id: MODULE:bombesin_receptor_signaling title: Bombesin receptor signaling pathway module description: >- The bombesin receptor signaling pathway (GO:0031989) is initiated when the secreted, C-terminally alpha-amidated mammalian bombesin-like neuropeptide hormones gastrin-releasing peptide (GRP, PANTHER:PTHR16866:SF2) and neuromedin B (NMB, PANTHER:PTHR16866:SF3) bind and activate their cognate seven-transmembrane G protein-coupled receptors GRPR (BB2, PANTHER:PTHR45695:SF7) and NMBR (BB1, PANTHER:PTHR45695:SF8) at the plasma membrane of central nervous system neurons, gastrointestinal endocrine/smooth-muscle cells, and anterior pituitary thyrotrophs. Agonist-bound GRPR and NMBR couple primarily to heterotrimeric Gq/11 proteins (exemplified by GNAQ, PANTHER:PTHR10218:SF329) to stimulate phospholipase C-beta (PLCB1, PANTHER:PTHR10336:SF12), generating inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) to mobilize intracellular Ca2+ and regulate gastrin secretion, smooth-muscle contraction, sighing, itch transmission, and circadian/neuroendocrine rhythms. status: DRAFT evidence: - source_id: GO:0031989 title: bombesin receptor signaling pathway statement: >- The module is grounded in the GO biological process term for the bombesin receptor signaling pathway (GO:0031989: the series of molecular signals generated as a consequence of a bombesin receptor binding to its physiological ligand). - source_id: Reactome:R-HSA-375384 title: Bombesin-like receptors bind bombesin homologues supporting_text: >- 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). statement: >- Establishes that mammalian bombesin-like peptides (GRP and NMB) bind and activate GRPR and NMBR to initiate bombesin receptor signaling. - source_id: PMID:3211139 title: Posttranslational processing of endogenous and of baculovirus-expressed human gastrin-releasing peptide precursor. supporting_text: >- 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 statement: >- Demonstrates proteolytic processing and C-terminal alpha-amidation of human pro-GRP to mature bioactive GRP1-27. - source_id: PMID:2458345 title: Molecular cloning of cDNAs encoding the human bombesin-like peptide neuromedin B. Chromosomal localization and comparison to cDNAs encoding its amphibian homolog ranatensin. supporting_text: >- The amidated decapeptide neuromedin B (NMB) is the mammalian homolog of the amphibian bombesin-like peptide ranatensin. cDNAs encoding human neuromedin B and amphibian ranatensin were isolated from human hypothalamic and Rana pipiens skin libraries, respectively. statement: >- Establishes human NMB as a secreted bombesin-like neuropeptide precursor homologous to amphibian ranatensin and GRP. - source_id: PANTHER:PTN008565241 title: PAINT node PTN008565241 for bombesin-like peptides (PTHR16866) statement: >- Local PAINT IBD node in PTHR16866 with propagated terms C:GO:0005576, F:GO:0005184, P:GO:0007218; PAINT date 20260529. notes: >- Curated signaling-pathway module for the bombesin receptor signaling pathway (GO:0031989) built with PANTHER FAMILY/subfamily selectors across the endogenous bombesin-like peptide ligands GRP (PANTHER:PTHR16866:SF2) and NMB (PANTHER:PTHR16866:SF3), their cognate G protein-coupled receptors GRPR (PANTHER:PTHR45695:SF7) and NMBR (PANTHER:PTHR45695:SF8), and downstream Gq/11 alpha (GNAQ, PANTHER:PTHR10218:SF329) and phospholipase C-beta (PLCB1, PANTHER:PTHR10336:SF12) signaling effectors. module: id: bombesin_receptor_signaling label: Bombesin receptor signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: bombesin receptor signaling pathway term: id: GO:0031989 label: bombesin receptor signaling pathway description: >- The series of molecular signals generated as a consequence of a bombesin receptor (GRPR or NMBR) binding to its physiological bombesin-like peptide ligand (GRP or NMB). context: taxa: - preferred_term: Euteleostomi term: id: NCBITaxon:117571 label: Euteleostomi cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol parts: - order: 1 role: bombesin-like peptide ligand-receptor engagement node: id: bombesin_receptor_engagement label: GRP and NMB engagement of bombesin receptors GRPR and NMBR module_type: REGULATORY_STEP description: >- Secreted C-terminally alpha-amidated gastrin-releasing peptide (GRP) and neuromedin B (NMB) bind the orthosteric pockets of their cognate seven-transmembrane bombesin receptors GRPR (BB2) and NMBR (BB1) at the plasma membrane of target neurons and endocrine/smooth-muscle cells. annotons: - id: grp_gastrin_releasing_peptide_ligand label: GRP gastrin-releasing peptide ligand participant: selector_type: FAMILY family: preferred_term: Gastrin-releasing peptide subfamily term: id: PANTHER:PTHR16866:SF2 label: GASTRIN-RELEASING PEPTIDE representative_members: - preferred_term: GRP term: id: UniProtKB:P07492 label: Gastrin-releasing peptide ancestral_nodes: - preferred_term: PAINT node PTN008565241 for bombesin-like peptides term: id: PANTHER:PTN008565241 label: PTN008565241 description: >- Local PAINT IBD node in PTHR16866 with propagated terms C:GO:0005576, F:GO:0005184, P:GO:0007218; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN008565241 in PTHR16866. evidence: - source_id: file:interpro/panther/PTHR16866/PTHR16866-review.yaml title: PTHR16866 PANTHER family review statement: >- PTHR16866 review confirms family-wide GO:0005184 (neuropeptide hormone activity) at PTN008565241 and scopes GO:0031989 (bombesin receptor signaling pathway) to PANTHER:PTHR16866:SF2 (GRP) and SF3 (NMB). function: preferred_term: neuropeptide hormone activity term: id: GO:0005184 label: neuropeptide hormone activity processes: - preferred_term: bombesin receptor signaling pathway term: id: GO:0031989 label: bombesin receptor signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Endogenous mammalian bombesin-like neuropeptide hormone that selectively binds and activates the gastrin-releasing peptide receptor (GRPR / BB2) to initiate bombesin receptor signaling. evidence: - source_id: Reactome:R-HSA-375384 title: Bombesin-like receptors bind bombesin homologues supporting_text: >- 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). statement: >- Establishes GRP as an endogenous bombesin-like peptide agonist of GRPR. - source_id: PMID:3211139 title: Posttranslational processing of endogenous and of baculovirus-expressed human gastrin-releasing peptide precursor. supporting_text: >- 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 statement: >- Establishes proteolytic cleavage and C-terminal alpha-amidation of human GRP. - id: nmb_neuromedin_b_ligand label: NMB neuromedin-B ligand participant: selector_type: FAMILY family: preferred_term: Neuromedin-B subfamily term: id: PANTHER:PTHR16866:SF3 label: NEUROMEDIN-B representative_members: - preferred_term: NMB term: id: UniProtKB:P08949 label: Neuromedin-B ancestral_nodes: - preferred_term: PAINT node PTN008565241 for bombesin-like peptides term: id: PANTHER:PTN008565241 label: PTN008565241 description: >- Local PAINT IBD node in PTHR16866 with propagated terms C:GO:0005576, F:GO:0005184, P:GO:0007218; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN008565241 in PTHR16866. evidence: - source_id: file:interpro/panther/PTHR16866/PTHR16866-review.yaml title: PTHR16866 PANTHER family review statement: >- PTHR16866 review confirms family-wide GO:0005184 (neuropeptide hormone activity) at PTN008565241 and scopes GO:0031989 (bombesin receptor signaling pathway) to PANTHER:PTHR16866:SF2 (GRP) and SF3 (NMB). function: preferred_term: neuropeptide hormone activity term: id: GO:0005184 label: neuropeptide hormone activity processes: - preferred_term: bombesin receptor signaling pathway term: id: GO:0031989 label: bombesin receptor signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Endogenous mammalian ranatensin/bombesin-like neuropeptide hormone that selectively binds and activates the neuromedin-B receptor (NMBR / BB1) to initiate bombesin receptor signaling. evidence: - source_id: Reactome:R-HSA-375384 title: Bombesin-like receptors bind bombesin homologues supporting_text: >- 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). statement: >- Establishes NMB as an endogenous bombesin-like peptide agonist of NMBR. - source_id: PMID:2458345 title: Molecular cloning of cDNAs encoding the human bombesin-like peptide neuromedin B. Chromosomal localization and comparison to cDNAs encoding its amphibian homolog ranatensin. supporting_text: >- The amidated decapeptide neuromedin B (NMB) is the mammalian homolog of the amphibian bombesin-like peptide ranatensin. cDNAs encoding human neuromedin B and amphibian ranatensin were isolated from human hypothalamic and Rana pipiens skin libraries, respectively. statement: >- Establishes human NMB as a secreted bombesin-like neuropeptide precursor. - id: grpr_receptor label: GRPR gastrin-releasing peptide receptor participant: selector_type: FAMILY family: preferred_term: Gastrin-releasing peptide receptor subfamily term: id: PANTHER:PTHR45695:SF7 label: GASTRIN-RELEASING PEPTIDE RECEPTOR representative_members: - preferred_term: GRPR term: id: UniProtKB:P30550 label: Gastrin-releasing peptide receptor (GRP-R) (GRP-preferring bombesin receptor) (BB2) evidence: - source_id: Reactome:R-HSA-375384 title: Bombesin-like receptors bind bombesin homologues supporting_text: >- 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). statement: >- Establishes GRPR as the high-affinity bombesin-like GPCR for GRP. function: preferred_term: bombesin receptor activity term: id: GO:0004946 label: bombesin receptor activity processes: - preferred_term: bombesin receptor signaling pathway term: id: GO:0031989 label: bombesin receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Seven-transmembrane G protein-coupled bombesin receptor (BB2) that binds GRP with high affinity and activates heterotrimeric Gq/11 signaling. evidence: - source_id: Reactome:R-HSA-375384 title: Bombesin-like receptors bind bombesin homologues supporting_text: >- 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). statement: >- Establishes GRPR as a principal mammalian bombesin receptor. - id: nmbr_receptor label: NMBR neuromedin-B receptor participant: selector_type: FAMILY family: preferred_term: Neuromedin-B receptor subfamily term: id: PANTHER:PTHR45695:SF8 label: NEUROMEDIN-B RECEPTOR representative_members: - preferred_term: NMBR term: id: UniProtKB:P28336 label: Neuromedin-B receptor (NMB-R) (Neuromedin-B-preferring bombesin receptor) (BB1) evidence: - source_id: Reactome:R-HSA-375384 title: Bombesin-like receptors bind bombesin homologues supporting_text: >- 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). statement: >- Establishes NMBR as the high-affinity bombesin-like GPCR for NMB. function: preferred_term: bombesin receptor activity term: id: GO:0004946 label: bombesin receptor activity processes: - preferred_term: bombesin receptor signaling pathway term: id: GO:0031989 label: bombesin receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Seven-transmembrane G protein-coupled bombesin receptor (BB1) that binds NMB with high affinity and activates heterotrimeric Gq/11 signaling. evidence: - source_id: Reactome:R-HSA-375384 title: Bombesin-like receptors bind bombesin homologues supporting_text: >- 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). statement: >- Establishes NMBR as a principal mammalian bombesin receptor. - order: 2 role: Gq/11 and phospholipase C-beta effector activation node: id: bombesin_gq_plc_coupling label: Gq/11 and phospholipase C-beta effector activation downstream of GRPR/NMBR module_type: REGULATORY_STEP description: >- Agonist-activated GRPR and NMBR catalyze GDP-to-GTP exchange on heterotrimeric Gq/11 alpha subunits (exemplified by GNAQ), which directly stimulate plasma-membrane phospholipase C-beta (exemplified by PLCB1) to hydrolyze PIP2 into IP3 and DAG. annotons: - id: gnaq_gq_alpha label: GNAQ Gq alpha subunit participant: selector_type: FAMILY family: preferred_term: Guanine nucleotide-binding protein G(q) subunit alpha subfamily term: id: PANTHER:PTHR10218:SF329 label: GUANINE NUCLEOTIDE-BINDING PROTEIN G(Q) SUBUNIT ALPHA representative_members: - preferred_term: GNAQ term: id: UniProtKB:P50148 label: Guanine nucleotide-binding protein G(q) subunit alpha evidence: - source_id: Reactome:R-HSA-375384 title: Bombesin-like receptors bind bombesin homologues statement: >- Bombesin receptors GRPR and NMBR couple to Gq/11 heterotrimeric G proteins. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: bombesin receptor signaling pathway term: id: GO:0031989 label: bombesin receptor signaling pathway - preferred_term: phospholipase C-activating G protein-coupled receptor signaling pathway term: id: GO:0007200 label: phospholipase C-activating G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Heterotrimeric Gq alpha subunit activated by ligand-bound GRPR and NMBR to stimulate phospholipase C-beta. evidence: - source_id: Reactome:R-HSA-375384 title: Bombesin-like receptors bind bombesin homologues statement: >- Demonstrates Gq/11 coupling downstream of bombesin-like receptors. - id: plcb1_phospholipase_c_beta label: PLCB1 phospholipase C-beta-1 effector participant: selector_type: FAMILY family: preferred_term: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 subfamily term: id: PANTHER:PTHR10336:SF12 label: 1-PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE PHOSPHODIESTERASE BETA-1 representative_members: - preferred_term: PLCB1 term: id: UniProtKB:Q9NQ66 label: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 evidence: - source_id: Reactome:R-HSA-375384 title: Bombesin-like receptors bind bombesin homologues statement: >- Gq/11-coupled bombesin receptors activate phospholipase C-beta to mobilize intracellular Ca2+. function: preferred_term: phosphatidylinositol phospholipase C activity term: id: GO:0004435 label: phosphatidylinositol phospholipase C activity processes: - preferred_term: bombesin receptor signaling pathway term: id: GO:0031989 label: bombesin receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Phospholipase C-beta effector activated by GTP-bound GNAQ downstream of GRPR and NMBR to generate IP3 and DAG. evidence: - source_id: Reactome:R-HSA-375384 title: Bombesin-like receptors bind bombesin homologues statement: >- Demonstrates PLC-beta activation in bombesin receptor signaling. connections: - source: bombesin_receptor_engagement target: bombesin_gq_plc_coupling connection_type: CAUSES description: >- Binding of mature alpha-amidated GRP or NMB to GRPR or NMBR stabilizes the active receptor conformation that catalyzes GDP-to-GTP exchange on GNAQ and activates PLCB1.