{"gene":"MMP23B","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":1998,"finding":"MMP23B (then called MMP22) was identified as a novel matrix metalloproteinase gene on human chromosome 1p36.3, encoding a protein with prepro, catalytic, cysteine-rich, interleukin-1 receptor-related, and proline-rich domains; its catalytic domain contains the consensus HEXXH zinc-binding region required for enzyme activation, and notably lacks the conserved 'cysteine switch' residue involved in autocatalytic activation of many metalloproteinases.","method":"Gene isolation, sequence characterization, domain analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — original isolation and domain characterization, single lab but multiple sequence analyses","pmids":["9740677"],"is_preprint":false},{"year":1998,"finding":"MMP22 (MMP23B) and MMP21 genes are each located less than 1 kb from the 3' regions of Cdc2L2 and Cdc2L1, respectively, in a duplicated genomic region on chromosome 1p36.3, organized in a tail-to-tail configuration with their linked Cdc2L genes.","method":"Genomic mapping, sequence analysis","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 — genomic organization established by direct sequencing and mapping, single lab","pmids":["9750192"],"is_preprint":false},{"year":2010,"finding":"Zebrafish mmp23b is required for normal hepatocyte proliferation and liver development; morpholino knockdown caused reduced liver size while pancreas and gut development remained relatively normal.","method":"Morpholino knockdown in zebrafish, liver size phenotypic analysis","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function with specific cellular phenotype, multiple rescue experiments","pmids":["21064033"],"is_preprint":false},{"year":2010,"finding":"Zebrafish mmp23b functions through the TNF signaling pathway in liver development: knockdown of tnfa or tnfb phenocopied mmp23b morphants, and overexpression of tnfa or tnfb rescued liver defects in mmp23b morphants but not vice versa, establishing mmp23b upstream of TNF signaling.","method":"Genetic epistasis in zebrafish (morpholino knockdown, mRNA overexpression rescue experiments)","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — reciprocal genetic epistasis with multiple orthogonal rescue experiments in a single rigorous study","pmids":["21064033"],"is_preprint":false},{"year":2010,"finding":"Human MMP23B directly interacts with TNF and mediates TNF release from the cell membrane, as demonstrated biochemically in a cell culture system.","method":"Biochemical interaction assay in cell culture (direct interaction and membrane release assay)","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical demonstration in cell culture, single lab","pmids":["21064033"],"is_preprint":false},{"year":2024,"finding":"Silencing of MMP23B in endometrial cancer cells reduced cell viability, inhibited migration and invasion, and upregulated expression of apoptotic caspases (CASP3, CASP8, CASP9), indicating MMP23B promotes cell survival and suppresses apoptosis in these cells.","method":"siRNA knockdown, CCK8 viability assay, scratch assay, transwell invasion assay, RT-qPCR","journal":"Reproductive sciences (Thousand Oaks, Calif.)","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with multiple defined cellular phenotype readouts, single lab","pmids":["38782818"],"is_preprint":false},{"year":2024,"finding":"MMP23B is elevated in intestinal tissue of diabetic mice and is associated with tight junction disruption, increased mucosal permeability, and mitochondrial dysfunction (reactive oxygen species accumulation, mitochondrial membrane potential depolarization); dexmedetomidine reduces MMP23B levels and reverses these defects, validated using intestinal epithelial-specific MMP23B conditional knockout (Villin-MMP23B flox/flox) mice.","method":"Conditional knockout mice (Villin-MMP23B flox/flox), immunofluorescence, in vitro Caco-2 cell culture, tight junction analysis","journal":"World journal of diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with multiple cellular readouts and in vitro validation, single lab","pmids":["39280187"],"is_preprint":false},{"year":2020,"finding":"IL-18 induces MMP-22 (MMP23B) expression in human aortic smooth muscle cells, as shown by immunoblot analysis.","method":"Immunoblot (Western blot) in human aortic smooth muscle cells treated with IL-18","journal":"Journal of Zhejiang University. Science. B","confidence":"Low","confidence_rationale":"Tier 3 — single method (Western blot), single lab, limited mechanistic follow-up","pmids":["28786243"],"is_preprint":false}],"current_model":"MMP23B is a zinc-dependent matrix metalloproteinase that lacks the canonical cysteine switch, directly interacts with TNF and mediates its release from the cell membrane, functions upstream of TNF signaling to promote hepatocyte proliferation and liver development (established in zebrafish), promotes cell survival and invasiveness in cancer cells via suppression of caspase-mediated apoptosis, and is associated with intestinal barrier integrity through regulation of tight junctions and mitochondrial function."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of MMP23B as a structurally atypical metalloproteinase — possessing the HEXXH zinc-binding catalytic motif but lacking the canonical cysteine switch — established that the MMP family includes members with fundamentally different activation mechanisms and novel domain architectures (cysteine-rich and IL-1 receptor-related domains).","evidence":"Gene isolation, sequence characterization, and domain analysis of human chromosome 1p36.3","pmids":["9740677","9750192"],"confidence":"Medium","gaps":["No enzymatic activity assay was performed to confirm catalytic function","Substrate specificity unknown","No structural model of the protein"]},{"year":2010,"claim":"Demonstration that MMP23B acts upstream of TNF signaling to control hepatocyte proliferation answered how this protease connects to a defined developmental signaling pathway: it physically interacts with TNF and mediates its membrane release, placing it as a TNF-processing enzyme required for liver organogenesis.","evidence":"Morpholino knockdown and reciprocal mRNA rescue epistasis in zebrafish; biochemical interaction and membrane-release assays in human cell culture","pmids":["21064033"],"confidence":"High","gaps":["Whether MMP23B directly cleaves TNF or releases it through an indirect mechanism was not resolved","Mammalian in vivo confirmation of the liver development role is lacking","Relationship to TACE/ADAM17-mediated TNF shedding is undefined"]},{"year":2024,"claim":"Functional studies in cancer cells and intestinal epithelium expanded MMP23B's roles beyond TNF processing, revealing it promotes cell survival by suppressing caspase-dependent apoptosis and regulates epithelial barrier integrity through tight junction and mitochondrial homeostasis.","evidence":"siRNA knockdown in endometrial cancer cells with viability, migration, invasion, and caspase expression assays; intestinal epithelial-specific conditional knockout (Villin-MMP23B flox/flox) mice with tight junction and mitochondrial readouts","pmids":["38782818","39280187"],"confidence":"Medium","gaps":["Direct substrates mediating the anti-apoptotic and tight junction effects are unknown","Whether the barrier and survival phenotypes depend on TNF signaling is untested","Findings are each from single laboratories without independent replication"]},{"year":null,"claim":"The direct enzymatic substrates of MMP23B, the structural basis for its atypical activation mechanism, and the extent to which its diverse biological effects (TNF processing, anti-apoptosis, barrier regulation) share a common proteolytic mechanism remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in vitro substrate cleavage assay has been reported","No crystal or cryo-EM structure exists","Physiological redundancy with the nearly identical MMP21/MMP23A paralog is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5]}],"complexes":[],"partners":["TNF"],"other_free_text":[]},"mechanistic_narrative":"MMP23B is an atypical matrix metalloproteinase containing a catalytic domain with the consensus HEXXH zinc-binding motif but lacking the conserved cysteine switch residue used for autoinhibition, and featuring unique cysteine-rich and interleukin-1 receptor-related domains [PMID:9740677]. MMP23B directly interacts with TNF and mediates its release from the cell membrane, functioning upstream of TNF signaling to promote hepatocyte proliferation during liver development, as established by genetic epistasis in zebrafish where TNF overexpression rescued mmp23b loss-of-function but not vice versa [PMID:21064033]. In endometrial cancer cells, MMP23B promotes cell survival, migration, and invasion while suppressing caspase-mediated apoptosis [PMID:38782818], and in intestinal epithelium it regulates tight junction integrity and mitochondrial function, with conditional knockout mice showing protection against mucosal barrier disruption [PMID:39280187]."},"prefetch_data":{"uniprot":{"accession":"O75900","full_name":"Matrix metalloproteinase-23","aliases":["Femalysin","MIFR-1","Matrix metalloproteinase-21","MMP-21","Matrix metalloproteinase-22","MMP-22"],"length_aa":390,"mass_kda":43.9,"function":"Protease. May regulate the surface expression of some potassium channels by retaining them in the endoplasmic reticulum (By similarity)","subcellular_location":"Endoplasmic reticulum membrane; Membrane","url":"https://www.uniprot.org/uniprotkb/O75900/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MMP23B","classification":"Not Classified","n_dependent_lines":42,"n_total_lines":1208,"dependency_fraction":0.0347682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MMP23B","total_profiled":1310},"omim":[{"mim_id":"613004","title":"HUNTINGTIN; HTT","url":"https://www.omim.org/entry/613004"},{"mim_id":"603321","title":"MATRIX METALLOPROTEINASE 23B; MMP23B","url":"https://www.omim.org/entry/603321"},{"mim_id":"603320","title":"MATRIX METALLOPROTEINASE 23A; MMP23A","url":"https://www.omim.org/entry/603320"},{"mim_id":"185260","title":"MATRIX METALLOPROTEINASE 10; MMP10","url":"https://www.omim.org/entry/185260"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"ovary","ntpm":26.3}],"url":"https://www.proteinatlas.org/search/MMP23B"},"hgnc":{"alias_symbol":["MIFR","MIFR-1"],"prev_symbol":["MMP22"]},"alphafold":{"accession":"O75900","domains":[{"cath_id":"3.40.390.10","chopping":"82-253","consensus_level":"high","plddt":88.7019,"start":82,"end":253},{"cath_id":"-","chopping":"256-283","consensus_level":"medium","plddt":93.165,"start":256,"end":283},{"cath_id":"2.60.40.10","chopping":"307-389","consensus_level":"high","plddt":85.5528,"start":307,"end":389}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75900","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75900-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75900-F1-predicted_aligned_error_v6.png","plddt_mean":76.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MMP23B","jax_strain_url":"https://www.jax.org/strain/search?query=MMP23B"},"sequence":{"accession":"O75900","fasta_url":"https://rest.uniprot.org/uniprotkb/O75900.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75900/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75900"}},"corpus_meta":[{"pmid":"19936057","id":"PMC_19936057","title":"A 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its catalytic domain contains the consensus HEXXH zinc-binding region required for enzyme activation, and notably lacks the conserved 'cysteine switch' residue involved in autocatalytic activation of many metalloproteinases.\",\n      \"method\": \"Gene isolation, sequence characterization, domain analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — original isolation and domain characterization, single lab but multiple sequence analyses\",\n      \"pmids\": [\"9740677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MMP22 (MMP23B) and MMP21 genes are each located less than 1 kb from the 3' regions of Cdc2L2 and Cdc2L1, respectively, in a duplicated genomic region on chromosome 1p36.3, organized in a tail-to-tail configuration with their linked Cdc2L genes.\",\n      \"method\": \"Genomic mapping, sequence analysis\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genomic organization established by direct sequencing and mapping, single lab\",\n      \"pmids\": [\"9750192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Zebrafish mmp23b is required for normal hepatocyte proliferation and liver development; morpholino knockdown caused reduced liver size while pancreas and gut development remained relatively normal.\",\n      \"method\": \"Morpholino knockdown in zebrafish, liver size phenotypic analysis\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with specific cellular phenotype, multiple rescue experiments\",\n      \"pmids\": [\"21064033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Zebrafish mmp23b functions through the TNF signaling pathway in liver development: knockdown of tnfa or tnfb phenocopied mmp23b morphants, and overexpression of tnfa or tnfb rescued liver defects in mmp23b morphants but not vice versa, establishing mmp23b upstream of TNF signaling.\",\n      \"method\": \"Genetic epistasis in zebrafish (morpholino knockdown, mRNA overexpression rescue experiments)\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic epistasis with multiple orthogonal rescue experiments in a single rigorous study\",\n      \"pmids\": [\"21064033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human MMP23B directly interacts with TNF and mediates TNF release from the cell membrane, as demonstrated biochemically in a cell culture system.\",\n      \"method\": \"Biochemical interaction assay in cell culture (direct interaction and membrane release assay)\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical demonstration in cell culture, single lab\",\n      \"pmids\": [\"21064033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Silencing of MMP23B in endometrial cancer cells reduced cell viability, inhibited migration and invasion, and upregulated expression of apoptotic caspases (CASP3, CASP8, CASP9), indicating MMP23B promotes cell survival and suppresses apoptosis in these cells.\",\n      \"method\": \"siRNA knockdown, CCK8 viability assay, scratch assay, transwell invasion assay, RT-qPCR\",\n      \"journal\": \"Reproductive sciences (Thousand Oaks, Calif.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with multiple defined cellular phenotype readouts, single lab\",\n      \"pmids\": [\"38782818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MMP23B is elevated in intestinal tissue of diabetic mice and is associated with tight junction disruption, increased mucosal permeability, and mitochondrial dysfunction (reactive oxygen species accumulation, mitochondrial membrane potential depolarization); dexmedetomidine reduces MMP23B levels and reverses these defects, validated using intestinal epithelial-specific MMP23B conditional knockout (Villin-MMP23B flox/flox) mice.\",\n      \"method\": \"Conditional knockout mice (Villin-MMP23B flox/flox), immunofluorescence, in vitro Caco-2 cell culture, tight junction analysis\",\n      \"journal\": \"World journal of diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple cellular readouts and in vitro validation, single lab\",\n      \"pmids\": [\"39280187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-18 induces MMP-22 (MMP23B) expression in human aortic smooth muscle cells, as shown by immunoblot analysis.\",\n      \"method\": \"Immunoblot (Western blot) in human aortic smooth muscle cells treated with IL-18\",\n      \"journal\": \"Journal of Zhejiang University. Science. B\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method (Western blot), single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"28786243\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MMP23B is a zinc-dependent matrix metalloproteinase that lacks the canonical cysteine switch, directly interacts with TNF and mediates its release from the cell membrane, functions upstream of TNF signaling to promote hepatocyte proliferation and liver development (established in zebrafish), promotes cell survival and invasiveness in cancer cells via suppression of caspase-mediated apoptosis, and is associated with intestinal barrier integrity through regulation of tight junctions and mitochondrial function.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MMP23B is an atypical matrix metalloproteinase containing a catalytic domain with the consensus HEXXH zinc-binding motif but lacking the conserved cysteine switch residue used for autoinhibition, and featuring unique cysteine-rich and interleukin-1 receptor-related domains [PMID:9740677]. MMP23B directly interacts with TNF and mediates its release from the cell membrane, functioning upstream of TNF signaling to promote hepatocyte proliferation during liver development, as established by genetic epistasis in zebrafish where TNF overexpression rescued mmp23b loss-of-function but not vice versa [PMID:21064033]. In endometrial cancer cells, MMP23B promotes cell survival, migration, and invasion while suppressing caspase-mediated apoptosis [PMID:38782818], and in intestinal epithelium it regulates tight junction integrity and mitochondrial function, with conditional knockout mice showing protection against mucosal barrier disruption [PMID:39280187].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of MMP23B as a structurally atypical metalloproteinase — possessing the HEXXH zinc-binding catalytic motif but lacking the canonical cysteine switch — established that the MMP family includes members with fundamentally different activation mechanisms and novel domain architectures (cysteine-rich and IL-1 receptor-related domains).\",\n      \"evidence\": \"Gene isolation, sequence characterization, and domain analysis of human chromosome 1p36.3\",\n      \"pmids\": [\"9740677\", \"9750192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No enzymatic activity assay was performed to confirm catalytic function\",\n        \"Substrate specificity unknown\",\n        \"No structural model of the protein\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstration that MMP23B acts upstream of TNF signaling to control hepatocyte proliferation answered how this protease connects to a defined developmental signaling pathway: it physically interacts with TNF and mediates its membrane release, placing it as a TNF-processing enzyme required for liver organogenesis.\",\n      \"evidence\": \"Morpholino knockdown and reciprocal mRNA rescue epistasis in zebrafish; biochemical interaction and membrane-release assays in human cell culture\",\n      \"pmids\": [\"21064033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether MMP23B directly cleaves TNF or releases it through an indirect mechanism was not resolved\",\n        \"Mammalian in vivo confirmation of the liver development role is lacking\",\n        \"Relationship to TACE/ADAM17-mediated TNF shedding is undefined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Functional studies in cancer cells and intestinal epithelium expanded MMP23B's roles beyond TNF processing, revealing it promotes cell survival by suppressing caspase-dependent apoptosis and regulates epithelial barrier integrity through tight junction and mitochondrial homeostasis.\",\n      \"evidence\": \"siRNA knockdown in endometrial cancer cells with viability, migration, invasion, and caspase expression assays; intestinal epithelial-specific conditional knockout (Villin-MMP23B flox/flox) mice with tight junction and mitochondrial readouts\",\n      \"pmids\": [\"38782818\", \"39280187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct substrates mediating the anti-apoptotic and tight junction effects are unknown\",\n        \"Whether the barrier and survival phenotypes depend on TNF signaling is untested\",\n        \"Findings are each from single laboratories without independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct enzymatic substrates of MMP23B, the structural basis for its atypical activation mechanism, and the extent to which its diverse biological effects (TNF processing, anti-apoptosis, barrier regulation) share a common proteolytic mechanism remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro substrate cleavage assay has been reported\",\n        \"No crystal or cryo-EM structure exists\",\n        \"Physiological redundancy with the nearly identical MMP21/MMP23A paralog is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TNF\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}