GCG (Proglucagon) — 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 α-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 |
— |
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; β-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)"] — clearance, not a core function.
- Glucagon self-assembles into amyloid fibrils in vitro PMID:22212535 — 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 / β-cell proliferation, inhibits beta cell apoptosis.
- IL-6 increases GLP-1 production from α-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 — 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) → Gs → adenylyl cyclase → 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 —
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 → 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 — 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 ×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 — flagged LOW relevance.