ECD) with its agonist, the incretin GIP(1-42)"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21314817
  qualifier: enables
  review:
    summary: >-
      Records GLP-1 as a (slow) substrate of fibroblast activation protein (FAP). Real
      protease:substrate interaction relevant to incretin clearance, but a generic and
      non-core molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects degradation of GLP-1 by FAP, not an activity GLP-1 enables; "protein binding"
      is uninformative.
    supported_by:
    - reference_id: PMID:21314817
      supporting_text: "FAP slowly hydrolysed other hormone peptides, such as the incretins
        glucagon-like peptide-1 and glucose-dependent insulinotropic peptide"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21314817
  qualifier: enables
  review:
    summary: >-
      Records GLP-1 as an efficient substrate of dipeptidyl peptidase 4 (DPP4, UniProt
      P27487). DPP4 is the primary enzyme responsible for GLP-1 inactivation in vivo
      (the pharmacological basis of gliptin-class antidiabetics). Real binary interaction
      but a generic, non-core molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects degradation of GLP-1 by DPP4, not an activity GLP-1 enables; "protein binding"
      is uninformative.
    supported_by:
    - reference_id: PMID:21314817
      supporting_text: "the incretins glucagon-like peptide-1 and glucose-dependent
        insulinotropic peptide, which are efficient DPP4 substrates"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22212535
  qualifier: enables
  review:
    summary: >-
      Reflects glucagon self-association into amyloid-like fibrils observed in vitro under
      acidic, concentrated conditions (relevant to pharmaceutical formulation). Not a
      physiological function of the secreted hormone.
    action: KEEP_AS_NON_CORE
    reason: >-
      Self-assembly into fibrils is an in-vitro biophysical property, not the in-vivo
      molecular function of glucagon; should not be treated as a core activity.
    supported_by:
    - reference_id: PMID:22212535
      supporting_text: "The 29-residue peptide hormone glucagon forms many different
        morphological types of amyloid-like fibrils"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Incorrect functional location for a secreted peptide hormone. Proglucagon transits the
      ER and secretory granules and is exported; it does not function in the cytoplasm. This
      is an over-broad electronic ortholog transfer.
    action: REMOVE
    reason: >-
      Glucagon and the other products are secreted; "cytoplasm" (located_in) misrepresents
      their site of action and is not supported. The correct locations (extracellular region,
      ER lumen, secretory granule lumen) are separately annotated.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: >-
      The secreted peptides engage receptors located in the target-cell plasma membrane from
      the extracellular side; the ligand itself is not "active in" the plasma membrane. Likely
      an Ensembl ortholog-transfer artifact.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "is_active_in plasma membrane" conflates the receptor's location with the ligand's; the
      hormone acts as an extracellular ligand, not as a plasma-membrane component.
- term:
    id: GO:0007189
    label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Glucagon/GLP-1/GLP-2 all activate Gs-coupled receptors that stimulate adenylyl cyclase
      and raise cAMP. Correct and appropriately specific.
    action: ACCEPT
    supported_by:
    - reference_id: UniProtKB:P01275
      supporting_text: "couples to the G(s) G protein and elevates intracellular cAMP"
- term:
    id: GO:0014823
    label: response to activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Weak, context-dependent term propagated by ortholog transfer. Glucagon participates in
      glucose mobilization during physical activity, but this is peripheral and not a core
      function.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0035774
    label: positive regulation of insulin secretion involved in cellular response to glucose
      stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: GLP-1 incretin effect; redundant with the IBA annotation of the same term. Core (GLP-1).
    action: ACCEPT
- term:
    id: GO:0042593
    label: glucose homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Central biological role: glucagon (and the incretins) regulate systemic glucose
      homeostasis. Correct, core.
    action: ACCEPT
    supported_by:
    - reference_id: UniProtKB:P01275
      supporting_text: "Plays a key role in glucose metabolism and homeostasis"
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Reflects GLP-1's inhibition of pancreatic beta-cell apoptosis. Real but a general term
      and an indirect, downstream effect of GLP-1 receptor signaling; keep as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: UniProtKB:P01275
      supporting_text: "Inhibits beta cell apoptosis"
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Accurate core molecular function: the proglucagon peptides are agonist ligands for
      their cognate GPCRs.
    action: ACCEPT
- term:
    id: GO:0070374
    label: positive regulation of ERK1 and ERK2 cascade
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Downstream intracellular consequence of GLP-1/glucagon receptor signaling in target
      cells (e.g., beta-cell proliferation). Indirect and several steps removed from the
      hormone's molecular function; non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0071377
    label: cellular response to glucagon stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Semantically inverted for this gene. GCG is the SOURCE of the glucagon stimulus; this
      term describes the response program of glucagon-target cells, not a process the hormone
      is involved_in. Over-propagated electronic annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "cellular response to glucagon stimulus" belongs to cells receiving glucagon, not to
      the glucagon-producing gene; annotating GCG as involved_in its own stimulus-response is
      not meaningful.
- term:
    id: GO:0090280
    label: positive regulation of calcium ion import
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      A downstream second-messenger effect of incretin/glucagon receptor signaling in target
      cells. Indirect; non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0032024
    label: positive regulation of insulin secretion
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-381676
  qualifier: involved_in
  review:
    summary: >-
      GLP-1 stimulates insulin secretion (incretin effect). Correct; a more general parent of
      the glucose-dependent term GO:0035774 also annotated here. Core (GLP-1).
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: EXP
  original_reference_id: PMID:22037645
  qualifier: located_in
  review:
    summary: >-
      Experimental support for secretion of GLP-1 (measured as a secreted/circulating
      hormone from L-cells and alpha-cells). Correct location.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:22037645
      supporting_text: "increasing glucagon-like peptide-1"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: EXP
  original_reference_id: PMID:40446798
  qualifier: located_in
  review:
    summary: >-
      Secreted GLP-1 measured in a study of glucose homeostasis. Correct extracellular
      location for the secreted peptide.
    action: ACCEPT
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-381612
  qualifier: enables
  review:
    summary: >-
      GLP-1 acts as the agonist ligand of GLP1R (Reactome reaction "GLP1R binds GLP1").
      Correct core molecular function.
    action: ACCEPT
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-381799
  qualifier: located_in
  review:
    summary: >-
      Correct biosynthetic transit location: preproglucagon is synthesized and folded in the
      ER lumen of L-cells. Appropriate as a pathway/location annotation.
    action: ACCEPT
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-421416
  qualifier: located_in
  review:
    summary: ER lumen transit during biosynthesis/trafficking. Redundant with the other ER-lumen annotation; correct.
    action: ACCEPT
- term:
    id: GO:0034774
    label: secretory granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-421416
  qualifier: located_in
  review:
    summary: >-
      Proglucagon and its products are stored in regulated secretory granules prior to
      exocytosis. Correct location.
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Secreted hormone; correct location. Redundant with other extracellular region annotations.
    action: ACCEPT
- term:
    id: GO:0014823
    label: response to activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Weak, context-dependent ortholog-transferred term; redundant with the IEA copy. Non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0042593
    label: glucose homeostasis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Systemic glucose homeostasis; correct and central. Redundant with the IEA copy.
    action: ACCEPT
- term:
    id: GO:0050796
    label: regulation of insulin secretion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      GLP-1 regulates insulin secretion (incretin). Correct; a general parent of the more
      specific positive-regulation terms also annotated. Core (GLP-1).
    action: ACCEPT
- term:
    id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:7929237
  qualifier: involved_in
  review:
    summary: >-
      Glucagon acts via a Gs-coupled GPCR; in this study glucagon was used as a Gs-coupled
      receptor agonist driving adenylyl cyclase. The GPCR-signaling annotation is correct,
      though general. The paper's focus is adenylyl cyclase regulation, with glucagon as a tool.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:7929237
      supporting_text: "500 nM glucagon alone did not stimulate the enzyme but the combination
        of A23187 and glucagon activated the enzyme"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-163625
  qualifier: located_in
  review:
    summary: >-
      Correct location (glucagon binding GCGR occurs in the extracellular space). One of many
      redundant Reactome reaction-level extracellular-region annotations.
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-379044
  qualifier: located_in
  review:
    summary: Correct but redundant Reactome extracellular-region annotation (Gs activation reaction).
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-379048
  qualifier: located_in
  review:
    summary: Correct but redundant Reactome extracellular-region annotation (Gq/11 activation reaction).
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-744886
  qualifier: located_in
  review:
    summary: Correct but redundant Reactome extracellular-region annotation (Ligand:GPCR:Gs dissociation).
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-744887
  qualifier: located_in
  review:
    summary: Correct but redundant Reactome extracellular-region annotation (Gs binding reaction).
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-749448
  qualifier: located_in
  review:
    summary: Correct but redundant Reactome extracellular-region annotation (Gq binding reaction).
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-749452
  qualifier: located_in
  review:
    summary: Correct but redundant Reactome extracellular-region annotation (Ligand:GPCR:Gq dissociation).
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-825631
  qualifier: located_in
  review:
    summary: Correct but redundant Reactome extracellular-region annotation (Glucagon:GCGR GTP-GDP exchange).
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-381612
  qualifier: located_in
  review:
    summary: Correct but redundant Reactome extracellular-region annotation (GLP1R binds GLP1).
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-383313
  qualifier: located_in
  review:
    summary: >-
      Correct location: GLP-1 is secreted from intestinal L-cells into the extracellular
      space. Redundant with other extracellular-region annotations.
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9023632
  qualifier: located_in
  review:
    summary: Correct but redundant Reactome extracellular-region annotation (DPP4 hydrolysis of GLP-1).
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9023633
  qualifier: located_in
  review:
    summary: Correct but redundant Reactome extracellular-region annotation (DPP4 hydrolysis of GLP-1).
    action: ACCEPT
- term:
    id: GO:0034774
    label: secretory granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-383313
  qualifier: located_in
  review:
    summary: >-
      GLP-1 is packaged in secretory granules prior to release. Correct location; redundant
      with the other secretory-granule-lumen annotation.
    action: ACCEPT
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-420123
  qualifier: located_in
  review:
    summary: Correct but redundant Reactome extracellular-region annotation (GLP2R binds GLP2).
    action: ACCEPT
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: TAS
  original_reference_id: PMID:9990065
  qualifier: enables
  review:
    summary: >-
      GLP-2 binds and activates its specific receptor GLP2R. Correct, informative molecular
      function for the GLP-2 chain.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9990065
      supporting_text: "GLP-2, like glucagon and GLP-1, exerts its actions through a distinct
        and specific novel receptor expressed in its principal target tissue"
- term:
    id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:9990065
  qualifier: involved_in
  review:
    summary: >-
      GLP-2 signals through the Gs-coupled GLP2R (increased cAMP). Correct GPCR-signaling
      annotation for the GLP-2 chain.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9990065
      supporting_text: "Cells expressing the GLP-2R responded to GLP-2"
- term:
    id: GO:0007631
    label: feeding behavior
  evidence_type: TAS
  original_reference_id: PMID:8538742
  qualifier: involved_in
  review:
    summary: >-
      Central GLP-1 inhibits feeding and is a physiological mediator of satiety. Correct
      process annotation for the GLP-1 chain.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:8538742
      supporting_text: "central GLP-1 is a new physiological mediator of satiety"

core_functions:
- description: >
    Serves as a secreted polyprotein hormone precursor that is proteolytically processed in a
    tissue-specific manner (PCSK2/PC2 in pancreatic alpha-cells; PCSK1/PC1 in intestinal
    L-cells and neurons) to yield multiple distinct peptide hormones. The precursor is
    synthesized in the ER, stored in secretory granules, and secreted; its biology is
    realized through its cleavage products.
  molecular_function:
    id: GO:0005179
    label: hormone activity
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  - id: GO:0034774
    label: secretory granule lumen
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: UniProtKB:P01275
    supporting_text: "Proglucagon is post-translationally processed in a tissue-specific
      manner in pancreatic A cells and intestinal L cells"
- description: >
    Via the glucagon peptide (residues 53-81, PRO_0000011256), binds and activates the
    glucagon receptor GCGR on hepatocytes, the principal counter-regulatory action to insulin:
    raises blood glucose by stimulating gluconeogenesis and glycogenolysis and decreasing
    glycolysis, signaling through Gs and elevating cAMP.
  molecular_function:
    id: GO:0031769
    label: glucagon receptor binding
  directly_involved_in:
  - id: GO:0045722
    label: positive regulation of gluconeogenesis
  - id: GO:0042593
    label: glucose homeostasis
  - id: GO:0007189
    label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: UniProtKB:P01275
    supporting_text: "Regulates blood glucose by increasing gluconeogenesis and decreasing
      glycolysis"
  - reference_id: UniProtKB:P01275
    supporting_text: "Binds to and activates the glucagon receptor GCGR"
- description: >
    Via glucagon-like peptide 1 (GLP-1; residues 92-128 and the active 7-37/7-36amide forms),
    acts as an incretin agonist of GLP1R to potentiate glucose-dependent insulin secretion,
    promote satiety, and support beta-cell survival. Produced chiefly by intestinal L-cells
    and also pancreatic alpha-cells and neurons.
  molecular_function:
    id: GO:0048018
    label: receptor ligand activity
  directly_involved_in:
  - id: GO:0035774
    label: positive regulation of insulin secretion involved in cellular response to glucose
      stimulus
  - id: GO:0007631
    label: feeding behavior
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: UniProtKB:P01275
    supporting_text: "Potent stimulator of glucose-dependent insulin release"
  - reference_id: PMID:8538742
    supporting_text: "central GLP-1 is a new physiological mediator of satiety"
- description: >
    Via glucagon-like peptide 2 (GLP-2; residues 146-178, PRO_0000011262), binds and
    activates the intestine-specific receptor GLP2R to stimulate intestinal growth: increased
    villus height and crypt cell proliferation with decreased enterocyte apoptosis, enhancing
    nutrient assimilation. A distinct receptor and function from glucagon and GLP-1.
  molecular_function:
    id: GO:0005102
    label: signaling receptor binding
  directly_involved_in:
  - id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  locations:
  - id: GO:0005576
    label: extracellular region
  anatomical_locations:
  - id: UBERON:0002108
    label: small intestine
  supported_by:
  - reference_id: PMID:9990065
    supporting_text: "GLP-2 stimulates intestinal growth and up-regulates villus height in the
      small intestine, concomitant with increased crypt cell proliferation and decreased
      enterocyte apoptosis"
  - reference_id: PMID:9990065
    supporting_text: "GLP-2, like glucagon and GLP-1, exerts its actions through a distinct
      and specific novel receptor expressed in its principal target tissue"

proposed_new_terms: []

suggested_questions:
- question: >-
    Should GO annotations for proglucagon-derived functions be made at the level of the
    individual peptide chains (PRO ids) rather than the gene/precursor, to avoid conflating
    glucagon (GCGR), GLP-1 (GLP1R), and GLP-2 (GLP2R) functions that act through different
    receptors and in different tissues?
- question: >-
    For oxyntomodulin and glicentin, which functions are sufficiently well-supported to
    warrant dedicated GO annotations versus remaining as UniProt FUNCTION statements
    (currently ECO:0000303)?

suggested_experiments:
- description: >-
    Chain-resolved functional annotation: use tissue-specific (alpha-cell vs L-cell)
    secretomics/peptidomics to confirm which mature peptides are produced where, and pair
    with receptor-specific (GCGR/GLP1R/GLP2R) reporter assays to assign each downstream
    process (insulin secretion, gluconeogenesis, intestinal growth) to the correct peptide.
- description: >-
    Knock-in mouse models that selectively ablate processing to individual products (e.g.,
    PC2-null pancreatic glucagon vs PC1/3-null intestinal GLP-1/GLP-2) to dissect which
    phenotypes (glucose mobilization, incretin/insulin secretion, intestinal trophic effects)
    depend on which proglucagon-derived peptide in vivo.

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- 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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: UniProtKB:P01275
  title: "UniProtKB entry P01275 (GLUC_HUMAN), Pro-glucagon"
  findings:
  - statement: Proglucagon is processed tissue-specifically; glucagon predominates in
      pancreatic A cells (PCSK2/PC2), while GLP-1, GLP-2, glicentin and oxyntomodulin are
      liberated in intestinal L cells (PCSK1/PC1).
    supporting_text: "Proglucagon is post-translationally processed in a tissue-specific
      manner in pancreatic A cells and intestinal L cells"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Canonical curated entry; FUNCTION blocks are split per cleavage product and are the
      backbone of the chain-resolved review.
- id: PMID:17051221
  title: Structures of human insulin-degrading enzyme reveal a new substrate recognition
    mechanism.
  findings:
  - statement: Glucagon is one of four substrates co-crystallized with insulin-degrading
      enzyme (IDE), supporting glucagon as an IDE degradation substrate.
    supporting_text: "structures of human IDE in complex with four substrates (insulin B
      chain, amyloid-beta peptide (1-40), amylin and glucagon)"
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Correctly cited for the GCG-IDE interaction (GO:0005515 IPI). Reflects hormone
      clearance, not a core function of glucagon.
- id: PMID:17715056
  title: Crystal structure of the incretin-bound extracellular domain of a G protein-coupled
    receptor.
  findings:
  - statement: Structural study of the GIP receptor extracellular domain bound to the
      incretin GIP; the structural principles are stated to be conserved among related class B
      hormone receptors such as GLP1R.
    supporting_text: "the crystal structure of the complex of human GIP receptor extracellular
      domain (ECD) with its agonist, the incretin GIP(1-42)"
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Paper structurally characterizes GIP (a paralogous incretin from a different gene), not
      a proglucagon peptide directly; underpins only a generic "protein binding" annotation.
- id: PMID:21314817
  title: Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel
    substrates of fibroblast activation protein-Ξ±.
  findings:
  - statement: GLP-1 is a (slow) substrate of fibroblast activation protein (FAP), in
      addition to being an efficient DPP4 substrate.
    supporting_text: "FAP slowly hydrolysed other hormone peptides, such as the incretins
      glucagon-like peptide-1 and glucose-dependent insulinotropic peptide"
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Supports the GCG-FAP interaction (GO:0005515 IPI); relevant to GLP-1 clearance, non-core.
- id: PMID:22037645
  title: Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1
    secretion from L cells and alpha cells.
  findings:
  - statement: IL-6 increases GLP-1 production from alpha cells by upregulating proglucagon
      (GCG) and prohormone convertase 1/3, enhancing insulin secretion.
    supporting_text: "IL-6 increased GLP-1 production from alpha cells through increased
      proglucagon (which is encoded by GCG) and prohormone convertase 1/3 expression"
  - statement: GLP-1 is a hormone that induces insulin secretion (incretin).
    supporting_text: "Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin
      secretion"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available; directly supports GLP-1 secretion (extracellular region, EXP) and
      the incretin/insulin-secretion functions.
- id: PMID:22212535
  title: Mapping out the multistage fibrillation of glucagon.
  findings:
  - statement: Glucagon self-assembles into multiple morphological types of amyloid-like
      fibrils in vitro, the basis of the identical protein binding annotation.
    supporting_text: "The 29-residue peptide hormone glucagon forms many different
      morphological types of amyloid-like fibrils"
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Correctly cited for glucagon self-association (GO:0042802 IPI), but the behavior is an
      in-vitro biophysical property, not a physiological function.
- id: PMID:40446798
  title: A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves
    glucose homeostasis via the orphan receptor MRGPRE.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: >-
      Cited (EXP) for secreted GLP-1/extracellular location; full text not in cache, so the
      precise supporting passage could not be quoted verbatim.
- id: PMID:7929237
  title: Synergistic activation of the type I adenylyl cyclase by Ca2+ and Gs-coupled
    receptors in vivo.
  findings:
  - statement: Glucagon, acting through its Gs-coupled receptor, synergizes with Ca2+ to
      activate type I adenylyl cyclase; used here as a Gs-coupled receptor agonist.
    supporting_text: "500 nM glucagon alone did not stimulate the enzyme but the combination
      of A23187 and glucagon activated the enzyme"
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      The paper is about adenylyl cyclase regulation; glucagon is a tool agonist. Adequately
      supports a general GPCR-signaling annotation but is not a primary GCG functional study.
- id: PMID:8538742
  title: A role for glucagon-like peptide-1 in the central regulation of feeding.
  findings:
  - statement: Central (ICV) GLP-1 inhibits feeding and is a physiological mediator of
      satiety, establishing GLP-1's role in feeding behavior.
    supporting_text: "central GLP-1 is a new physiological mediator of satiety"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Classic study underpinning the GLP-1 feeding-behavior annotation (GO:0007631 TAS).
- id: PMID:9990065
  title: Prototypic G protein-coupled receptor for the intestinotrophic factor glucagon-like
    peptide 2.
  findings:
  - statement: GLP-2 is intestinotrophic and acts through its own distinct receptor (GLP2R),
      stimulating villus growth, crypt proliferation, and reduced enterocyte apoptosis.
    supporting_text: "GLP-2 stimulates intestinal growth and up-regulates villus height in the
      small intestine, concomitant with increased crypt cell proliferation and decreased
      enterocyte apoptosis"
  - statement: GLP-2 exerts its actions through a distinct, specific receptor expressed in the
      gut, like glucagon and GLP-1 acting through their own receptors.
    supporting_text: "GLP-2, like glucagon and GLP-1, exerts its actions through a distinct
      and specific novel receptor expressed in its principal target tissue"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Defines the GLP-2 chain function and its dedicated receptor; supports the GLP-2
      signaling-receptor-binding and GPCR-signaling annotations.
- id: Reactome:R-HSA-163625
  title: Glucagon binds to Glucagon receptor
  findings: []
- id: Reactome:R-HSA-379044
  title: Liganded Gs-activating GPCR acts as a GEF for Gs
  findings: []
- id: Reactome:R-HSA-379048
  title: Liganded Gq/11-activating GPCRs act as GEFs for Gq/11
  findings: []
- id: Reactome:R-HSA-381612
  title: GLP1R binds GLP1
  findings: []
- id: Reactome:R-HSA-381676
  title: Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
  findings: []
- id: Reactome:R-HSA-381799
  title: Synthesis of Preproglucagon in intestinal L cells
  findings: []
- id: Reactome:R-HSA-383313
  title: Glucagon-like Peptide 1 is secreted from intestinal L cells
  findings: []
- id: Reactome:R-HSA-420123
  title: Glucagon-like receptor 2 binds GLP2
  findings: []
- id: Reactome:R-HSA-421416
  title: Proglucagon translocates from the ER Lumen to secretory granules
  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-749448
  title: Liganded Gq-activating GPCRs bind inactive heterotrimeric Gq
  findings: []
- id: Reactome:R-HSA-749452
  title: The Ligand:GPCR:Gq complex dissociates
  findings: []
- id: Reactome:R-HSA-825631
  title: Glucagon:GCGR mediates GTP-GDP exchange
  findings: []
- id: Reactome:R-HSA-9023632
  title: DPP4(39-766) hydrolyzes Glucagon-like Peptide-1 (GLP-1)
  findings: []
- id: Reactome:R-HSA-9023633
  title: DPP4(1-766) hydrolyzes Glucagon-like Peptide-1 (GLP-1)
  findings: []