GIPR is the class B1 G protein-coupled receptor for glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone released from intestinal K cells after a meal. The receptor sits in the plasma membrane with an N-glycosylated extracellular domain that captures the C-terminal helix of GIP, while the transmembrane core engages the hormone's N-terminus and couples to Gs to activate adenylyl cyclase and raise cAMP. In pancreatic beta cells this potentiates glucose-stimulated insulin secretion (the incretin effect); GIPR is also expressed in adipose tissue, bone and brain. Common GIPR variants are associated with post-challenge glucose levels and reduced insulin secretion.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002029 desensitization of G protein-coupled receptor signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Desensitization of GPCR signaling transferred from rat. Reason: Homologous desensitization is a general GPCR regulatory property; peripheral to the core function and not examined in the cached human literature. |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic transmembrane signaling receptor activity. Reason: Correct but too general; the gene carries the specific gastric inhibitory peptide receptor activity. Proposed replacements: gastric inhibitory peptide receptor activity Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels |
| GO:0004888 transmembrane signaling receptor activity | TAS PMID:7556958 Cloning, functional expression, and chromosomal localization... | MODIFY | Summary: Generic transmembrane signaling receptor activity. Reason: Correct but too general; the gene carries the specific gastric inhibitory peptide receptor activity. Proposed replacements: gastric inhibitory peptide receptor activity Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic GPCR activity. Reason: Correct but too general; GIP receptor activity is the supported descendant already annotated. Proposed replacements: gastric inhibitory peptide receptor activity Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels |
| GO:0005515 protein binding | IPI PMID:17715056 Crystal structure of the incretin-bound extracellular domain... | REMOVE | Summary: Generic protein binding from interaction screens. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:17715056 Crystal structure of the incretin-bound extracellular domain... | MODIFY | Summary: GIPR ECD binds GIP in the crystal structure. Reason: This is hormone-receptor binding; peptide hormone binding is the informative term, already annotated from the same paper. Proposed replacements: peptide hormone binding Supporting Evidence: PMID:17715056 The hormone binds in an alpha-helical conformation in a surface groove of the ECD |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: Generic protein binding from interaction screens. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: Generic protein binding from interaction screens. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: Generic protein binding from interaction screens. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane inherited from the class B GPCR node. Reason: Matches direct evidence. Supporting Evidence: file:human/GIPR/GIPR-uniprot.txt N-glycosylation is required for cell surface expression |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: GIPR is a seven-transmembrane receptor of the plasma membrane. Reason: Topology, ligand binding to the extracellular domain and glycosylation-dependent cell-surface expression place GIPR at the plasma membrane. Supporting Evidence: PMID:7589426 The cloned cDNA encoded a seven transmembrane domain protein of 466 amino acids file:human/GIPR/GIPR-uniprot.txt N-glycosylation is required for cell surface expression |
| GO:0005886 plasma membrane | TAS PMID:7556958 Cloning, functional expression, and chromosomal localization... | ACCEPT | Summary: GIPR is a seven-transmembrane receptor of the plasma membrane. Reason: Topology, ligand binding to the extracellular domain and glycosylation-dependent cell-surface expression place GIPR at the plasma membrane. Supporting Evidence: PMID:7589426 The cloned cDNA encoded a seven transmembrane domain protein of 466 amino acids file:human/GIPR/GIPR-uniprot.txt N-glycosylation is required for cell surface expression |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-379044 | ACCEPT | Summary: GIPR is a seven-transmembrane receptor of the plasma membrane. Reason: Topology, ligand binding to the extracellular domain and glycosylation-dependent cell-surface expression place GIPR at the plasma membrane. Supporting Evidence: PMID:7589426 The cloned cDNA encoded a seven transmembrane domain protein of 466 amino acids file:human/GIPR/GIPR-uniprot.txt N-glycosylation is required for cell surface expression |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-420274 | ACCEPT | Summary: GIPR is a seven-transmembrane receptor of the plasma membrane. Reason: Topology, ligand binding to the extracellular domain and glycosylation-dependent cell-surface expression place GIPR at the plasma membrane. Supporting Evidence: PMID:7589426 The cloned cDNA encoded a seven transmembrane domain protein of 466 amino acids file:human/GIPR/GIPR-uniprot.txt N-glycosylation is required for cell surface expression |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-744886 | ACCEPT | Summary: GIPR is a seven-transmembrane receptor of the plasma membrane. Reason: Topology, ligand binding to the extracellular domain and glycosylation-dependent cell-surface expression place GIPR at the plasma membrane. Supporting Evidence: PMID:7589426 The cloned cDNA encoded a seven transmembrane domain protein of 466 amino acids file:human/GIPR/GIPR-uniprot.txt N-glycosylation is required for cell surface expression |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-744887 | ACCEPT | Summary: GIPR is a seven-transmembrane receptor of the plasma membrane. Reason: Topology, ligand binding to the extracellular domain and glycosylation-dependent cell-surface expression place GIPR at the plasma membrane. Supporting Evidence: PMID:7589426 The cloned cDNA encoded a seven transmembrane domain protein of 466 amino acids file:human/GIPR/GIPR-uniprot.txt N-glycosylation is required for cell surface expression |
| GO:0006091 generation of precursor metabolites and energy | TAS PMID:7556958 Cloning, functional expression, and chromosomal localization... | MARK AS OVER ANNOTATED | Summary: Generation of precursor metabolites and energy. Reason: GIPR regulates insulin secretion through cAMP signaling; it does not participate in energy-generating metabolism. Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: Generic cell surface receptor signaling. Reason: Correct but too general; the specific gastric inhibitory peptide signaling pathway is annotated. Proposed replacements: gastric inhibitory peptide signaling pathway Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels |
| GO:0007166 cell surface receptor signaling pathway | TAS PMID:7556958 Cloning, functional expression, and chromosomal localization... | MODIFY | Summary: Generic cell surface receptor signaling. Reason: Correct but too general; the specific gastric inhibitory peptide signaling pathway is annotated. Proposed replacements: gastric inhibitory peptide signaling pathway Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: Generic GPCR signaling. Reason: Correct but too general. Proposed replacements: gastric inhibitory peptide signaling pathway Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels |
| GO:0007188 adenylate cyclase-modulating G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | MODIFY | Summary: Adenylate cyclase-modulating GPCR signaling inherited from the family node. Reason: GIPR stimulates cAMP production via Gs, so the activating child term is supported and already annotated by IDA. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001737881 SUPPORTS TRANSFER Class B1 secretin-family node; adenylate cyclase modulation is sound family-wide, with the activating direction established for GIPR itself. Proposed replacements: adenylate cyclase-activating G protein-coupled receptor signaling pathway Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA PMID:26572091 N-terminally and C-terminally truncated forms of glucose-dep... | ACCEPT | Summary: Gs-coupled adenylate cyclase activation by GIPR. Reason: GIP raises cAMP in GIPR-expressing cells. Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels PMID:26572091 The human GIP receptor transiently transfected in COS‐7 cells was used in cAMP accumulation assay |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Gs-coupled adenylate cyclase activation by GIPR. Reason: GIP raises cAMP in GIPR-expressing cells. Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels PMID:26572091 The human GIP receptor transiently transfected in COS‐7 cells was used in cAMP accumulation assay |
| GO:0007190 activation of adenylate cyclase activity | TAS PMID:7589426 Molecular cloning, functional expression, and signal transdu... | MODIFY | Summary: Activation of adenylate cyclase activity. Reason: Adenylyl cyclase is activated by Gs-alpha, not by the receptor; the receptor's role is captured by the adenylate cyclase-activating GPCR signaling pathway. Proposed replacements: adenylate cyclase-activating G protein-coupled receptor signaling pathway Supporting Evidence: PMID:7589426 a high affinity receptor was expressed which coupled to the adenylate cyclase |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of cytosolic Ca2+ transferred from rat. Reason: Both human cloning studies found no elevation of cytosolic calcium on GIP stimulation; any Ca2+ rise in beta cells is secondary to cAMP effects on excitability. Supporting Evidence: PMID:7556958 no elevation of cytoplasmic calcium concentrations |
| GO:0007584 response to nutrient | TAS PMID:7556958 Cloning, functional expression, and chromosomal localization... | MARK AS OVER ANNOTATED | Summary: Response to nutrient. Reason: GIPR responds to a hormone, not to a nutrient; the nutrient link is via K-cell GIP secretion. Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels |
| GO:0008528 G protein-coupled peptide receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: G protein-coupled peptide receptor activity inherited from the family node. Reason: Correct but less specific than supported; gastric inhibitory peptide receptor activity is the descendant the gene already carries. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001737881 SUPPORTS TRANSFER Class B1 peptide-receptor node; broad term sound across members with different peptide ligands. Proposed replacements: gastric inhibitory peptide receptor activity Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels |
| GO:0009749 response to glucose | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Response to glucose transferred from rat. Reason: Likely reflects glucose-regulated receptor expression in islets; GIPR does not sense glucose. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Generic membrane. Reason: Correct but too general; plasma membrane is annotated. Proposed replacements: plasma membrane Supporting Evidence: PMID:7589426 The cloned cDNA encoded a seven transmembrane domain protein of 466 amino acids |
| GO:0016020 membrane | TAS PMID:7556958 Cloning, functional expression, and chromosomal localization... | MODIFY | Summary: Generic membrane. Reason: Correct but too general; plasma membrane is annotated. Proposed replacements: plasma membrane Supporting Evidence: PMID:7589426 The cloned cDNA encoded a seven transmembrane domain protein of 466 amino acids |
| GO:0016519 gastric inhibitory peptide receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: GIPR binds GIP and signals via cAMP. Reason: Core molecular function. Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels PMID:26572091 The human GIP receptor transiently transfected in COS‐7 cells was used in cAMP accumulation assay |
| GO:0016519 gastric inhibitory peptide receptor activity | IDA PMID:26572091 N-terminally and C-terminally truncated forms of glucose-dep... | ACCEPT | Summary: GIPR binds GIP and signals via cAMP. Reason: Core molecular function. Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels PMID:26572091 The human GIP receptor transiently transfected in COS‐7 cells was used in cAMP accumulation assay |
| GO:0016519 gastric inhibitory peptide receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: GIPR binds GIP and signals via cAMP. Reason: Core molecular function. Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels PMID:26572091 The human GIP receptor transiently transfected in COS‐7 cells was used in cAMP accumulation assay |
| GO:0017046 peptide hormone binding | IEA GO_REF:0000107 | ACCEPT | Summary: GIP binds the GIPR extracellular domain. Reason: Supported by the GIP-ECD crystal structure and competition binding. Supporting Evidence: PMID:17715056 The hormone binds in an alpha-helical conformation in a surface groove of the ECD |
| GO:0017046 peptide hormone binding | IPI PMID:17715056 Crystal structure of the incretin-bound extracellular domain... | ACCEPT | Summary: GIP binds the GIPR extracellular domain. Reason: Supported by the GIP-ECD crystal structure and competition binding. Supporting Evidence: PMID:17715056 The hormone binds in an alpha-helical conformation in a surface groove of the ECD |
| GO:0017046 peptide hormone binding | IPI PMID:26572091 N-terminally and C-terminally truncated forms of glucose-dep... | ACCEPT | Summary: GIP binds the GIPR extracellular domain. Reason: Supported by the GIP-ECD crystal structure and competition binding. Supporting Evidence: PMID:17715056 The hormone binds in an alpha-helical conformation in a surface groove of the ECD |
| GO:0032024 positive regulation of insulin secretion | IEA GO_REF:0000107 | ACCEPT | Summary: Positive regulation of insulin secretion transferred from rat. Reason: Potentiation of glucose-stimulated insulin secretion (the incretin effect) is the principal physiological output of GIPR signaling in beta cells; human GIPR variants reduce insulin secretion. Supporting Evidence: PMID:20081857 The GIPR A-allele carriers also showed decreased insulin secretion |
| GO:0038192 gastric inhibitory peptide signaling pathway | IDA PMID:26572091 N-terminally and C-terminally truncated forms of glucose-dep... | ACCEPT | Summary: GIP signaling pathway. Reason: GIPR is the receptor initiating GIP signaling. Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels PMID:26572091 The human GIP receptor transiently transfected in COS‐7 cells was used in cAMP accumulation assay |
| GO:0038192 gastric inhibitory peptide signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: GIP signaling pathway. Reason: GIPR is the receptor initiating GIP signaling. Supporting Evidence: PMID:7556958 GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels PMID:26572091 The human GIP receptor transiently transfected in COS‐7 cells was used in cAMP accumulation assay |
| GO:0048678 response to axon injury | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Response to axon injury transferred from rat. Reason: Likely an expression change after injury; no evidence GIPR participates in the response. |
| GO:0050796 regulation of insulin secretion | TAS PMID:20081857 Genetic variation in GIPR influences the glucose and insulin... | MODIFY | Summary: Regulation of insulin secretion from a GWAS. Reason: The direction is known (GIPR potentiates insulin secretion; risk allele reduces it), so positive regulation of insulin secretion is the more accurate term. Proposed replacements: positive regulation of insulin secretion Supporting Evidence: PMID:20081857 The GIPR A-allele carriers also showed decreased insulin secretion |
| GO:0051592 response to calcium ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Response to calcium ion transferred from rat. Reason: No evidence that GIPR participates in a calcium-ion response. |
| GO:0070542 response to fatty acid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Response to fatty acid transferred from rat. Reason: Likely an expression change in adipose tissue; GIPR is not a fatty-acid sensor. |
| GO:0120022 glucagon family peptide binding | IPI PMID:17715056 Crystal structure of the incretin-bound extracellular domain... | ACCEPT | Summary: GIPR ECD binds incretin peptides of the glucagon family. Reason: GIP is a member of the glucagon/secretin peptide family and binds the ECD directly. Supporting Evidence: PMID:17715056 The hormone binds in an alpha-helical conformation in a surface groove of the ECD |
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Experiment: Measure ligand-induced GIPR internalization and recycling in human adipocytes and beta cells with surface-labeled receptor to relate trafficking to sustained cAMP signaling.
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