GRP

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005102 signaling receptor binding	NAS PMID:3027901 Human gastrin-releasing peptide gene maps to chromosome band...	MODIFY	Summary: Correct but general receptor-binding claim on a chromosomal mapping paper; refine to the specific molecular function neuropeptide hormone activity (GO:0005184) already carried on GRP. Reason: GRP is an extracellular neuropeptide hormone that binds and activates the bombesin-family GPCR GRPR. GO:0005102 (signaling receptor binding) is a broad ancestor of GO:0005184 (neuropeptide hormone activity), which is already annotated on GRP by IDA and IBA. Proposed replacements: neuropeptide hormone activity Supporting Evidence: Reactome:R-HSA-375384 There are two homologues of bombesin-like peptides; Gastrin-releasing peptide (GRP) (Sausville EA et al, 1986) and Neuromedin-B (NMB) (Krane IM et al, 1988).
GO:0005184 neuropeptide hormone activity	IBA GO_REF:0000033	ACCEPT	Summary: Core molecular function of GRP as a bombesin-family neuropeptide hormone; phylogenetic inference from the jawed-vertebrate root PTN008565241 is well supported. Reason: PAINT node PTN008565241 (jawed-vertebrate root of PANTHER:PTHR16866) is directly seeded by human GRP (UniProtKB:P07492) and accurately captures the conserved neuropeptide hormone activity of mature amidated GRP peptides. Supporting Evidence: PMID:3211139 The 27-amino-acid gastrin-releasing peptide (GRP1-27) is a neuropeptide and growth factor that is synthesized by various neural and neuroendocrine cells.
GO:0005184 neuropeptide hormone activity	IDA PMID:8756537 Proglucagon gene expression is induced by gastrin-releasing ...	ACCEPT	Summary: Direct experimental demonstration that GRP acts as a bioactive neuropeptide hormone inducing proglucagon transcription in enteroendocrine cells. Reason: PMID:8756537 demonstrates that exogenous GRP stimulates proglucagon mRNA expression in enteroendocrine cells via protein kinase C-dependent and -independent signaling pathways, supporting its core neuropeptide hormone activity. Supporting Evidence: PMID:8756537 We show here that gastrin-releasing peptide (GRP) induces proglucagon messenger RNA transcripts in STC-1 enteroendocrine cells.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Remove uninformative bare protein binding row from a high-throughput yeast two-hybrid screen reporting interaction with nuclear transcription factor ALX1. Reason: Bare GO:0005515 (protein binding) is uninformative per GO curation policy, and an interaction between the secreted peptide precursor GRP and the nuclear homeobox transcription factor ALX1 (UniProtKB:Q15699) in a yeast two-hybrid screen is compartmentalized away from GRP's secretory pathway biology.
GO:0005576 extracellular region	IBA GO_REF:0000033	ACCEPT	Summary: Core site of action of mature secreted GRP peptides; phylogenetic inference from PTN008565241 is well supported. Reason: GRP is synthesized with an N-terminal signal peptide (aa 1-23) and secreted into the extracellular space, where mature GRP(1-27) and neuromedin C bind cell-surface GRPR. Supporting Evidence: PMID:3211139 In the small-cell lung cancer cell line, GRP1-27 was cleaved as expected from the endogenous prohormone at a pair of basic amino acids (29 and 30) and alpha-amidated at its C-terminal methionine
GO:0005576 extracellular region	IDA PMID:3211139 Posttranslational processing of endogenous and of baculoviru...	ACCEPT	Summary: Direct experimental characterization of secreted, processed human GRP peptides in the extracellular medium. Reason: PMID:3211139 directly characterizes the posttranslational processing and secretion of human GRP precursor into mature extracellular peptides. Supporting Evidence: PMID:3211139 In the small-cell lung cancer cell line, GRP1-27 was cleaved as expected from the endogenous prohormone at a pair of basic amino acids (29 and 30) and alpha-amidated at its C-terminal methionine
GO:0005576 extracellular region	IDA PMID:8756537 Proglucagon gene expression is induced by gastrin-releasing ...	ACCEPT	Summary: Consistent with extracellular action of secreted GRP on enteroendocrine target cells. Reason: GRP acts as an extracellular peptide hormone on cell-surface receptors of enteroendocrine cells. Supporting Evidence: PMID:8756537 We show here that gastrin-releasing peptide (GRP) induces proglucagon messenger RNA transcripts in STC-1 enteroendocrine cells.
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: Accurate UniProt subcellular location mapping for secreted GRP. Reason: UniProtKB-SubCell:SL-0243 (Secreted) correctly maps GRP to the extracellular region.
GO:0005576 extracellular region	TAS Reactome:R-HSA-375384	ACCEPT	Summary: Accurate Reactome pathway location for extracellular GRP binding to GRPR. Reason: Reactome R-HSA-375384 models extracellular GRP binding to plasma-membrane bombesin-like receptors. Supporting Evidence: Reactome:R-HSA-375384 There are two homologues of bombesin-like peptides; Gastrin-releasing peptide (GRP) (Sausville EA et al, 1986) and Neuromedin-B (NMB) (Krane IM et al, 1988).
GO:0005576 extracellular region	TAS Reactome:R-HSA-379048	ACCEPT	Summary: Accurate Reactome location for GRP in the extracellular ligand-bound GPCR-Gq complex. Reason: Secreted GRP remains bound to the extracellular face of GRPR during Gq/11 activation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-749448	ACCEPT	Summary: Accurate Reactome location for extracellular GRP during GPCR-Gq recruitment. Reason: Secreted GRP acts in the extracellular region as the ligand in the GRPR:Gq complex.
GO:0005576 extracellular region	TAS Reactome:R-HSA-749452	ACCEPT	Summary: Accurate Reactome location for extracellular GRP during ligand:GPCR:Gq dissociation. Reason: GRP is localized to the extracellular region throughout the GRPR signaling cycle.
GO:0007165 signal transduction	NAS PMID:3027901 Human gastrin-releasing peptide gene maps to chromosome band...	MODIFY	Summary: Correct but overly general biological process on a gene-mapping paper; refine to bombesin receptor signaling pathway (GO:0031989) and neuropeptide signaling pathway (GO:0007218). Reason: GO:0007165 (signal transduction) is a high-level parent term. GRP specifically initiates the bombesin receptor signaling pathway (GO:0031989) and neuropeptide signaling pathway (GO:0007218) by binding and activating GRPR. Proposed replacements: bombesin receptor signaling pathway neuropeptide signaling pathway Supporting Evidence: Reactome:R-HSA-375384 Bombesin-like receptors are widely distributed in the CNS as well as in the GI tract where they modulate smooth-muscle contraction, exocrine and endocrine processes, metabolism, and behaviour through the binding of bombesin-like peptides.
GO:0007218 neuropeptide signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: Core biological process of GRP as a secreted neuropeptide hormone; phylogenetic inference from PTN008565241 is well supported. Reason: PAINT node PTN008565241 (jawed-vertebrate root of PANTHER:PTHR16866) is seeded by human GRP and rat Grp and accurately captures the conserved role of bombesin-like peptides in neuropeptide signaling. Note that in GO, GO:0031989 (bombesin receptor signaling pathway) sits under GO:0007186 (G protein-coupled receptor signaling pathway) rather than under GO:0007218, so GO:0007218 and GO:0031989 are complementary core annotations. Supporting Evidence: PMID:8756537 We show here that gastrin-releasing peptide (GRP) induces proglucagon messenger RNA transcripts in STC-1 enteroendocrine cells.
GO:0007218 neuropeptide signaling pathway	IDA PMID:8756537 Proglucagon gene expression is induced by gastrin-releasing ...	ACCEPT	Summary: Experimental support for GRP signaling in enteroendocrine cells; retain as a core pathway term alongside GO:0031989. Reason: PMID:8756537 demonstrates GRP-induced intracellular signaling and proglucagon gene induction in enteroendocrine cells. Supporting Evidence: PMID:8756537 We show here that gastrin-releasing peptide (GRP) induces proglucagon messenger RNA transcripts in STC-1 enteroendocrine cells.
GO:0007218 neuropeptide signaling pathway	IEA GO_REF:0000002	ACCEPT	Summary: Accurate InterPro2GO mapping from the bombesin-like peptide domain (IPR000874) to neuropeptide signaling pathway. Reason: InterPro:IPR000874 identifies bombesin-like neuropeptides (GRP and NMB), all of which signal through neuropeptide GPCR pathways.
GO:0031410 cytoplasmic vesicle	IEA GO_REF:0000044	MODIFY	Summary: Correct but broad vesicle term; refine to secretory granule lumen (GO:0034774), which GRP already carries. Reason: GO:0031410 (cytoplasmic vesicle) is a broad parent of secretory granules. As a soluble neuropeptide prohormone stored in and released from neuroendocrine dense-core secretory vesicles, the more specific supported compartment is GO:0034774 (secretory granule lumen), which is already annotated on GRP. Proposed replacements: secretory granule lumen
GO:0034774 secretory granule lumen	ISS GO_REF:0000024	ACCEPT	Summary: Accurate subcellular localization of pro-GRP and mature GRP peptides within neuroendocrine secretory granules prior to exocytosis. Reason: Pro-GRP is cleaved at dibasic residues and alpha-amidated within the secretory granule lumen of neuroendocrine cells and peptidergic neurons before regulated secretion. Supporting Evidence: PMID:3211139 In the small-cell lung cancer cell line, GRP1-27 was cleaved as expected from the endogenous prohormone at a pair of basic amino acids (29 and 30) and alpha-amidated at its C-terminal methionine
GO:0035176 social behavior	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Downstream organismal behavioral phenotype transferred from mouse Grp; retain as non-core. Reason: Modulation of social behavior is a downstream organismal consequence of central GRP-GRPR neurotransmission rather than the direct molecular function of the peptide ligand.
GO:0036343 psychomotor behavior	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Downstream behavioral phenotype transferred from mouse Grp; retain as non-core. Reason: Psychomotor behavioral effects are downstream systems-level outcomes of central GRPR activation.
GO:0043005 neuron projection	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Plausible cellular localization for a neuropeptide transported along axons and dendrites; retain as non-core relative to secretory granule lumen and extracellular region. Reason: GRP is trafficked in peptidergic neuron projections prior to release into the extracellular space.
GO:0043005 neuron projection	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Orthology transfer of neuron projection localization from mouse Grp; retain as non-core. Reason: Consistent with axonal and dendritic trafficking of peptidergic vesicles containing GRP.
GO:0043207 response to external biotic stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Broad downstream contextual term transferred from mouse Grp; retain as non-core. Reason: Reflects downstream sensory or neuroimmune responses mediated by GRP release rather than the core ligand-receptor signaling mechanism.
GO:0043303 mast cell degranulation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Downstream neuroimmune effector process transferred from mouse Grp; retain as non-core. Reason: Peptidergic GRP release can stimulate mast cell degranulation in peripheral tissues as a downstream effector outcome of receptor activation.
GO:0043303 mast cell degranulation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Orthology transfer of mast cell degranulation from mouse Grp; retain as non-core. Reason: Downstream physiological effect of peripheral GRP signaling.
GO:0051970 negative regulation of transmission of nerve impulse	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Downstream neuromodulatory phenotype transferred from rat Grp; retain as non-core. Reason: Modulation of synaptic transmission is a circuit-level consequence of GRPR activation in specific neural pathways.
GO:0090277 positive regulation of peptide hormone secretion	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Well-established physiological role of GRP in stimulating gastrin and other gastrointestinal peptide hormones; retain as non-core physiological outcome. Reason: Stimulation of gastrin and other GI hormone secretion is the eponymous downstream endocrine outcome of GRPR activation on G cells and enteroendocrine cells.
GO:1900738 positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway	IEA GO_REF:0000107	MODIFY	Summary: GRP is the obligate initiating agonist of the GRPR-Gq/11-phospholipase C-beta pathway (a direct participant rather than an external regulator); modify to phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200). Reason: GRP directly binds and activates GRPR, a Gq/11-coupled GPCR that stimulates phospholipase C-beta activity. Because the endogenous peptide ligand is an integral initiating component of the signaling pathway rather than an external modulator, GO:0007200 (phospholipase C-activating G protein-coupled receptor signaling pathway) is more accurate than the regulation term GO:1900738. Proposed replacements: phospholipase C-activating G protein-coupled receptor signaling pathway Supporting Evidence: Reactome:R-HSA-379048 G alpha q protein (or Gq/11) consists of four family members (G-alpha 11, -alpha 14, -alpha 15 and -alpha q). It activates phospholipase C (PLC) (Dowal L et al, 2006).
GO:1900738 positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway	ISS GO_REF:0000024	MODIFY	Summary: Orthology transfer of PLC-activating GPCR pathway regulation; modify to direct pathway participation in GO:0007200 (phospholipase C-activating G protein-coupled receptor signaling pathway). Reason: GRP is the direct initiating agonist of Gq/11-coupled GRPR signaling rather than an external regulator of the pathway; replace GO:1900738 with the process term GO:0007200 (phospholipase C-activating G protein-coupled receptor signaling pathway). Proposed replacements: phospholipase C-activating G protein-coupled receptor signaling pathway Supporting Evidence: Reactome:R-HSA-379048 G alpha q protein (or Gq/11) consists of four family members (G-alpha 11, -alpha 14, -alpha 15 and -alpha q). It activates phospholipase C (PLC) (Dowal L et al, 2006).
GO:1903942 positive regulation of respiratory gaseous exchange	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Downstream physiological role of central bombesin-like peptide neurons in sighing and breathing control; retain as non-core. Reason: GRP and NMB released by medullary peptidergic circuit neurons stimulate pre-Botzinger complex neurons to regulate sighing and respiratory exchange, a downstream physiological circuit role.
GO:1903942 positive regulation of respiratory gaseous exchange	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Orthology transfer of respiratory gaseous exchange regulation from mouse Grp; retain as non-core. Reason: Downstream physiological outcome of brainstem GRPR activation.
GO:2000987 positive regulation of behavioral fear response	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Downstream behavioral phenotype from PTN002704045 (GRP subfamily); retain as non-core. Reason: Regulation of learned fear behavior is a downstream systems-level function of amygdalar and cortical GRP-GRPR circuits rather than the direct biochemical activity of the peptide.
GO:2000987 positive regulation of behavioral fear response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Compara transfer of behavioral fear response regulation from mouse Grp; retain as non-core. Reason: Downstream behavioral phenotype mediated by central GRPR signaling.
GO:2000987 positive regulation of behavioral fear response	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Orthology transfer of behavioral fear response regulation from mouse Grp; retain as non-core. Reason: Downstream behavioral phenotype mediated by central GRPR signaling.
GO:0031989 bombesin receptor signaling pathway	IC Reactome:R-HSA-375384	NEW	Summary: Propose NEW annotation for bombesin receptor signaling pathway (GO:0031989); GRP is the canonical mammalian bombesin-like peptide ligand that activates GRPR to initiate this pathway. Reason: In human GOA, GO:0031989 (bombesin receptor signaling pathway) is annotated on the receptors GRPR, NMBR, and BRS3, but missing on the endogenous peptide ligands GRP and NMB (a Category A receptor-only pathway gap). Mature GRP(1-27) and neuromedin C (GRP-10) directly bind and activate GRPR to initiate the bombesin receptor signaling pathway. Supporting Evidence: Reactome:R-HSA-375384 Bombesin-like receptors are widely distributed in the CNS as well as in the GI tract where they modulate smooth-muscle contraction, exocrine and endocrine processes, metabolism, and behaviour through the binding of bombesin-like peptides. They include gastrin-releasing peptide receptor (GRP-R), neuromedin B receptor (NMB-R) (Corjay MH et al, 1991) and bombesin-like receptor-3 (BRS-3) (Fathi Z et al, 1993).

Gene Description

Existing Annotations Review

Core Functions

Secreted bombesin-like neuropeptide hormone that binds and activates the Gq/11-coupled gastrin-releasing peptide receptor (GRPR) on target neuroendocrine, smooth muscle, and neuronal cells to initiate the bombesin receptor signaling pathway and stimulate phospholipase C-beta signaling.

References

Suggested Questions for Experts

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Notes

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