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.
Curated functional classes representing distinct biological activities. These may be splice variants, cleavage products, or other forms with different functions.
GCG_GLUCAGONPRO_0000011256 (residues 53-81) GCG_GLP1PRO_0000011258, PRO_0000011259, PRO_0000011260 (residues 92-128 / 98-128 / 98-127) GCG_GLP2PRO_0000011262 (residues 146-178) GCG_OXYNTOMODULINPRO_0000011255 (residues 53-89) GCG_GLICENTINPRO_0000011253 (residues 21-89) GCG_GRPPPRO_0000011254 (residues 21-50) | 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 |
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Download this section (compressed HTML)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)?
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.
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Download this section (compressed HTML)Loading supporting content…
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