Neuromedin-B (NMB) is a secreted bombesin-like neuropeptide and hormone synthesized as a preprohormone and processed by proteolytic cleavage and C-terminal alpha-amidation into the 32-amino-acid peptide neuromedin B-32 and the amidated decapeptide neuromedin B (NMB-10), the mammalian homolog of amphibian ranatensin. Released into the extracellular space by peptidergic neurons and endocrine cells, NMB binds with high affinity to the Gq/11-coupled neuromedin-B receptor (NMBR) to initiate the bombesin receptor signaling pathway, stimulating phospholipase C activation, intracellular calcium mobilization, smooth muscle contraction, exocrine and endocrine secretion, and sensory reflex circuits including the sneeze and itch pathways.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005179 hormone activity | TAS PMID:2458345 Molecular cloning of cDNAs encoding the human bombesin-like ... | MODIFY | Summary: Correct but general molecular function; refine to the child term neuropeptide hormone activity (GO:0005184) already carried on NMB. Reason: GO:0005179 (hormone activity) is the parent of GO:0005184 (neuropeptide hormone activity). NMB is a secreted bombesin-family neuropeptide hormone, and GO:0005184 is already annotated on NMB via IBA. Proposed replacements: neuropeptide hormone activity Supporting Evidence: PMID:2458345 The amidated decapeptide neuromedin B (NMB) is the mammalian homolog of the amphibian bombesin-like peptide ranatensin. |
| GO:0005184 neuropeptide hormone activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of NMB as a bombesin-family neuropeptide hormone; phylogenetic inference from PTN008565241 is well supported. Reason: PAINT node PTN008565241 (jawed-vertebrate root of PANTHER:PTHR16866) accurately captures the conserved neuropeptide hormone activity shared by GRP and NMB. Supporting Evidence: PMID:2458345 The amidated decapeptide neuromedin B (NMB) is the mammalian homolog of the amphibian bombesin-like peptide ranatensin. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Remove uninformative bare protein binding row from a high-throughput yeast two-hybrid screen reporting interaction with cytosolic E3 ubiquitin ligase BIRC2. Reason: Bare GO:0005515 (protein binding) is uninformative per GO curation policy, and a yeast two-hybrid interaction between the secreted peptide precursor NMB and the cytosolic IAP family E3 ubiquitin ligase BIRC2 (UniProtKB:Q13490) does not reflect NMB's extracellular signaling biology. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Core site of action of mature secreted NMB peptides; phylogenetic inference from PTN008565241 is well supported. Reason: NMB is synthesized with an N-terminal signal peptide (aa 1-24) and secreted into the extracellular space, where mature NMB-32 and NMB-10 bind plasma-membrane NMBR. 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 | IEA GO_REF:0000120 | ACCEPT | Summary: Accurate automated subcellular location mapping for secreted NMB. Reason: UniProtKB-SubCell:SL-0243 (Secreted) and orthology with mouse Nmb correctly place mature NMB in the extracellular region. |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | ACCEPT | Summary: Accurate orthology transfer of extracellular localization from mouse Nmb. Reason: Mature NMB is secreted into the extracellular space across mammals. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-375384 | ACCEPT | Summary: Accurate Reactome pathway location for extracellular NMB binding to NMBR. Reason: Reactome R-HSA-375384 models extracellular NMB 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 NMB in the extracellular ligand-bound GPCR-Gq complex. Reason: Secreted NMB remains bound to the extracellular face of NMBR during Gq/11 activation. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749448 | ACCEPT | Summary: Accurate Reactome location for extracellular NMB during GPCR-Gq recruitment. Reason: Secreted NMB acts in the extracellular region as the ligand in the NMBR:Gq complex. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749452 | ACCEPT | Summary: Accurate Reactome location for extracellular NMB during ligand:GPCR:Gq dissociation. Reason: NMB is localized to the extracellular region throughout the NMBR signaling cycle. |
| GO:0007165 signal transduction | TAS PMID:2458345 Molecular cloning of cDNAs encoding the human bombesin-like ... | MODIFY | Summary: Correct but overly general biological process; 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. NMB specifically initiates the bombesin receptor signaling pathway (GO:0031989) and neuropeptide signaling pathway (GO:0007218) by binding and activating NMBR. 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:0007204 positive regulation of cytosolic calcium ion concentration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Accurate downstream second-messenger response to Gq/11-coupled NMBR activation; retain as non-core downstream effect. Reason: Activation of NMBR by NMB stimulates Gq/11 and phospholipase C-beta, generating IP3 and elevating cytosolic Ca2+ in target cells. |
| GO:0007218 neuropeptide signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process of NMB as a secreted neuropeptide hormone; phylogenetic inference from PTN008565241 is well supported. Reason: PAINT node PTN008565241 (jawed-vertebrate root of PANTHER:PTHR16866) accurately captures the conserved role of bombesin-like peptides in neuropeptide signaling. Because GO:0031989 (bombesin receptor signaling pathway) sits under GO:0007186 rather than under GO:0007218 in the GO hierarchy, GO:0007218 and GO:0031989 are complementary core pathway annotations. Supporting Evidence: PMID:31601264 The peptide neuromedin B (NMB) and its receptor (NMBR) represent a system (NMB/NMBR) of neuromodulation. |
| 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:0007267 cell-cell signaling | TAS PMID:2458345 Molecular cloning of cDNAs encoding the human bombesin-like ... | KEEP AS NON CORE | Summary: Broad intercellular signaling process supported by NMB's paracrine and neurocrine role; retain as non-core alongside the specific receptor pathway terms. Reason: NMB mediates paracrine and synaptic cell-cell communication via NMBR; note that GO:0031989 and GO:0007218 sit under GO:0007165 (signal transduction) rather than directly under GO:0007267 in the GO hierarchy, so GO:0007267 is retained as non-core. |
| GO:0008284 positive regulation of cell population proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream mitogenic effect of NMB-NMBR signaling in target tissues; retain as non-core. Reason: Like GRP, NMB acts as an autocrine/paracrine mitogenic factor in several cell types via NMBR activation, a downstream cellular outcome. |
| GO:0031710 neuromedin B receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Core receptor-specific binding activity of NMB from the NMB subfamily node PTN002704034. Reason: PAINT node PTN002704034 (PANTHER:PTHR16866:SF3, neuromedin-B subfamily) is seeded by rat Nmb (RGD:1562710) and accurately captures the high-affinity binding of mature NMB to NMBR. 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). |
| GO:0031710 neuromedin B receptor binding | IEA GO_REF:0000107 | ACCEPT | Summary: Accurate Compara orthology transfer of neuromedin B receptor binding from rat Nmb. Reason: Human and rodent NMB share an identical mature amidated decapeptide sequence (GNLWATGHFM-NH2) that binds NMBR with high affinity. |
| GO:0032715 negative regulation of interleukin-6 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream immunomodulatory phenotype during influenza A infection transferred from mouse Nmb; retain as non-core. Reason: Exogenous NMB reduces IL-6 expression during influenza A virus infection (PMID:31601264), a downstream contextual immunomodulatory effect of NMBR signaling. Supporting Evidence: PMID:31601264 Additionally, the results showed that exogenous NMB not only enhanced IFN-Ξ± expression but also appeared to inhibit the expression of NP and IL-6 in PR8-infected cells and animals. |
| GO:0032715 negative regulation of interleukin-6 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Orthology transfer of negative regulation of IL-6 production from mouse Nmb; retain as non-core. Reason: Downstream immunomodulatory consequence of NMB-NMBR signaling during viral infection. |
| GO:0032727 positive regulation of interferon-alpha production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream antiviral cytokine response transferred from mouse Nmb; retain as non-core. Reason: Exogenous NMB enhances IFN-alpha expression in influenza A virus-infected cells and mice (PMID:31601264), a downstream contextual immune effect of NMBR activation. Supporting Evidence: PMID:31601264 Additionally, the results showed that exogenous NMB not only enhanced IFN-Ξ± expression but also appeared to inhibit the expression of NP and IL-6 in PR8-infected cells and animals. |
| GO:0032727 positive regulation of interferon-alpha production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Orthology transfer of positive regulation of IFN-alpha production from mouse Nmb; retain as non-core. Reason: Downstream immunomodulatory consequence of NMB-NMBR signaling during viral infection. |
| GO:0043005 neuron projection | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Plausible localization for a neuropeptide trafficked in sensory and central axons; retain as non-core relative to extracellular region. Reason: NMB is transported within peptidergic sensory and central neuron projections prior to synaptic/paracrine release. |
| GO:0043005 neuron projection | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Orthology transfer of neuron projection localization from mouse Nmb; retain as non-core. Reason: Consistent with axonal transport of NMB-containing secretory vesicles in peptidergic neurons. |
| GO:0046887 positive regulation of hormone secretion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Downstream endocrine regulatory role of NMB from subfamily node PTN002704034; retain as non-core. Reason: NMB modulates endocrine hormone secretion in pituitary, gastrointestinal, and gonadal tissues downstream of NMBR activation. |
| GO:0046887 positive regulation of hormone secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Compara transfer of positive regulation of hormone secretion from rat Nmb; retain as non-core. Reason: Downstream endocrine outcome of NMBR signaling. |
| GO:0046888 negative regulation of hormone secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Compara transfer of negative regulation of hormone secretion (such as pituitary TSH suppression) from rat Nmb; retain as non-core. Reason: In the anterior pituitary, NMB acts as a local paracrine inhibitor of thyrotropin (TSH) release via NMBR, a tissue-specific downstream endocrine effect. |
| GO:0050482 arachidonate secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream phospholipase A2/C-coupled lipid release response transferred from rat Nmb; retain as non-core. Reason: Arachidonic acid release is a downstream secondary consequence of Gq/11-coupled NMBR activation and Ca2+ mobilization. |
| GO:0090290 positive regulation of osteoclast proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream cell-type-specific proliferation phenotype transferred from mouse Nmb; retain as non-core. Reason: Regulation of osteoclast precursor proliferation is a tissue-specific downstream effect of NMB-NMBR signaling. |
| GO:0090290 positive regulation of osteoclast proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Orthology transfer of osteoclast proliferation regulation from mouse Nmb; retain as non-core. Reason: Tissue-specific downstream cellular effect of NMBR signaling. |
| GO:0140374 antiviral innate immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream immunomodulatory role during viral infection transferred from mouse Nmb; retain as non-core. Reason: Reflects the downstream effect of NMB-NMBR signaling on IFN-alpha and IL-6 responses during influenza A virus infection (PMID:31601264). Supporting Evidence: PMID:31601264 Additionally, the results showed that exogenous NMB not only enhanced IFN-Ξ± expression but also appeared to inhibit the expression of NP and IL-6 in PR8-infected cells and animals. |
| GO:0140374 antiviral innate immune response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Orthology transfer of antiviral innate immune response from mouse Nmb; retain as non-core. Reason: Downstream immunomodulatory outcome of NMB-NMBR signaling. |
| GO:0160023 sneeze reflex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Downstream sensory reflex circuit role transferred via PAINT; retain as non-core. Note that PTN000370826 places this mouse Nmb-seeded phenotype at the Euteleostomi root of PTHR16866. Reason: NMB released by nasal sensory neurons activates NMBR-expressing brainstem sneeze-evoking region neurons to drive the sneeze reflex, a specialized downstream circuit function. |
| GO:0160023 sneeze reflex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Compara transfer of sneeze reflex from mouse Nmb; retain as non-core physiological circuit role. Reason: Downstream sensory-motor reflex mediated by NMB-NMBR neurotransmission in the brainstem. |
| GO:0160023 sneeze reflex | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Orthology transfer of sneeze reflex from mouse Nmb; retain as non-core physiological circuit role. Reason: Downstream sensory-motor reflex mediated by NMB-NMBR neurotransmission. |
| GO:0160024 Leydig cell proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Downstream cell-type-specific proliferation phenotype; retain as non-core. Reason: Stimulation of Leydig cell proliferation is a tissue-specific downstream outcome of NMB-NMBR signaling. |
| GO:0160025 sensory perception of itch | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream somatosensory circuit role in pruriception transferred from mouse Nmb; retain as non-core. Reason: NMB released from primary pruriceptive dorsal root ganglion neurons activates spinal cord NMBR interneurons to transmit itch sensation, a downstream circuit function. |
| GO:0160025 sensory perception of itch | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Orthology transfer of sensory perception of itch from mouse Nmb; retain as non-core. Reason: Downstream somatosensory circuit function mediated by spinal NMB-NMBR neurotransmission. |
| GO:1903942 positive regulation of respiratory gaseous exchange | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream physiological role of medullary NMB neurons in control of sighing and breathing; retain as non-core. Reason: NMB and GRP released by retrotrapezoid/parafacial neurons activate pre-Botzinger complex NMBR/GRPR neurons to stimulate sighing and respiratory exchange, a downstream 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 Nmb; retain as non-core. Reason: Downstream physiological outcome of brainstem NMB-NMBR signaling. |
| GO:2000845 positive regulation of testosterone secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Downstream gonadal endocrine phenotype; retain as non-core. Reason: Modulation of testosterone secretion is a downstream tissue-specific endocrine effect of NMB-NMBR signaling in the testis. |
| GO:0031989 bombesin receptor signaling pathway | IC Reactome:R-HSA-375384 | NEW | Summary: Propose NEW annotation for bombesin receptor signaling pathway (GO:0031989); NMB is one of the two canonical mammalian bombesin-like peptide ligands and directly activates NMBR to initiate this pathway. Reason: In human GOA, GO:0031989 (bombesin receptor signaling pathway) is annotated on the receptors NMBR, GRPR, and BRS3, whereas NMB carries GO:0031710 (neuromedin B receptor binding) and GO:0007218 (neuropeptide signaling pathway) but lacks GO:0031989 (a Category A receptor-only pathway gap). Mature NMB peptides directly bind and activate NMBR 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). |
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Download this section (compressed HTML)Q: Should PAINT node PTN000370826 (Euteleostomi root of PTHR16866) restrict GO:0160023 (sneeze reflex) to the mammalian NMB subfamily clade (PTN002704034) rather than propagating it across all jawed-vertebrate GRP and NMB paralogs?
Q: Should PAINT add GO:0031989 (bombesin receptor signaling pathway) to PTN008565241 alongside GO:0007218 (neuropeptide signaling pathway)?
Experiment: Compare the receptor-binding kinetics and Gq/11 versus beta-arrestin signaling bias of N-terminally extended neuromedin B-32 (NMB-32) and the decapeptide neuromedin B-10 (NMB-10) at human NMBR and GRPR using BRET biosensor assays.
Hypothesis: Both NMB-32 and NMB-10 potently activate Gq/11 via NMBR, but NMB-32 exhibits slower dissociation kinetics and distinct receptor internalization dynamics due to contacts with the NMBR extracellular vestibule.
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