{"gene":"MON1B","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2010,"finding":"Mon1b (mammalian ortholog of C. elegans SAND-1) forms a complex with Ccz1 that acts as a Rab5 effector (binding GTP-bound Rab5) and promotes progression from the Rab5-positive to the Rab7-positive stage of phagosome maturation; the Mon1-Ccz1 complex (but not either protein alone) can bind Rab7 and influence Rab7 activation.","method":"Genetic epistasis in C. elegans, RNAi knockdown in mammalian cells, co-immunoprecipitation, GTPase-binding assays (GTP-bound vs GDP-bound Rab5/Rab7), phagosome maturation imaging","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, epistasis, loss-of-function with defined cellular phenotype, replicated across two organisms","pmids":["20305638"],"is_preprint":false},{"year":2016,"finding":"Mon1b is recruited from the cytosol to early endosome (EE) membranes by the endocytic adaptor Numb, where it acts as a docking regulator required for homotypic fusion of early endosomes; depletion of either Numb or Mon1b causes clustered but unfused EEs.","method":"Numb-Mon1b co-immunoprecipitation/binding assay, siRNA knockdown of Numb and Mon1b, time-lapse live-cell imaging of EE fusion, rescue experiments with cytosolic vs membrane-attached Numb isoforms","journal":"Cell Research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, live imaging, loss-of-function with defined organelle phenotype, isoform-specific rescue","pmids":["26987402"],"is_preprint":false},{"year":2018,"finding":"Mycobacterial PknG does not interact with Mon1b (or Mon1a), indicating Mon1b is not a direct target of PknG-mediated phagosome maturation blockade; Mon1b's role in phagosome-lysosome fusion is thus independent of the PknG-Rab7l1 axis.","method":"Co-immunoprecipitation/interaction assay testing PknG against Mon1a, Mon1b, and other phagolysosomal factors","journal":"Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP negative result providing pathway placement information","pmids":["30037848"],"is_preprint":false},{"year":2018,"finding":"Knockdown of MON1B in colon cancer cells inhibits cell proliferation, migration, and invasion, accompanied by decreased MMP-2, MMP-9, MTA-1, NF-κB, and CXCR-4 levels and increased TIMP-2 and IκB levels, placing MON1B upstream of the NF-κB/MMP signaling axis in these cells.","method":"siRNA knockdown of MON1B in LoVo cells, CCK-8 proliferation assay, wound-healing migration assay, Transwell invasion assay, RT-qPCR and Western blot for downstream markers","journal":"Medical Science Monitor","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single knockdown approach, no direct biochemical mechanism established","pmids":["30368516"],"is_preprint":false}],"current_model":"MON1B forms a complex with CCZ1 that acts downstream of GTP-bound RAB5 as a RAB5 effector and guanine nucleotide exchange factor (GEF) complex for RAB7, thereby driving phagosome/endosome maturation from the RAB5-positive to the RAB7-positive stage; at early endosomes, MON1B is recruited to the membrane by the adaptor protein Numb to mediate homotypic EE docking and fusion."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing MON1B as a RAB5-to-RAB7 conversion factor resolved how endosomal identity transitions are controlled: the MON1B–CCZ1 complex reads RAB5-GTP on early compartments and activates RAB7 to drive phagosome maturation.","evidence":"Genetic epistasis in C. elegans combined with mammalian RNAi, co-immunoprecipitation, and GTPase-binding assays comparing GTP- versus GDP-locked RAB5/RAB7","pmids":["20305638"],"confidence":"High","gaps":["Structural basis for how the MON1B–CCZ1 complex catalyzes nucleotide exchange on RAB7 was not determined","Whether MON1A and MON1B are functionally redundant or context-specific was not addressed","Membrane recruitment mechanism for the complex independent of Numb was unknown"]},{"year":2016,"claim":"Identifying Numb as the membrane recruiter of MON1B at early endosomes answered how MON1B reaches its site of action and revealed an unexpected role for MON1B in homotypic early-endosome fusion upstream of the RAB5-to-RAB7 switch.","evidence":"Reciprocal co-immunoprecipitation, siRNA knockdown of Numb and MON1B, live-cell imaging of early-endosome fusion, and isoform-specific rescue experiments","pmids":["26987402"],"confidence":"High","gaps":["The binding interface between Numb and MON1B has not been mapped","Whether MON1B's role in EE fusion requires CCZ1 or RAB7 GEF activity was not dissected","Physiological consequences of impaired MON1B-dependent EE fusion in vivo remain uncharacterized"]},{"year":2018,"claim":"Negative interaction data with mycobacterial PknG placed MON1B's phagosome maturation function outside the PknG–RAB7L1 virulence axis, refining the pathway wiring of phagolysosomal biogenesis.","evidence":"Co-immunoprecipitation testing PknG against MON1B and other phagolysosomal factors","pmids":["30037848"],"confidence":"Medium","gaps":["Only a single Co-IP approach was used; orthogonal interaction assays were not reported","Whether other mycobacterial effectors target MON1B remains untested"]},{"year":2018,"claim":"MON1B knockdown in colon cancer cells linked the gene to proliferation and invasion phenotypes, but the biochemical mechanism connecting endosomal trafficking to NF-κB/MMP signaling was not established.","evidence":"siRNA knockdown in LoVo cells with proliferation, migration, and invasion assays plus RT-qPCR/Western blot for downstream markers","pmids":["30368516"],"confidence":"Low","gaps":["Single knockdown approach in one cell line without rescue or specificity controls","No direct biochemical link between MON1B's GEF activity and NF-κB regulation was demonstrated","Not independently replicated"]},{"year":null,"claim":"Key open questions include the structural basis of the MON1B–CCZ1 GEF complex on human RAB7, whether MON1A and MON1B are functionally redundant, and the molecular mechanism linking endosomal MON1B activity to downstream signaling pathways.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of the human MON1B–CCZ1–RAB7 complex exists","Functional redundancy between MON1A and MON1B has not been systematically tested","In vivo physiological roles (development, immunity) of MON1B loss are uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1]}],"complexes":["MON1B–CCZ1"],"partners":["CCZ1","RAB5","RAB7","NUMB"],"other_free_text":[]},"mechanistic_narrative":"MON1B forms a heterodimeric complex with CCZ1 that functions as a RAB5 effector and guanine nucleotide exchange factor (GEF) for RAB7, driving the conversion of RAB5-positive endosomes/phagosomes to RAB7-positive compartments during endosomal and phagosomal maturation [PMID:20305638]. The MON1B–CCZ1 complex selectively binds GTP-loaded RAB5 on membranes and recruits and activates RAB7; neither subunit alone is sufficient for RAB7 binding [PMID:20305638]. At early endosomes, MON1B is recruited from the cytosol by the adaptor protein Numb, where it mediates homotypic early-endosome docking and fusion; loss of either Numb or MON1B results in clustered but unfused early endosomes [PMID:26987402]."},"prefetch_data":{"uniprot":{"accession":"Q7L1V2","full_name":"Vacuolar fusion protein MON1 homolog B","aliases":["HSV-1 stimulation-related gene 1 protein","HSV-I stimulating-related protein"],"length_aa":547,"mass_kda":59.2,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q7L1V2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MON1B","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MON1B","total_profiled":1310},"omim":[{"mim_id":"620660","title":"CCZ1 HOMOLOG, VACUOLAR PROTEIN TRAFFICKING- AND BIOGENESIS-ASSOCIATED PROTEIN; CCZ1","url":"https://www.omim.org/entry/620660"},{"mim_id":"611464","title":"MON1 HOMOLOG A, SECRETORY TRAFFICKING-ASSOCIATED; MON1A","url":"https://www.omim.org/entry/611464"},{"mim_id":"608954","title":"MON1 HOMOLOG B, SECRETORY TRAFFICKING-ASSOCIATED; MON1B","url":"https://www.omim.org/entry/608954"},{"mim_id":"179512","title":"RAS-ASSOCIATED PROTEIN RAB5A; RAB5A","url":"https://www.omim.org/entry/179512"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MON1B"},"hgnc":{"alias_symbol":["SAND2","HSRG1","KIAA0872"],"prev_symbol":[]},"alphafold":{"accession":"Q7L1V2","domains":[{"cath_id":"3.30.450.70","chopping":"104-239","consensus_level":"high","plddt":93.5479,"start":104,"end":239},{"cath_id":"3.30.450.30","chopping":"249-394","consensus_level":"medium","plddt":87.7395,"start":249,"end":394},{"cath_id":"3.30.450","chopping":"403-520","consensus_level":"medium","plddt":92.2086,"start":403,"end":520}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L1V2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L1V2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L1V2-F1-predicted_aligned_error_v6.png","plddt_mean":77.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MON1B","jax_strain_url":"https://www.jax.org/strain/search?query=MON1B"},"sequence":{"accession":"Q7L1V2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7L1V2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7L1V2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L1V2"}},"corpus_meta":[{"pmid":"20305638","id":"PMC_20305638","title":"Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20305638","citation_count":202,"is_preprint":false},{"pmid":"30037848","id":"PMC_30037848","title":"Mycobacterial PknG Targets the Rab7l1 Signaling Pathway To Inhibit Phagosome-Lysosome Fusion.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/30037848","citation_count":59,"is_preprint":false},{"pmid":"23904513","id":"PMC_23904513","title":"Single nucleotide polymorphisms in candidate genes associated with fertilizing ability of sperm and subsequent embryonic development in cattle.","date":"2013","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/23904513","citation_count":37,"is_preprint":false},{"pmid":"26987402","id":"PMC_26987402","title":"Numb regulates vesicular docking for homotypic fusion of early endosomes via membrane recruitment of Mon1b.","date":"2016","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/26987402","citation_count":26,"is_preprint":false},{"pmid":"23920401","id":"PMC_23920401","title":"Genetic variants in nuclear factor-kappa B binding sites are associated with clinical outcomes in prostate cancer patients.","date":"2013","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/23920401","citation_count":22,"is_preprint":false},{"pmid":"28542629","id":"PMC_28542629","title":"Characteristics of candidate genes associated with embryonic development in the cow: Evidence for a role for WBP1 in development to the blastocyst stage.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28542629","citation_count":16,"is_preprint":false},{"pmid":"12828340","id":"PMC_12828340","title":"Identification of a novel human sand family protein in human fibroblasts induced by herpes simplex virus 1 binding.","date":"2003","source":"Acta virologica","url":"https://pubmed.ncbi.nlm.nih.gov/12828340","citation_count":7,"is_preprint":false},{"pmid":"17109635","id":"PMC_17109635","title":"Protein encoded by HSV-1 stimulation-related gene 1 (HSRG1) interacts with and inhibits SV40 large T antigen.","date":"2006","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/17109635","citation_count":6,"is_preprint":false},{"pmid":"21509660","id":"PMC_21509660","title":"HSV-1 stimulation-related protein HSRG1 inhibits viral gene transcriptional elongation by interacting with Cyclin T2.","date":"2011","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/21509660","citation_count":3,"is_preprint":false},{"pmid":"30368516","id":"PMC_30368516","title":"Knockdown of MON1B Exerts Anti-Tumor Effects in Colon Cancer In Vitro.","date":"2018","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/30368516","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6165,"output_tokens":1119,"usd":0.01764},"stage2":{"model":"claude-opus-4-6","input_tokens":4327,"output_tokens":1566,"usd":0.091177},"total_usd":0.108817,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"Mon1b (mammalian ortholog of C. elegans SAND-1) forms a complex with Ccz1 that acts as a Rab5 effector (binding GTP-bound Rab5) and promotes progression from the Rab5-positive to the Rab7-positive stage of phagosome maturation; the Mon1-Ccz1 complex (but not either protein alone) can bind Rab7 and influence Rab7 activation.\",\n      \"method\": \"Genetic epistasis in C. elegans, RNAi knockdown in mammalian cells, co-immunoprecipitation, GTPase-binding assays (GTP-bound vs GDP-bound Rab5/Rab7), phagosome maturation imaging\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, epistasis, loss-of-function with defined cellular phenotype, replicated across two organisms\",\n      \"pmids\": [\"20305638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mon1b is recruited from the cytosol to early endosome (EE) membranes by the endocytic adaptor Numb, where it acts as a docking regulator required for homotypic fusion of early endosomes; depletion of either Numb or Mon1b causes clustered but unfused EEs.\",\n      \"method\": \"Numb-Mon1b co-immunoprecipitation/binding assay, siRNA knockdown of Numb and Mon1b, time-lapse live-cell imaging of EE fusion, rescue experiments with cytosolic vs membrane-attached Numb isoforms\",\n      \"journal\": \"Cell Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, live imaging, loss-of-function with defined organelle phenotype, isoform-specific rescue\",\n      \"pmids\": [\"26987402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mycobacterial PknG does not interact with Mon1b (or Mon1a), indicating Mon1b is not a direct target of PknG-mediated phagosome maturation blockade; Mon1b's role in phagosome-lysosome fusion is thus independent of the PknG-Rab7l1 axis.\",\n      \"method\": \"Co-immunoprecipitation/interaction assay testing PknG against Mon1a, Mon1b, and other phagolysosomal factors\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP negative result providing pathway placement information\",\n      \"pmids\": [\"30037848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Knockdown of MON1B in colon cancer cells inhibits cell proliferation, migration, and invasion, accompanied by decreased MMP-2, MMP-9, MTA-1, NF-κB, and CXCR-4 levels and increased TIMP-2 and IκB levels, placing MON1B upstream of the NF-κB/MMP signaling axis in these cells.\",\n      \"method\": \"siRNA knockdown of MON1B in LoVo cells, CCK-8 proliferation assay, wound-healing migration assay, Transwell invasion assay, RT-qPCR and Western blot for downstream markers\",\n      \"journal\": \"Medical Science Monitor\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single knockdown approach, no direct biochemical mechanism established\",\n      \"pmids\": [\"30368516\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MON1B forms a complex with CCZ1 that acts downstream of GTP-bound RAB5 as a RAB5 effector and guanine nucleotide exchange factor (GEF) complex for RAB7, thereby driving phagosome/endosome maturation from the RAB5-positive to the RAB7-positive stage; at early endosomes, MON1B is recruited to the membrane by the adaptor protein Numb to mediate homotypic EE docking and fusion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MON1B forms a heterodimeric complex with CCZ1 that functions as a RAB5 effector and guanine nucleotide exchange factor (GEF) for RAB7, driving the conversion of RAB5-positive endosomes/phagosomes to RAB7-positive compartments during endosomal and phagosomal maturation [PMID:20305638]. The MON1B–CCZ1 complex selectively binds GTP-loaded RAB5 on membranes and recruits and activates RAB7; neither subunit alone is sufficient for RAB7 binding [PMID:20305638]. At early endosomes, MON1B is recruited from the cytosol by the adaptor protein Numb, where it mediates homotypic early-endosome docking and fusion; loss of either Numb or MON1B results in clustered but unfused early endosomes [PMID:26987402].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing MON1B as a RAB5-to-RAB7 conversion factor resolved how endosomal identity transitions are controlled: the MON1B–CCZ1 complex reads RAB5-GTP on early compartments and activates RAB7 to drive phagosome maturation.\",\n      \"evidence\": \"Genetic epistasis in C. elegans combined with mammalian RNAi, co-immunoprecipitation, and GTPase-binding assays comparing GTP- versus GDP-locked RAB5/RAB7\",\n      \"pmids\": [\"20305638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for how the MON1B–CCZ1 complex catalyzes nucleotide exchange on RAB7 was not determined\",\n        \"Whether MON1A and MON1B are functionally redundant or context-specific was not addressed\",\n        \"Membrane recruitment mechanism for the complex independent of Numb was unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying Numb as the membrane recruiter of MON1B at early endosomes answered how MON1B reaches its site of action and revealed an unexpected role for MON1B in homotypic early-endosome fusion upstream of the RAB5-to-RAB7 switch.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, siRNA knockdown of Numb and MON1B, live-cell imaging of early-endosome fusion, and isoform-specific rescue experiments\",\n      \"pmids\": [\"26987402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The binding interface between Numb and MON1B has not been mapped\",\n        \"Whether MON1B's role in EE fusion requires CCZ1 or RAB7 GEF activity was not dissected\",\n        \"Physiological consequences of impaired MON1B-dependent EE fusion in vivo remain uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Negative interaction data with mycobacterial PknG placed MON1B's phagosome maturation function outside the PknG–RAB7L1 virulence axis, refining the pathway wiring of phagolysosomal biogenesis.\",\n      \"evidence\": \"Co-immunoprecipitation testing PknG against MON1B and other phagolysosomal factors\",\n      \"pmids\": [\"30037848\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only a single Co-IP approach was used; orthogonal interaction assays were not reported\",\n        \"Whether other mycobacterial effectors target MON1B remains untested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"MON1B knockdown in colon cancer cells linked the gene to proliferation and invasion phenotypes, but the biochemical mechanism connecting endosomal trafficking to NF-κB/MMP signaling was not established.\",\n      \"evidence\": \"siRNA knockdown in LoVo cells with proliferation, migration, and invasion assays plus RT-qPCR/Western blot for downstream markers\",\n      \"pmids\": [\"30368516\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single knockdown approach in one cell line without rescue or specificity controls\",\n        \"No direct biochemical link between MON1B's GEF activity and NF-κB regulation was demonstrated\",\n        \"Not independently replicated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of the MON1B–CCZ1 GEF complex on human RAB7, whether MON1A and MON1B are functionally redundant, and the molecular mechanism linking endosomal MON1B activity to downstream signaling pathways.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of the human MON1B–CCZ1–RAB7 complex exists\",\n        \"Functional redundancy between MON1A and MON1B has not been systematically tested\",\n        \"In vivo physiological roles (development, immunity) of MON1B loss are uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"MON1B–CCZ1\"\n    ],\n    \"partners\": [\n      \"CCZ1\",\n      \"RAB5\",\n      \"RAB7\",\n      \"NUMB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}