{"gene":"NMB","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1995,"finding":"NMB (GPNMB) encodes a putative transmembrane glycoprotein with highest homology to the precursor of pMEL17; transfection of partial NMB cDNA into a highly metastatic melanoma cell line reduced subcutaneous tumor growth and metastatic potential in nude mice, establishing a role in suppressing metastasis.","method":"cDNA cloning, sequence analysis, transfection into BLM melanoma cells, in vivo xenograft assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function/gain-of-function with specific in vivo phenotypic readout, single lab","pmids":["7814155"],"is_preprint":false},{"year":2002,"finding":"GPNMB is a highly glycosylated type I transmembrane protein that localizes to vesicular, endosomal-like structures via a conserved di-leucine-based endosomal/melanosomal-sorting signal (ExxPLL) in its cytoplasmic domain, as shown in COS7 and HEK293 cells using EGFP-tagged GPNMB.","method":"EGFP fusion protein transfection, live-cell fluorescence imaging, sequence motif analysis","journal":"Brain research. Gene expression patterns","confidence":"Medium","confidence_rationale":"Tier 3 — direct subcellular localization experiment tied to sorting signal identification, single lab","pmids":["12638126"],"is_preprint":false},{"year":2010,"finding":"DC-HIL/GPNMB expressed on melanoma cells attenuates T-cell activation by binding to syndecan-4 (SD-4) on activated T cells; siRNA knockdown of DC-HIL/Gpnmb in B16F10 cells markedly reduced in vivo tumor growth in immunocompetent but not immunodeficient mice, demonstrating immune evasion via the DC-HIL/SD-4 inhibitory pathway.","method":"siRNA knockdown, in vivo syngeneic tumor models (immunocompetent vs. immunodeficient mice), in vitro T-cell activation assays, SD-4 blocking experiments","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional validation with multiple orthogonal methods (KD, in vivo immunocompetent vs immunodeficient comparison, receptor blocking), single lab but strong evidence","pmids":["20570888"],"is_preprint":false},{"year":2007,"finding":"GPNMB (HGFIN/NMB) expression is regulated by p53 through multiple binding sites in the 5' flanking region; ectopic overexpression reduced breast cancer cell growth and migration, while p53 overexpression increased HGFIN reporter gene activity, placing GPNMB downstream of p53 as a tumor suppressor.","method":"siRNA knockdown, ectopic overexpression, reporter gene assays (transient transfection), RT-PCR, immunoblotting, matrigel invasion assay","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in single lab establishing p53-GPNMB regulatory axis","pmids":["17845721"],"is_preprint":false},{"year":2012,"finding":"GPNMB overexpression in PC-3 prostate carcinoma cells attenuated cell proliferation and invasion in vitro and in vivo; androgen treatment downregulated GPNMB protein in AR-expressing cells; GPNMB overexpression induced expression of Ndrg1 and maspin, accounting for its anti-proliferative and anti-invasive function.","method":"Ectopic overexpression, xenograft model, 3H-thymidine incorporation, matrigel invasion, soft agar cloning, RT-PCR, immunoblotting, transient gene expression assays","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays with mechanistic follow-up (Ndrg1/maspin induction), single lab","pmids":["22290289"],"is_preprint":false},{"year":2018,"finding":"GPNMB is exposed on the surface of dormant breast cancer cells in 3D sphere culture and, via its hemITAM motif (tyrosine residue required for activity), induces cancer stem cell properties including high sphere-forming frequency and expression of CSC and EMT-TF genes; a tumorigenic mutant (YF) lacking hemITAM activity failed to induce these properties.","method":"3D sphere culture, FACS-based cell surface isolation, sphere-forming assay, gene expression analysis, mutagenesis (YF mutant), breast tumor transplant model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of functional domain combined with multiple orthogonal assays (3D culture, FACS isolation, in vivo transplant), single lab with strong internal controls","pmids":["30224376"],"is_preprint":false},{"year":2019,"finding":"The kringle-like domain (KLD) in the extracellular domain of GPNMB is required for its tumorigenic potential; GPNMB(ΔKLD) deletion mutant lost sphere and tumor formation activity as well as cell migration promoting activity, despite retaining normal subcellular localization, Src-induced tyrosine phosphorylation, and homo-oligomerization.","method":"Deletion mutagenesis, sphere formation assay, tumor formation assay, cell migration assay, subcellular localization analysis, immunoblotting","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 1-2 — domain deletion mutagenesis with multiple functional readouts, single lab","pmids":["31127873"],"is_preprint":false},{"year":2020,"finding":"Macrophage-derived soluble GPNMB signals through the CD44 receptor on cancer cells to activate IL-33 expression and its receptor IL-1RL1, driving cancer stem cell self-renewal and metastasis; recombinant IL-33 binding to IL-1RL1 was sufficient to induce tumor spheroid formation with CSC features.","method":"Mouse tumor models (Gpnmb-mutant DBA/2J mice), spheroid formation assay, receptor blocking (CD44), recombinant protein treatment, in vivo metastasis assay","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic mouse model combined with receptor-specific functional rescue and recombinant ligand reconstitution, multiple orthogonal approaches","pmids":["32728200"],"is_preprint":false},{"year":2021,"finding":"NMB (neuromedin B) signaling through the NMB receptor (NMBR) activates the ERK1/2 and NF-κB/p65 signaling pathways, promoting cervical cancer cell proliferation and TNF-α expression; pharmacological inhibition of NMBR with PD168368 abrogated proliferation and promoted apoptosis.","method":"Knockdown/inhibition (PD168368), Western blotting for pathway activation, proliferation and apoptosis assays","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 — pathway activation demonstrated with both genetic and pharmacological inhibition, single lab","pmids":["36095918"],"is_preprint":false},{"year":2021,"finding":"BNP facilitates NMB-encoded histaminergic itch via a NPRC-NMBR cross-signaling mechanism in mice: NPRC expression in dorsal horn overlaps with NMBR; BNP significantly facilitates scratching mediated by NMB but not GRP, and BNP evokes Ca2+ responses in NMBR/NPRC co-expressing cells via Gq-coupled PLCβ-Ca2+ signaling.","method":"Knockout mouse behavioral studies, calcium imaging in HEK293 cells co-expressing NMBR/NPRC, intrathecal injections, itch scratch behavioral assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout combined with cell-based reconstitution and receptor-specific pharmacology, multiple orthogonal methods","pmids":["34919054"],"is_preprint":false},{"year":2025,"finding":"GPNMB mediates bidirectional GSC-TAM communication in glioblastoma: TAM-secreted GPNMB interacts with CD44 on glioblastoma stem cells to promote glycolytic metabolism and self-renewal via activating the PYK2/RSK2 signaling axis; disrupting this interaction suppressed tumor progression in mouse GBM models.","method":"Co-culture experiments, Co-IP, in vivo GBM mouse models, signaling pathway analysis (PYK2/RSK2), GPNMB-CD44 interaction assays","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — receptor-ligand interaction (CD44) with downstream signaling cascade identified and in vivo validation, single lab","pmids":["40626360"],"is_preprint":false},{"year":2025,"finding":"NMB protein stability in colorectal cancer is regulated through USP21-dependent deubiquitination, which leads to subsequent activation of the NF-κB signaling cascade and tumor progression.","method":"Co-immunoprecipitation, GSEA, Western blot validation, in vitro functional assays (proliferation, migration, invasion)","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP identifying USP21 as deubiquitinase plus pathway validation, single lab","pmids":["40486508"],"is_preprint":false},{"year":2025,"finding":"In colorectal cancer with liver metastases, NMB secreted by NMB+CXCL13+CD4+ T cells activates NPSR1 on malignant cells, triggering Wnt signaling and EMT to enhance cellular malignancy and invasion; pharmacological inhibition of NPSR1 with SHA68 combined with anti-PD1 showed antitumor effects in mouse CRC metastasis models.","method":"Single-cell RNA sequencing, experimental mouse models, NPSR1 inhibitor (SHA68), anti-PD1 combination treatment, functional in vitro assays","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 — scRNA-seq discovery validated in mouse models with pharmacological intervention and defined downstream signaling, single study","pmids":["42029557"],"is_preprint":false},{"year":2024,"finding":"Nmb activates Cav3.2 (T-type calcium channel) in spinal cord neurons following ischemia-reperfusion injury; NmbR inhibition (PD168368) or Cav3.2-siRNA suppressed IL-1β expression, and miR-214-3p was identified as a direct negative regulator of Nmb by dual-luciferase reporter assay, establishing the miR-214-3p/Nmb/Cav3.2/IL-1β pathway in neuroinflammation.","method":"Western blotting, dual-luciferase reporter gene assay, Cav3.2-siRNA, intrathecal injection of PD168368, immunofluorescence, behavioral (Tarlov scores), rat SCII model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — direct reporter assay validating miR-214-3p/Nmb interaction, multiple pharmacological approaches with functional outcome, single lab","pmids":["38631219"],"is_preprint":false},{"year":1994,"finding":"The NMB receptor (NMB-R) undergoes rapid homologous desensitization upon agonist stimulation mediated by receptor down-regulation and internalization; resensitization is independent of new protein synthesis and is due to receptor recycling from an intracellular compartment, blocked by monensin but not cycloheximide.","method":"Radioligand binding, inositol phosphate assay, [Ca2+]i measurement, monensin/cycloheximide treatment, native C-6 glioblastoma cells and stably transfected Balb/3T3 fibroblasts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted receptor system with pharmacological dissection of recycling vs. synthesis, replicated in native and transfected cells","pmids":["8163469"],"is_preprint":false},{"year":2025,"finding":"GPNMB is secreted by macrophages via lysosomal exocytosis in response to lysosomal stress, and LRRK2 (a Parkinson's disease risk factor) strongly modulates this secretion, establishing GPNMB as a biomarker of lysosomal dysfunction.","method":"Lysosomal stress assays, secretion assays, LRRK2 modulation in macrophages","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, single lab, mechanism of secretion without full reconstitution","pmids":[],"is_preprint":true}],"current_model":"GPNMB/NMB is a type I transmembrane glycoprotein that localizes to endosomal/melanosomal compartments via a cytoplasmic di-leucine sorting signal; its extracellular domain (including the kringle-like domain) mediates interactions with receptors such as CD44 and syndecan-4 to suppress T-cell activation and drive cancer stem cell properties and metastasis, while its intracellular hemITAM motif activates downstream signaling (including PYK2/RSK2 and NF-κB pathways); the soluble ectodomain shed by macrophages acts as a paracrine ligand activating CD44-IL-33-IL-1RL1 and NF-κB axes to promote tumor progression, and its secretion is regulated by lysosomal exocytosis modulated by LRRK2; as a neuropeptide, NMB signals through NMB-R coupled to phospholipase C/Ca2+ and ERK1/2/NF-κB pathways, with receptor desensitization occurring via internalization and recycling."},"narrative":{"teleology":[{"year":1994,"claim":"Establishing how the NMB receptor resets after activation resolved a key question about signal duration: NMB-R desensitizes via internalization and resensitizes by recycling from intracellular stores, independent of new protein synthesis.","evidence":"Radioligand binding, inositol phosphate, and Ca²⁺ assays with monensin/cycloheximide in native C-6 glioblastoma cells and stably transfected Balb/3T3 fibroblasts","pmids":["8163469"],"confidence":"High","gaps":["Molecular identity of kinases and adaptors mediating NMB-R internalization not defined","Recycling kinetics not measured in vivo"]},{"year":2010,"claim":"Determining whether GPNMB/NMB acts in immune evasion revealed that membrane-bound GPNMB on tumor cells directly suppresses T-cell activation through binding syndecan-4, as knockdown eliminated tumor growth only in immunocompetent hosts.","evidence":"siRNA knockdown of Gpnmb in B16F10 cells, syngeneic tumor models in immunocompetent vs. immunodeficient mice, SD-4 blocking experiments","pmids":["20570888"],"confidence":"High","gaps":["Structural basis of GPNMB–syndecan-4 interaction unknown","Whether other co-inhibitory ligands compensate for GPNMB loss not tested"]},{"year":2018,"claim":"Identifying the intracellular signaling requirement for GPNMB's tumorigenic function showed that its hemITAM motif is essential for cancer stem cell induction, as a tyrosine-to-phenylalanine mutant abolished sphere-forming and CSC/EMT gene expression.","evidence":"3D sphere culture, FACS, mutagenesis (YF mutant), breast tumor transplant model","pmids":["30224376"],"confidence":"High","gaps":["Kinase that phosphorylates the hemITAM in vivo not identified","Downstream signaling intermediates between hemITAM and CSC gene expression uncharacterized"]},{"year":2019,"claim":"Defining the extracellular domain requirement showed that the kringle-like domain (KLD) is indispensable for GPNMB's pro-tumorigenic and migratory activities, independent of its subcellular trafficking and homo-oligomerization.","evidence":"KLD deletion mutagenesis with sphere, tumor formation, and migration assays","pmids":["31127873"],"confidence":"Medium","gaps":["Binding partner(s) recognized by the KLD not identified at this point","Whether KLD mediates receptor engagement or acts structurally unknown"]},{"year":2020,"claim":"Identifying CD44 as the receptor for soluble GPNMB shed by macrophages resolved how paracrine GPNMB promotes metastasis: macrophage-derived GPNMB activates IL-33/IL-1RL1 signaling in cancer cells to drive CSC self-renewal.","evidence":"Gpnmb-mutant DBA/2J mice, CD44 blocking, recombinant IL-33 rescue, in vivo metastasis assay","pmids":["32728200"],"confidence":"High","gaps":["Protease responsible for GPNMB ectodomain shedding not defined","Whether IL-33/IL-1RL1 axis is active in all GPNMB-driven tumor types untested"]},{"year":2021,"claim":"Demonstrating NMB's role in itch neurotransmission showed that BNP facilitates NMB-mediated histaminergic itch through NPRC-NMBR cross-signaling via Gq-coupled PLCβ-Ca²⁺ in spinal cord neurons.","evidence":"Knockout mouse behavioral assays, calcium imaging in NMBR/NPRC co-expressing HEK293 cells, intrathecal injections","pmids":["34919054"],"confidence":"High","gaps":["Whether NPRC-NMBR cross-talk occurs in human spinal cord not verified","Downstream transcriptional consequences of this itch circuit not mapped"]},{"year":2021,"claim":"Defining NMB-NMBR signaling in cancer proliferation showed that NMBR engagement activates ERK1/2 and NF-κB/p65 in cervical cancer cells, promoting proliferation and TNF-α expression, reversible by the NMBR antagonist PD168368.","evidence":"Pharmacological inhibition (PD168368), Western blot pathway analysis, proliferation and apoptosis assays","pmids":["36095918"],"confidence":"Medium","gaps":["Whether NMB acts as autocrine or paracrine ligand in cervical cancer not resolved","In vivo therapeutic efficacy of NMBR blockade not tested"]},{"year":2024,"claim":"Linking NMB to neuroinflammation in spinal cord ischemia-reperfusion injury established the miR-214-3p → NMB → Cav3.2 → IL-1β axis, with miR-214-3p directly repressing NMB and NMB activating T-type calcium channels to drive IL-1β.","evidence":"Dual-luciferase reporter assay, Cav3.2-siRNA, intrathecal PD168368, rat spinal cord ischemia-reperfusion model","pmids":["38631219"],"confidence":"Medium","gaps":["Whether Cav3.2 activation by NMB is direct or mediated through intermediate effectors unknown","Relevance of this pathway in human spinal cord injury not demonstrated"]},{"year":2025,"claim":"Identifying GPNMB–CD44 signaling through PYK2/RSK2 in glioblastoma defined how tumor-associated macrophage-secreted GPNMB promotes glioblastoma stem cell glycolytic metabolism and self-renewal.","evidence":"Co-culture, Co-IP, in vivo GBM mouse models, PYK2/RSK2 signaling analysis","pmids":["40626360"],"confidence":"Medium","gaps":["Whether PYK2/RSK2 and IL-33/IL-1RL1 represent parallel or sequential arms of CD44 signaling unresolved","How GPNMB promotes glycolytic reprogramming at the metabolic enzyme level not mapped"]},{"year":2025,"claim":"Demonstrating USP21-dependent deubiquitination of NMB protein in colorectal cancer revealed a post-translational mechanism stabilizing NMB to activate NF-κB-driven tumor progression.","evidence":"Co-immunoprecipitation, Western blot, proliferation/migration/invasion assays in CRC cells","pmids":["40486508"],"confidence":"Medium","gaps":["Ubiquitin chain linkage type on NMB not characterized","E3 ligase targeting NMB for degradation not identified"]},{"year":2025,"claim":"Identifying NMB as a paracrine signal from CD4⁺ T cells that activates NPSR1 on colorectal cancer cells to trigger Wnt/EMT expanded the receptor repertoire of NMB beyond NMBR and linked it to liver metastasis.","evidence":"Single-cell RNA-seq, SHA68 (NPSR1 inhibitor) + anti-PD1 in mouse CRC metastasis models","pmids":["42029557"],"confidence":"Medium","gaps":["NMB–NPSR1 binding affinity and specificity not biochemically validated","Whether NMB–NPSR1 interaction is direct or involves co-receptors unknown"]},{"year":null,"claim":"A unified structural and signaling model integrating NMB's engagement of NMBR, NPSR1, and the GPNMB ectodomain's engagement of CD44/syndecan-4 — including the relative contributions of autocrine versus paracrine signaling — remains to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of NMB–receptor complexes available","Tissue-specific proteolytic processing and post-translational regulation of NMB are incompletely defined","Quantitative in vivo contribution of NMB versus GRP in overlapping receptor systems not delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[7,8,9,10,12]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8,9,12]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[7,10,12]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,8,9,10,12,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,7,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,10,11,12]}],"complexes":[],"partners":["NMBR","NPSR1","CD44","SDC4","USP21","NPRC"],"other_free_text":[]},"mechanistic_narrative":"NMB encodes neuromedin B, a neuropeptide that signals through G-protein-coupled receptors (NMBR, NPSR1) to activate phospholipase C/Ca²⁺, ERK1/2, NF-κB, and Wnt pathways, functioning in itch sensation, neuroinflammation, and cancer cell proliferation [PMID:34919054, PMID:36095918, PMID:42029557]. NMB-R undergoes rapid agonist-induced internalization and recycling-dependent resensitization, providing a mechanism for signal attenuation [PMID:8163469]. In spinal cord neurons, NMB activates Cav3.2 T-type calcium channels to drive IL-1β expression and neuroinflammation, and NMB itself is negatively regulated by miR-214-3p and stabilized by USP21-dependent deubiquitination [PMID:38631219, PMID:40486508]. In colorectal cancer, NMB secreted by CD4⁺ T cells activates NPSR1 on malignant cells to trigger Wnt/EMT-driven invasion, which can be antagonized pharmacologically [PMID:42029557]."},"prefetch_data":{"uniprot":{"accession":"P08949","full_name":"Neuromedin-B","aliases":[],"length_aa":121,"mass_kda":13.3,"function":"Stimulates smooth muscle contraction (By similarity). Induces sighing by acting directly on the pre-Botzinger complex, a cluster of several thousand neurons in the ventrolateral medulla responsible for inspiration during respiratory activity (By similarity). Contributes to the induction of sneezing following exposure to chemical irritants or allergens which causes release of NMB by nasal sensory neurons and activation of NMBR-expressing neurons in the sneeze-evoking region of the brainstem (By similarity). These in turn activate neurons of the caudal ventral respiratory group, giving rise to the sneezing response (By similarity). Contributes to induction of acute itch, possibly through activation of the NMBR receptor on dorsal root ganglion neurons (By similarity). Increases expression of NMBR and steroidogenic mediators STAR, CYP11A1 and HSD3B1 in Leydig cells, induces secretion of testosterone by Leydig cells and also promotes Leydig cell proliferation (By similarity). Plays a role in the innate immune response to influenza A virus infection by enhancing interferon alpha expression and reducing expression of IL6 (PubMed:31601264). Plays a role in CSF1-induced proliferation of osteoclast precursors by contributing to the positive regulation of the expression of the CSF1 receptor CSF1R (By similarity)","subcellular_location":"Secreted; Cell projection, neuron projection","url":"https://www.uniprot.org/uniprotkb/P08949/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NMB","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NMB","total_profiled":1310},"omim":[{"mim_id":"617920","title":"AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 3; PLCA3","url":"https://www.omim.org/entry/617920"},{"mim_id":"604444","title":"BMP AND ACTIVIN MEMBRANE-BOUND INHIBITOR; BAMBI","url":"https://www.omim.org/entry/604444"},{"mim_id":"604368","title":"GLYCOPROTEIN NMB; GPNMB","url":"https://www.omim.org/entry/604368"},{"mim_id":"600185","title":"BRCA2 DNA REPAIR-ASSOCIATED PROTEIN; BRCA2","url":"https://www.omim.org/entry/600185"},{"mim_id":"173870","title":"POLY(ADP-RIBOSE) POLYMERASE 1; PARP1","url":"https://www.omim.org/entry/173870"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Focal adhesion sites","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adipose tissue","ntpm":75.6}],"url":"https://www.proteinatlas.org/search/NMB"},"hgnc":{"alias_symbol":["MGC2277","MGC3936","MGC17211"],"prev_symbol":[]},"alphafold":{"accession":"P08949","domains":[{"cath_id":"-","chopping":"7-121","consensus_level":"medium","plddt":68.655,"start":7,"end":121}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08949","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08949-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08949-F1-predicted_aligned_error_v6.png","plddt_mean":67.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NMB","jax_strain_url":"https://www.jax.org/strain/search?query=NMB"},"sequence":{"accession":"P08949","fasta_url":"https://rest.uniprot.org/uniprotkb/P08949.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08949/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08949"}},"corpus_meta":[{"pmid":"7814155","id":"PMC_7814155","title":"nmb, a novel gene, is expressed in low-metastatic human melanoma cell lines and xenografts.","date":"1995","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/7814155","citation_count":232,"is_preprint":false},{"pmid":"25847941","id":"PMC_25847941","title":"EMERGE: A Randomized Phase II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB-Expressing Breast Cancer.","date":"2015","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25847941","citation_count":146,"is_preprint":false},{"pmid":"30340518","id":"PMC_30340518","title":"Glycoprotein NMB: a novel Alzheimer's disease associated marker expressed in a subset of activated microglia.","date":"2018","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/30340518","citation_count":123,"is_preprint":false},{"pmid":"2109181","id":"PMC_2109181","title":"Immunochemical characterization of multiple forms of cytochrome P-450 in rabbit nasal microsomes and evidence for tissue-specific expression of P-450s NMa and NMb.","date":"1990","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/2109181","citation_count":109,"is_preprint":false},{"pmid":"32728200","id":"PMC_32728200","title":"The soluble glycoprotein NMB (GPNMB) produced by macrophages induces cancer stemness and metastasis via CD44 and IL-33.","date":"2020","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32728200","citation_count":105,"is_preprint":false},{"pmid":"20570888","id":"PMC_20570888","title":"DC-HIL/glycoprotein Nmb promotes growth of melanoma in mice by inhibiting the activation of tumor-reactive T cells.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20570888","citation_count":67,"is_preprint":false},{"pmid":"30690710","id":"PMC_30690710","title":"A phase 2 study of glembatumumab vedotin, an antibody-drug conjugate targeting glycoprotein NMB, in patients with advanced melanoma.","date":"2019","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30690710","citation_count":54,"is_preprint":false},{"pmid":"26305408","id":"PMC_26305408","title":"Targeting Glycoprotein NMB With Antibody-Drug Conjugate, Glembatumumab Vedotin, for the Treatment of Osteosarcoma.","date":"2015","source":"Pediatric blood & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26305408","citation_count":46,"is_preprint":false},{"pmid":"30224376","id":"PMC_30224376","title":"Glycoprotein nmb Is Exposed on the Surface of Dormant Breast Cancer Cells and Induces Stem Cell-like Properties.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30224376","citation_count":46,"is_preprint":false},{"pmid":"16909223","id":"PMC_16909223","title":"Selective in vitro targeting of GRP and NMB receptors in human tumours with the new bombesin tracer 177Lu-AMBA.","date":"2006","source":"European journal of nuclear 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via a conserved di-leucine-based endosomal/melanosomal-sorting signal (ExxPLL) in its cytoplasmic domain, as shown in COS7 and HEK293 cells using EGFP-tagged GPNMB.\",\n      \"method\": \"EGFP fusion protein transfection, live-cell fluorescence imaging, sequence motif analysis\",\n      \"journal\": \"Brain research. Gene expression patterns\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct subcellular localization experiment tied to sorting signal identification, single lab\",\n      \"pmids\": [\"12638126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DC-HIL/GPNMB expressed on melanoma cells attenuates T-cell activation by binding to syndecan-4 (SD-4) on activated T cells; siRNA knockdown of DC-HIL/Gpnmb in B16F10 cells markedly reduced in vivo tumor growth in immunocompetent but not immunodeficient mice, demonstrating immune evasion via the DC-HIL/SD-4 inhibitory pathway.\",\n      \"method\": \"siRNA knockdown, in vivo syngeneic tumor models (immunocompetent vs. immunodeficient mice), in vitro T-cell activation assays, SD-4 blocking experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional validation with multiple orthogonal methods (KD, in vivo immunocompetent vs immunodeficient comparison, receptor blocking), single lab but strong evidence\",\n      \"pmids\": [\"20570888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GPNMB (HGFIN/NMB) expression is regulated by p53 through multiple binding sites in the 5' flanking region; ectopic overexpression reduced breast cancer cell growth and migration, while p53 overexpression increased HGFIN reporter gene activity, placing GPNMB downstream of p53 as a tumor suppressor.\",\n      \"method\": \"siRNA knockdown, ectopic overexpression, reporter gene assays (transient transfection), RT-PCR, immunoblotting, matrigel invasion assay\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in single lab establishing p53-GPNMB regulatory axis\",\n      \"pmids\": [\"17845721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GPNMB overexpression in PC-3 prostate carcinoma cells attenuated cell proliferation and invasion in vitro and in vivo; androgen treatment downregulated GPNMB protein in AR-expressing cells; GPNMB overexpression induced expression of Ndrg1 and maspin, accounting for its anti-proliferative and anti-invasive function.\",\n      \"method\": \"Ectopic overexpression, xenograft model, 3H-thymidine incorporation, matrigel invasion, soft agar cloning, RT-PCR, immunoblotting, transient gene expression assays\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with mechanistic follow-up (Ndrg1/maspin induction), single lab\",\n      \"pmids\": [\"22290289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GPNMB is exposed on the surface of dormant breast cancer cells in 3D sphere culture and, via its hemITAM motif (tyrosine residue required for activity), induces cancer stem cell properties including high sphere-forming frequency and expression of CSC and EMT-TF genes; a tumorigenic mutant (YF) lacking hemITAM activity failed to induce these properties.\",\n      \"method\": \"3D sphere culture, FACS-based cell surface isolation, sphere-forming assay, gene expression analysis, mutagenesis (YF mutant), breast tumor transplant model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of functional domain combined with multiple orthogonal assays (3D culture, FACS isolation, in vivo transplant), single lab with strong internal controls\",\n      \"pmids\": [\"30224376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The kringle-like domain (KLD) in the extracellular domain of GPNMB is required for its tumorigenic potential; GPNMB(ΔKLD) deletion mutant lost sphere and tumor formation activity as well as cell migration promoting activity, despite retaining normal subcellular localization, Src-induced tyrosine phosphorylation, and homo-oligomerization.\",\n      \"method\": \"Deletion mutagenesis, sphere formation assay, tumor formation assay, cell migration assay, subcellular localization analysis, immunoblotting\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — domain deletion mutagenesis with multiple functional readouts, single lab\",\n      \"pmids\": [\"31127873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Macrophage-derived soluble GPNMB signals through the CD44 receptor on cancer cells to activate IL-33 expression and its receptor IL-1RL1, driving cancer stem cell self-renewal and metastasis; recombinant IL-33 binding to IL-1RL1 was sufficient to induce tumor spheroid formation with CSC features.\",\n      \"method\": \"Mouse tumor models (Gpnmb-mutant DBA/2J mice), spheroid formation assay, receptor blocking (CD44), recombinant protein treatment, in vivo metastasis assay\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mouse model combined with receptor-specific functional rescue and recombinant ligand reconstitution, multiple orthogonal approaches\",\n      \"pmids\": [\"32728200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NMB (neuromedin B) signaling through the NMB receptor (NMBR) activates the ERK1/2 and NF-κB/p65 signaling pathways, promoting cervical cancer cell proliferation and TNF-α expression; pharmacological inhibition of NMBR with PD168368 abrogated proliferation and promoted apoptosis.\",\n      \"method\": \"Knockdown/inhibition (PD168368), Western blotting for pathway activation, proliferation and apoptosis assays\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway activation demonstrated with both genetic and pharmacological inhibition, single lab\",\n      \"pmids\": [\"36095918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BNP facilitates NMB-encoded histaminergic itch via a NPRC-NMBR cross-signaling mechanism in mice: NPRC expression in dorsal horn overlaps with NMBR; BNP significantly facilitates scratching mediated by NMB but not GRP, and BNP evokes Ca2+ responses in NMBR/NPRC co-expressing cells via Gq-coupled PLCβ-Ca2+ signaling.\",\n      \"method\": \"Knockout mouse behavioral studies, calcium imaging in HEK293 cells co-expressing NMBR/NPRC, intrathecal injections, itch scratch behavioral assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout combined with cell-based reconstitution and receptor-specific pharmacology, multiple orthogonal methods\",\n      \"pmids\": [\"34919054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPNMB mediates bidirectional GSC-TAM communication in glioblastoma: TAM-secreted GPNMB interacts with CD44 on glioblastoma stem cells to promote glycolytic metabolism and self-renewal via activating the PYK2/RSK2 signaling axis; disrupting this interaction suppressed tumor progression in mouse GBM models.\",\n      \"method\": \"Co-culture experiments, Co-IP, in vivo GBM mouse models, signaling pathway analysis (PYK2/RSK2), GPNMB-CD44 interaction assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor-ligand interaction (CD44) with downstream signaling cascade identified and in vivo validation, single lab\",\n      \"pmids\": [\"40626360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NMB protein stability in colorectal cancer is regulated through USP21-dependent deubiquitination, which leads to subsequent activation of the NF-κB signaling cascade and tumor progression.\",\n      \"method\": \"Co-immunoprecipitation, GSEA, Western blot validation, in vitro functional assays (proliferation, migration, invasion)\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying USP21 as deubiquitinase plus pathway validation, single lab\",\n      \"pmids\": [\"40486508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In colorectal cancer with liver metastases, NMB secreted by NMB+CXCL13+CD4+ T cells activates NPSR1 on malignant cells, triggering Wnt signaling and EMT to enhance cellular malignancy and invasion; pharmacological inhibition of NPSR1 with SHA68 combined with anti-PD1 showed antitumor effects in mouse CRC metastasis models.\",\n      \"method\": \"Single-cell RNA sequencing, experimental mouse models, NPSR1 inhibitor (SHA68), anti-PD1 combination treatment, functional in vitro assays\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — scRNA-seq discovery validated in mouse models with pharmacological intervention and defined downstream signaling, single study\",\n      \"pmids\": [\"42029557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nmb activates Cav3.2 (T-type calcium channel) in spinal cord neurons following ischemia-reperfusion injury; NmbR inhibition (PD168368) or Cav3.2-siRNA suppressed IL-1β expression, and miR-214-3p was identified as a direct negative regulator of Nmb by dual-luciferase reporter assay, establishing the miR-214-3p/Nmb/Cav3.2/IL-1β pathway in neuroinflammation.\",\n      \"method\": \"Western blotting, dual-luciferase reporter gene assay, Cav3.2-siRNA, intrathecal injection of PD168368, immunofluorescence, behavioral (Tarlov scores), rat SCII model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct reporter assay validating miR-214-3p/Nmb interaction, multiple pharmacological approaches with functional outcome, single lab\",\n      \"pmids\": [\"38631219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The NMB receptor (NMB-R) undergoes rapid homologous desensitization upon agonist stimulation mediated by receptor down-regulation and internalization; resensitization is independent of new protein synthesis and is due to receptor recycling from an intracellular compartment, blocked by monensin but not cycloheximide.\",\n      \"method\": \"Radioligand binding, inositol phosphate assay, [Ca2+]i measurement, monensin/cycloheximide treatment, native C-6 glioblastoma cells and stably transfected Balb/3T3 fibroblasts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted receptor system with pharmacological dissection of recycling vs. synthesis, replicated in native and transfected cells\",\n      \"pmids\": [\"8163469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPNMB is secreted by macrophages via lysosomal exocytosis in response to lysosomal stress, and LRRK2 (a Parkinson's disease risk factor) strongly modulates this secretion, establishing GPNMB as a biomarker of lysosomal dysfunction.\",\n      \"method\": \"Lysosomal stress assays, secretion assays, LRRK2 modulation in macrophages\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, mechanism of secretion without full reconstitution\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"GPNMB/NMB is a type I transmembrane glycoprotein that localizes to endosomal/melanosomal compartments via a cytoplasmic di-leucine sorting signal; its extracellular domain (including the kringle-like domain) mediates interactions with receptors such as CD44 and syndecan-4 to suppress T-cell activation and drive cancer stem cell properties and metastasis, while its intracellular hemITAM motif activates downstream signaling (including PYK2/RSK2 and NF-κB pathways); the soluble ectodomain shed by macrophages acts as a paracrine ligand activating CD44-IL-33-IL-1RL1 and NF-κB axes to promote tumor progression, and its secretion is regulated by lysosomal exocytosis modulated by LRRK2; as a neuropeptide, NMB signals through NMB-R coupled to phospholipase C/Ca2+ and ERK1/2/NF-κB pathways, with receptor desensitization occurring via internalization and recycling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NMB encodes neuromedin B, a neuropeptide that signals through G-protein-coupled receptors (NMBR, NPSR1) to activate phospholipase C/Ca²⁺, ERK1/2, NF-κB, and Wnt pathways, functioning in itch sensation, neuroinflammation, and cancer cell proliferation [PMID:34919054, PMID:36095918, PMID:42029557]. NMB-R undergoes rapid agonist-induced internalization and recycling-dependent resensitization, providing a mechanism for signal attenuation [PMID:8163469]. In spinal cord neurons, NMB activates Cav3.2 T-type calcium channels to drive IL-1β expression and neuroinflammation, and NMB itself is negatively regulated by miR-214-3p and stabilized by USP21-dependent deubiquitination [PMID:38631219, PMID:40486508]. In colorectal cancer, NMB secreted by CD4⁺ T cells activates NPSR1 on malignant cells to trigger Wnt/EMT-driven invasion, which can be antagonized pharmacologically [PMID:42029557].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing how the NMB receptor resets after activation resolved a key question about signal duration: NMB-R desensitizes via internalization and resensitizes by recycling from intracellular stores, independent of new protein synthesis.\",\n      \"evidence\": \"Radioligand binding, inositol phosphate, and Ca²⁺ assays with monensin/cycloheximide in native C-6 glioblastoma cells and stably transfected Balb/3T3 fibroblasts\",\n      \"pmids\": [\"8163469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of kinases and adaptors mediating NMB-R internalization not defined\", \"Recycling kinetics not measured in vivo\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Determining whether GPNMB/NMB acts in immune evasion revealed that membrane-bound GPNMB on tumor cells directly suppresses T-cell activation through binding syndecan-4, as knockdown eliminated tumor growth only in immunocompetent hosts.\",\n      \"evidence\": \"siRNA knockdown of Gpnmb in B16F10 cells, syngeneic tumor models in immunocompetent vs. immunodeficient mice, SD-4 blocking experiments\",\n      \"pmids\": [\"20570888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GPNMB–syndecan-4 interaction unknown\", \"Whether other co-inhibitory ligands compensate for GPNMB loss not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying the intracellular signaling requirement for GPNMB's tumorigenic function showed that its hemITAM motif is essential for cancer stem cell induction, as a tyrosine-to-phenylalanine mutant abolished sphere-forming and CSC/EMT gene expression.\",\n      \"evidence\": \"3D sphere culture, FACS, mutagenesis (YF mutant), breast tumor transplant model\",\n      \"pmids\": [\"30224376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase that phosphorylates the hemITAM in vivo not identified\", \"Downstream signaling intermediates between hemITAM and CSC gene expression uncharacterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining the extracellular domain requirement showed that the kringle-like domain (KLD) is indispensable for GPNMB's pro-tumorigenic and migratory activities, independent of its subcellular trafficking and homo-oligomerization.\",\n      \"evidence\": \"KLD deletion mutagenesis with sphere, tumor formation, and migration assays\",\n      \"pmids\": [\"31127873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding partner(s) recognized by the KLD not identified at this point\", \"Whether KLD mediates receptor engagement or acts structurally unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying CD44 as the receptor for soluble GPNMB shed by macrophages resolved how paracrine GPNMB promotes metastasis: macrophage-derived GPNMB activates IL-33/IL-1RL1 signaling in cancer cells to drive CSC self-renewal.\",\n      \"evidence\": \"Gpnmb-mutant DBA/2J mice, CD44 blocking, recombinant IL-33 rescue, in vivo metastasis assay\",\n      \"pmids\": [\"32728200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for GPNMB ectodomain shedding not defined\", \"Whether IL-33/IL-1RL1 axis is active in all GPNMB-driven tumor types untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating NMB's role in itch neurotransmission showed that BNP facilitates NMB-mediated histaminergic itch through NPRC-NMBR cross-signaling via Gq-coupled PLCβ-Ca²⁺ in spinal cord neurons.\",\n      \"evidence\": \"Knockout mouse behavioral assays, calcium imaging in NMBR/NPRC co-expressing HEK293 cells, intrathecal injections\",\n      \"pmids\": [\"34919054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NPRC-NMBR cross-talk occurs in human spinal cord not verified\", \"Downstream transcriptional consequences of this itch circuit not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining NMB-NMBR signaling in cancer proliferation showed that NMBR engagement activates ERK1/2 and NF-κB/p65 in cervical cancer cells, promoting proliferation and TNF-α expression, reversible by the NMBR antagonist PD168368.\",\n      \"evidence\": \"Pharmacological inhibition (PD168368), Western blot pathway analysis, proliferation and apoptosis assays\",\n      \"pmids\": [\"36095918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NMB acts as autocrine or paracrine ligand in cervical cancer not resolved\", \"In vivo therapeutic efficacy of NMBR blockade not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking NMB to neuroinflammation in spinal cord ischemia-reperfusion injury established the miR-214-3p → NMB → Cav3.2 → IL-1β axis, with miR-214-3p directly repressing NMB and NMB activating T-type calcium channels to drive IL-1β.\",\n      \"evidence\": \"Dual-luciferase reporter assay, Cav3.2-siRNA, intrathecal PD168368, rat spinal cord ischemia-reperfusion model\",\n      \"pmids\": [\"38631219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Cav3.2 activation by NMB is direct or mediated through intermediate effectors unknown\", \"Relevance of this pathway in human spinal cord injury not demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying GPNMB–CD44 signaling through PYK2/RSK2 in glioblastoma defined how tumor-associated macrophage-secreted GPNMB promotes glioblastoma stem cell glycolytic metabolism and self-renewal.\",\n      \"evidence\": \"Co-culture, Co-IP, in vivo GBM mouse models, PYK2/RSK2 signaling analysis\",\n      \"pmids\": [\"40626360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PYK2/RSK2 and IL-33/IL-1RL1 represent parallel or sequential arms of CD44 signaling unresolved\", \"How GPNMB promotes glycolytic reprogramming at the metabolic enzyme level not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating USP21-dependent deubiquitination of NMB protein in colorectal cancer revealed a post-translational mechanism stabilizing NMB to activate NF-κB-driven tumor progression.\",\n      \"evidence\": \"Co-immunoprecipitation, Western blot, proliferation/migration/invasion assays in CRC cells\",\n      \"pmids\": [\"40486508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain linkage type on NMB not characterized\", \"E3 ligase targeting NMB for degradation not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying NMB as a paracrine signal from CD4⁺ T cells that activates NPSR1 on colorectal cancer cells to trigger Wnt/EMT expanded the receptor repertoire of NMB beyond NMBR and linked it to liver metastasis.\",\n      \"evidence\": \"Single-cell RNA-seq, SHA68 (NPSR1 inhibitor) + anti-PD1 in mouse CRC metastasis models\",\n      \"pmids\": [\"42029557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NMB–NPSR1 binding affinity and specificity not biochemically validated\", \"Whether NMB–NPSR1 interaction is direct or involves co-receptors unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural and signaling model integrating NMB's engagement of NMBR, NPSR1, and the GPNMB ectodomain's engagement of CD44/syndecan-4 — including the relative contributions of autocrine versus paracrine signaling — remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of NMB–receptor complexes available\", \"Tissue-specific proteolytic processing and post-translational regulation of NMB are incompletely defined\", \"Quantitative in vivo contribution of NMB versus GRP in overlapping receptor systems not delineated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [7, 8, 9, 10, 12]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8, 9, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7, 10, 12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 8, 9, 10, 12, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 7, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 10, 11, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NMBR\",\n      \"NPSR1\",\n      \"CD44\",\n      \"SDC4\",\n      \"USP21\",\n      \"NPRC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}