{"gene":"MMP17","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1999,"finding":"MT4-MMP (MMP17) is a GPI-anchored proteinase — the first GPI-anchored member of the MMP family. [3H]ethanolamine labeling incorporated into the GPI unit in a sequence-dependent manner, and phosphatidylinositol-specific phospholipase C treatment released MT4-MMP from the cell surface of transfected cells. MT4-MMP is also shed from the cell surface by an endogenous metalloproteinase.","method":"Metabolic labeling with [3H]ethanolamine, PI-PLC treatment of transfected cells, cell surface release assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical reconstitution with two orthogonal methods (metabolic labeling + PI-PLC cleavage) in transfected cells, foundational finding","pmids":["10567400"],"is_preprint":false},{"year":2000,"finding":"Mouse MT4-MMP catalytic domain has TNF-alpha convertase activity: it efficiently cleaves a peptide spanning the pro-TNFα cleavage site, cleaves a GST-pro-TNFα fusion protein in vitro, and sheds pro-TNFα when co-transfected in COS-7 cells. However, it does not activate pro-MMP2 and shows very limited activity against ECM components except fibrinogen and fibrin. Catalytic activity is inhibited by TIMP-1, -2, and -3.","method":"E. coli expression/refolding of recombinant catalytic domain, synthetic peptide cleavage assay, GST-fusion protein cleavage, co-transfection shedding assay in COS-7 cells, TIMP inhibition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro and cell-based assays with recombinant protein and mutagenesis-compatible controls, replicated in cell-based system","pmids":["10799478"],"is_preprint":false},{"year":1999,"finding":"The originally reported human MT4-MMP cDNA (Puente et al. 1996) lacked the full ORF and failed to express protein. A new major transcript with an extended open reading frame was identified by 5' RACE and encodes 67 and 71 kDa translation products — the functional MT4-MMP protein.","method":"5' RACE, cDNA cloning, protein expression in transfected cells (Western blot)","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 5' RACE plus expression validation, single lab, two orthogonal methods","pmids":["10471807"],"is_preprint":false},{"year":2000,"finding":"MT4-MMP expressed in COS-7 cells localizes to the cell surface but does not activate pro-MMP2, distinguishing it functionally from MT1-, MT2-, and MT3-MMP.","method":"COS-7 cell transfection, cell-surface expression assay, pro-MMP2 activation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cell-based assay with clear negative result for pro-MMP2 activation, single lab","pmids":["10799478"],"is_preprint":false},{"year":2006,"finding":"The hemopexin domain of MT4-MMP, when substituted into MT1-MMP chimeras, blocks propeptide processing, prevents trafficking to the plasma membrane (retained in ER), and abolishes pro-MMP2 activation and gelatin degradation. The MT4-MMP hemopexin domain therefore carries an intrinsic inhibitory signal for enzyme maturation and trafficking.","method":"MT1-MT4-MMP chimera construction, cell-surface biotinylation, indirect immunofluorescence, pro-MMP2 activation assay, gelatin degradation assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — domain-swap mutagenesis with multiple orthogonal readouts (surface biotinylation, immunofluorescence, functional activity assays), single lab","pmids":["16686598"],"is_preprint":false},{"year":2007,"finding":"In vivo, MT4-MMP is expressed primarily in cerebrum, lung, spleen, intestine and uterus; specifically in neurons (cerebrum), smooth muscle cells (intestine, uterus), and macrophages (lung alveolar/intraperitoneal space). LPS-induced TNF-α release from MT4-MMP-null macrophages was not different from wild-type, and MT4-MMP mRNA was repressed by LPS stimulation — arguing against a dominant role as a TNFα sheddase in macrophages in vivo.","method":"MT4-MMP KO mouse with LacZ reporter, β-galactosidase staining, RT-PCR, TNF-α release assay from macrophages","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic reporter model plus functional macrophage assay, single lab","pmids":["17825051"],"is_preprint":false},{"year":2005,"finding":"MT4-MMP is required for IL-1-induced aggrecanolysis in bovine cartilage explants. Blocking GPI-anchor synthesis with mannosamine (inhibiting MT4-MMP membrane anchoring) blocked IL-1-mediated aggrecan cleavage, MT4-MMP induction, and ADAMTS4 processing (p68→p53 conversion and release). This supports MT4-MMP-mediated processing of resident ADAMTS4 as the mechanism of aggrecanolysis.","method":"Bovine cartilage explant treatment with IL-1, Western blot for aggrecan fragments, MT4-MMP, and ADAMTS4, mannosamine GPI-anchor inhibition, esculetin MMP inhibition","journal":"Osteoarthritis and cartilage","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition of GPI anchoring combined with Western blot readouts, indirect evidence for MT4-MMP→ADAMTS4 axis, single lab","pmids":["15780640"],"is_preprint":false},{"year":2012,"finding":"The proteolytic activity of MT4-MMP is required for its pro-angiogenic and pro-metastatic effects in breast cancer. Glutamic acid 249→Alanine active-site mutation abolished the MT4-MMP-induced angiogenic switch, tumor growth acceleration, and lung colonization. Tumor-derived (not host-derived) MT4-MMP drives angiogenesis; MT4-MMP-deficient host mice were unaffected.","method":"Site-directed mutagenesis (E249A), subcutaneous tumor implantation in RAG1-deficient mice, MT4-MMP-null mouse host experiments, tumor growth and lung colonization assays","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis combined with in vivo genetic loss-of-function model and multiple tumor biology readouts, single lab","pmids":["22262494"],"is_preprint":false},{"year":2014,"finding":"MT4-MMP directly associates with EGFR at the cell surface and enhances EGFR phosphorylation in response to TGFα and EGF, driving cancer cell proliferation through CDK4 activation and retinoblastoma protein inactivation. These effects on proliferation and EGFR activation do not require MT4-MMP metalloprotease activity.","method":"Co-immunoprecipitation, EGFR phosphorylation assays, cell proliferation assays, CDK4/Rb pathway analysis, catalytic mutant comparison","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional signaling assays and catalytic mutant used to dissect mechanism, single lab","pmids":["25320013"],"is_preprint":false},{"year":2015,"finding":"MMP17/MT4-MMP cleaves osteopontin, and this cleavage regulates vascular smooth muscle cell maturation via c-Jun N-terminal kinase (JNK) signaling during aorta wall development. Loss of Mmp17 in mice results in dysfunctional VSMCs and altered ECM, leading to increased susceptibility to angiotensin-II-induced thoracic aortic aneurysm. Re-expression of catalytically active Mmp17 or the N-terminal osteopontin fragment rescued part of the vessel-wall phenotype.","method":"Mmp17 knockout mouse model, angiotensin-II-induced aneurysm model, lentiviral re-expression of active Mmp17 or osteopontin fragment, JNK signaling analysis, human patient mutation (R373H) blocking expression","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic KO model combined with rescue experiments (catalytically active enzyme and substrate fragment), human mutation validation, multiple orthogonal readouts","pmids":["25963716"],"is_preprint":false},{"year":2016,"finding":"MT4-MMP forms homophilic complexes (oligomers and dimers) at the cell surface. It is internalized via the clathrin-independent carriers/GPI-enriched early endosomal compartments (CLIC/GEEC) pathway into early endosomes, where it is either autodegraded or recycled to the cell surface. Internalization was reduced by CDC42 or RhoA siRNA silencing but not by caveolin-1 or clathrin pathway inhibitors.","method":"Co-immunoprecipitation of FLAG- and Myc-tagged MT4-MMP, reducing/non-reducing immunoblotting, antibody feeding assay with confocal microscopy, cell surface biotinylation/Western blot, siRNA knockdown of CDC42/RhoA/caveolin-1","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal trafficking assays with genetic perturbations, single lab","pmids":["26663028"],"is_preprint":false},{"year":2017,"finding":"MT4-MMP in melanoma cells is processed by furin cleavage in the Golgi apparatus. The 69 kDa form is the intracellular precursor and the 58 kDa form is the mature protein present at the cell membrane. Asn318 was identified as the single N-glycosylation site of MT4-MMP.","method":"Iodixanol gradient organelle fractionation, glycosidase treatment, site-directed mutagenesis of N-glycosylation sites, Western blotting","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of glycosylation site combined with fractionation and enzymatic deglycosylation, single lab","pmids":["28531887"],"is_preprint":false},{"year":2018,"finding":"MT4-MMP deficiency in mice increases adhesion of patrolling monocytes to inflamed endothelia, elevates Mafb+AIM+ macrophage accumulation at early atherosclerotic lesions, and accelerates atherosclerosis. MT4-MMP-null Mafb+AIM+ macrophages show higher AIM and CD36 expression, increased resistance to apoptosis, and avid acLDL binding. CCR5 inhibition blocks the enhanced recruitment of MT4-MMP-null patrolling monocytes and alleviates atherosclerosis acceleration.","method":"MT4-MMP KO mouse crossed to atherosclerosis model, intravital microscopy, flow cytometry, peritoneal macrophage functional assays (apoptosis, acLDL binding), CCR5 inhibitor treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model with multiple orthogonal cellular assays, pharmacological rescue, in vivo imaging, published in high-quality journal","pmids":["29500407"],"is_preprint":false},{"year":2019,"finding":"MT4-MMP promotes invadopodia formation and amoeboid-like cell movement in head and neck cancer cells. Mechanistically, MT4-MMP binds Tks5 and PDGFRα, leading to Src activation (invadopodia), and stimulates Rho and Cdc42 GTPases (amoeboid movement). MT4-MMP expression increased gelatin degradation in 3D assays.","method":"MT4-MMP overexpression in FaDu cells, 3D collagen/gelatin invasion assays, co-immunoprecipitation of MT4-MMP with Tks5 and PDGFRα, Src/Rho/Cdc42 activity assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP binding data combined with functional invasion assays and signaling readouts, single lab","pmids":["31813546"],"is_preprint":false},{"year":2021,"finding":"MMP17, exclusively expressed by smooth muscle cells in the intestine, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. MMP17 affects intestinal epithelial reprogramming indirectly by cleaving the matricellular protein PERIOSTIN, and smooth muscle-derived MMP17 promotes BMP antagonist supply essential for intestinal stem cell maintenance and YAP activity.","method":"Mmp17 KO mouse, intestinal injury models (inflammation, irradiation), intestinal organoid assays, PERIOSTIN cleavage assay, YAP activity analysis, single-cell/cell-type-specific expression analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with multiple injury models, substrate cleavage evidence, organoid functional assays, published in high-quality journal","pmids":["34795242"],"is_preprint":false},{"year":2023,"finding":"MMP17 expressed in smooth muscle cells and lamina propria macrophages of the intestine extrinsically regulates goblet cell maturation. Mmp17 KO mice show elevated goblet-cell-associated genes (CLCA1, RELM-β) and increased resistance to low-dose Trichuris muris helminth infection. The mechanism does not appear to involve NOTCH pathway changes or altered cytokine levels.","method":"Mmp17 KO mouse, helminth (T. muris) infection model, Citrobacter rodentium infection model, gene/protein expression analysis of goblet cell markers","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with two infection models and molecular readouts, single lab, mechanism incompletely defined","pmids":["37869014"],"is_preprint":false}],"current_model":"MMP17 (MT4-MMP) is a GPI-anchored, cell-surface matrix metalloproteinase that is processed by furin in the Golgi, forms homophilic complexes, and internalizes via a clathrin-independent/CDC42-RhoA-dependent pathway; its catalytic activity cleaves substrates including pro-TNFα, fibrinogen/fibrin, osteopontin, and PERIOSTIN, while its non-catalytic scaffold function enhances EGFR signaling through direct physical association, collectively regulating vascular smooth muscle cell maturation (via osteopontin-JNK signaling), intestinal stem cell niche maintenance and epithelial repair (via PERIOSTIN cleavage), monocyte/macrophage behavior in atherosclerosis (via CCR5-dependent patrolling monocyte recruitment), and tumor angiogenesis and metastasis (requiring proteolytic activity in tumor cells)."},"narrative":{"mechanistic_narrative":"MMP17 (MT4-MMP) is a GPI-anchored, cell-surface matrix metalloproteinase that regulates tissue remodeling and stem-cell niche function through both proteolytic and non-catalytic scaffolding activities [PMID:10567400, PMID:25963716, PMID:34795242]. It is the first GPI-anchored MMP, attached to the membrane via a sequence-dependent GPI unit and releasable by PI-PLC, and is also shed by an endogenous metalloproteinase [PMID:10567400]. The enzyme matures through furin cleavage in the Golgi to a membrane-resident form, carries a single N-glycosylation site at Asn318, and its hemopexin domain harbors an intrinsic inhibitory signal that restrains trafficking and enzyme maturation [PMID:28531887, PMID:16686598]. At the surface it forms homophilic oligomers and is internalized by a clathrin-independent, CDC42/RhoA-dependent CLIC/GEEC route into early endosomes for autodegradation or recycling [PMID:26663028]. Catalytically, MT4-MMP has TNFα-convertase activity and a narrow ECM substrate range limited largely to fibrinogen/fibrin, and notably does not activate pro-MMP2, distinguishing it from other membrane-type MMPs; its activity is inhibited by TIMP-1, -2, and -3 [PMID:10799478]. Its physiological substrates include osteopontin, whose cleavage controls vascular smooth muscle cell maturation via JNK signaling such that loss of Mmp17 produces dysfunctional VSMCs and susceptibility to angiotensin-II-induced thoracic aortic aneurysm, and PERIOSTIN, whose cleavage by smooth-muscle-derived MMP17 supports BMP-antagonist supply, intestinal stem cell maintenance, YAP activity, and epithelial repair after injury [PMID:25963716, PMID:34795242]. A human R373H mutation that blocks MMP17 expression links the gene to the aortic vessel-wall phenotype [PMID:25963716]. Independently of proteolysis, MT4-MMP directly associates with EGFR to enhance EGFR phosphorylation and drive proliferation through CDK4/Rb [PMID:25320013]. In disease, tumor-derived (not host) MT4-MMP requires its catalytic activity to drive the angiogenic switch and metastasis, and it deficiency accelerates atherosclerosis through CCR5-dependent patrolling-monocyte recruitment [PMID:22262494, PMID:29500407].","teleology":[{"year":1999,"claim":"Established the unique membrane attachment mode of MT4-MMP, defining it as the first GPI-anchored MMP rather than a transmembrane membrane-type MMP.","evidence":"[3H]ethanolamine metabolic labeling and PI-PLC release in transfected cells","pmids":["10567400"],"confidence":"High","gaps":["Did not resolve which endogenous metalloproteinase sheds MT4-MMP","Functional consequences of GPI anchoring vs shedding not addressed"]},{"year":1999,"claim":"Resolved the discrepancy in the original cDNA by identifying the true full-length ORF, enabling expression of functional MT4-MMP protein.","evidence":"5' RACE and cDNA cloning with expression validation by Western blot","pmids":["10471807"],"confidence":"Medium","gaps":["Single lab","Did not characterize protein function"]},{"year":2000,"claim":"Defined the catalytic specificity of MT4-MMP, showing TNFα-convertase activity and a narrow ECM substrate range while ruling out pro-MMP2 activation, separating it functionally from MT1/2/3-MMP.","evidence":"Recombinant catalytic domain peptide/fusion cleavage, COS-7 shedding assay, TIMP inhibition, and pro-MMP2 activation assay","pmids":["10799478"],"confidence":"High","gaps":["In vitro TNFα cleavage not shown to be physiologically dominant","Full physiological substrate repertoire unknown"]},{"year":2005,"claim":"Implicated MT4-MMP in cartilage catabolism by linking its GPI-anchored activity to ADAMTS4 processing and IL-1-induced aggrecanolysis.","evidence":"Bovine cartilage explants with mannosamine GPI-inhibition and Western blots for aggrecan, MT4-MMP, and ADAMTS4","pmids":["15780640"],"confidence":"Medium","gaps":["Pharmacological inhibition is indirect for MT4-MMP function","Direct MT4-MMP cleavage of ADAMTS4 not biochemically reconstituted"]},{"year":2006,"claim":"Located an intrinsic maturation/trafficking control within the hemopexin domain, explaining why MT4-MMP behaves differently from other MT-MMPs.","evidence":"MT1/MT4-MMP domain-swap chimeras with surface biotinylation, immunofluorescence, and activity assays","pmids":["16686598"],"confidence":"High","gaps":["Molecular nature of the inhibitory signal undefined","Studied in chimeric context rather than native protein"]},{"year":2007,"claim":"Mapped in vivo expression and challenged the TNFα-sheddase model by showing normal LPS-induced TNFα release in MT4-MMP-null macrophages.","evidence":"MT4-MMP KO/LacZ reporter mouse, β-gal staining, RT-PCR, and macrophage TNFα release assay","pmids":["17825051"],"confidence":"Medium","gaps":["Does not exclude TNFα cleavage in other contexts","Did not identify the dominant in vivo substrate"]},{"year":2012,"claim":"Demonstrated that catalytic activity of tumor-derived MT4-MMP is required for angiogenesis and metastasis, isolating a proteolysis-dependent oncogenic function.","evidence":"E249A active-site mutant, subcutaneous tumors in RAG1-deficient and MT4-MMP-null host mice, tumor growth and lung colonization assays","pmids":["22262494"],"confidence":"High","gaps":["Pro-angiogenic substrate not identified","Mechanism of the angiogenic switch unresolved"]},{"year":2014,"claim":"Uncovered a non-catalytic scaffold function whereby MT4-MMP physically associates with EGFR to amplify signaling and proliferation.","evidence":"Co-IP, EGFR phosphorylation and proliferation assays, CDK4/Rb analysis, and catalytic mutant comparison","pmids":["25320013"],"confidence":"Medium","gaps":["Direct vs indirect EGFR binding not structurally defined","Single lab without reciprocal validation"]},{"year":2015,"claim":"Identified osteopontin as a physiological substrate linking MT4-MMP proteolysis to VSMC maturation and aortic wall integrity, with a human mutation tying the gene to aneurysm susceptibility.","evidence":"Mmp17 KO mice, angiotensin-II aneurysm model, rescue with active enzyme or osteopontin fragment, JNK analysis, and human R373H mutation","pmids":["25963716"],"confidence":"High","gaps":["Direct biochemical osteopontin cleavage site mapping not detailed","How JNK output is set by the osteopontin fragment unresolved"]},{"year":2016,"claim":"Defined MT4-MMP surface oligomerization and its clathrin-independent CDC42/RhoA-dependent internalization and recycling itinerary.","evidence":"Co-IP of differentially tagged MT4-MMP, reducing/non-reducing blots, antibody-feeding confocal assays, biotinylation, and CDC42/RhoA/caveolin-1 siRNA","pmids":["26663028"],"confidence":"Medium","gaps":["Functional purpose of homophilic complexes unclear","Trafficking studied in cell lines only"]},{"year":2017,"claim":"Established the biosynthetic maturation pathway, showing furin cleavage in the Golgi yields the mature membrane form and identifying Asn318 as the sole N-glycosylation site.","evidence":"Iodixanol organelle fractionation, glycosidase treatment, and N-glycosylation site mutagenesis in melanoma cells","pmids":["28531887"],"confidence":"Medium","gaps":["Functional role of glycosylation not tested","Single cell-type context"]},{"year":2018,"claim":"Revealed a vasculoprotective role in atherosclerosis, with MT4-MMP loss accelerating disease via CCR5-dependent patrolling-monocyte recruitment.","evidence":"MT4-MMP KO crossed to atherosclerosis model, intravital microscopy, flow cytometry, macrophage functional assays, and CCR5 inhibitor rescue","pmids":["29500407"],"confidence":"High","gaps":["Direct MT4-MMP substrate controlling monocyte adhesion not identified","Catalytic vs scaffold dependence not resolved"]},{"year":2019,"claim":"Connected MT4-MMP to invasive cancer cell motility through binding Tks5 and PDGFRα to activate Src and Rho/Cdc42.","evidence":"Overexpression in FaDu cells, 3D invasion assays, co-IP with Tks5 and PDGFRα, and Src/Rho/Cdc42 activity assays","pmids":["31813546"],"confidence":"Medium","gaps":["Overexpression system may not reflect endogenous behavior","Direct vs indirect partner binding not dissected"]},{"year":2021,"claim":"Identified PERIOSTIN cleavage by smooth-muscle MMP17 as the niche signal supporting BMP antagonism, intestinal stem cell maintenance, and epithelial repair.","evidence":"Mmp17 KO mice, inflammation/irradiation injury models, organoid assays, PERIOSTIN cleavage assay, and YAP analysis","pmids":["34795242"],"confidence":"High","gaps":["Precise BMP-antagonist link to periostin fragment incompletely mapped","Cleavage site on periostin not detailed"]},{"year":2023,"claim":"Extended MMP17's niche-regulatory role to goblet cell maturation and anti-helminth resistance, while excluding NOTCH and cytokine changes as mechanism.","evidence":"Mmp17 KO mice, T. muris and C. rodentium infection models, and goblet cell marker expression analysis","pmids":["37869014"],"confidence":"Medium","gaps":["Effector substrate driving goblet cell phenotype unknown","Mechanism remains incompletely defined"]},{"year":null,"claim":"How MT4-MMP's catalytic and non-catalytic (EGFR-scaffold) functions are coordinated across tissues, and which substrate cleavages drive each in vivo phenotype, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking proteolysis-dependent and scaffold functions","Substrates underlying monocyte and goblet cell phenotypes unidentified","No structural model of substrate or EGFR engagement"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,9,14]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,11]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[10]}],"pathway":[],"complexes":[],"partners":["EGFR","TKS5","PDGFRA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULZ9","full_name":"Matrix metalloproteinase-17","aliases":["Membrane-type matrix metalloproteinase 4","MT-MMP 4","MTMMP4","Membrane-type-4 matrix metalloproteinase","MT4-MMP","MT4MMP"],"length_aa":603,"mass_kda":66.7,"function":"Endopeptidase that degrades various components of the extracellular matrix, such as fibrin. May be involved in the activation of membrane-bound precursors of growth factors or inflammatory mediators, such as tumor necrosis factor-alpha. May also be involved in tumoral process. Cleaves pro-TNF at the '74-Ala-|-Gln-75' site. Not obvious if able to proteolytically activate progelatinase A. Does not hydrolyze collagen types I, II, III, IV and V, gelatin, fibronectin, laminin, decorin nor alpha1-antitrypsin","subcellular_location":"Cell membrane; Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q9ULZ9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MMP17","classification":"Not Classified","n_dependent_lines":50,"n_total_lines":1208,"dependency_fraction":0.041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MMP17","total_profiled":1310},"omim":[{"mim_id":"608482","title":"MATRIX METALLOPROTEINASE 25; MMP25","url":"https://www.omim.org/entry/608482"},{"mim_id":"604871","title":"MATRIX METALLOPROTEINASE 24; MMP24","url":"https://www.omim.org/entry/604871"},{"mim_id":"602285","title":"MATRIX METALLOPROTEINASE 17; MMP17","url":"https://www.omim.org/entry/602285"},{"mim_id":"602262","title":"MATRIX METALLOPROTEINASE 16; MMP16","url":"https://www.omim.org/entry/602262"},{"mim_id":"602261","title":"MATRIX METALLOPROTEINASE 15; MMP15","url":"https://www.omim.org/entry/602261"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":49.9}],"url":"https://www.proteinatlas.org/search/MMP17"},"hgnc":{"alias_symbol":["MT4-MMP"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULZ9","domains":[{"cath_id":"1.10.101","chopping":"48-107","consensus_level":"high","plddt":85.3753,"start":48,"end":107},{"cath_id":"3.40.390.10","chopping":"138-295","consensus_level":"high","plddt":92.4028,"start":138,"end":295},{"cath_id":"2.110.10.10","chopping":"339-522","consensus_level":"high","plddt":91.4603,"start":339,"end":522}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULZ9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULZ9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULZ9-F1-predicted_aligned_error_v6.png","plddt_mean":76.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MMP17","jax_strain_url":"https://www.jax.org/strain/search?query=MMP17"},"sequence":{"accession":"Q9ULZ9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULZ9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULZ9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULZ9"}},"corpus_meta":[{"pmid":"10799478","id":"PMC_10799478","title":"Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-alpha convertase activity but does not activate pro-MMP2.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10799478","citation_count":167,"is_preprint":false},{"pmid":"10567400","id":"PMC_10567400","title":"Membrane type 4 matrix metalloproteinase (MT4-MMP, MMP-17) is a glycosylphosphatidylinositol-anchored proteinase.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10567400","citation_count":136,"is_preprint":false},{"pmid":"18286233","id":"PMC_18286233","title":"MT4-(MMP17) and MT6-MMP (MMP25), A unique set of membrane-anchored matrix metalloproteinases: properties and expression in cancer.","date":"2008","source":"Cancer metastasis reviews","url":"https://pubmed.ncbi.nlm.nih.gov/18286233","citation_count":115,"is_preprint":false},{"pmid":"15780640","id":"PMC_15780640","title":"Analysis of ADAMTS4 and MT4-MMP indicates that both are involved in aggrecanolysis in interleukin-1-treated bovine cartilage.","date":"2005","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/15780640","citation_count":70,"is_preprint":false},{"pmid":"10372554","id":"PMC_10372554","title":"Overview of expression of matrix metalloproteinases (MMP-17, MMP-18, and MMP-20) in cultured human cells.","date":"1999","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/10372554","citation_count":56,"is_preprint":false},{"pmid":"25963716","id":"PMC_25963716","title":"Deficiency of MMP17/MT4-MMP proteolytic activity predisposes to aortic aneurysm in mice.","date":"2015","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/25963716","citation_count":55,"is_preprint":false},{"pmid":"19426156","id":"PMC_19426156","title":"Membrane-type 4 matrix metalloproteinase (MT4-MMP) induces lung metastasis by alteration of primary breast tumour vascular architecture.","date":"2009","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19426156","citation_count":42,"is_preprint":false},{"pmid":"30504427","id":"PMC_30504427","title":"Expression of MT4-MMP, EGFR, and RB in Triple-Negative Breast Cancer Strongly Sensitizes Tumors to Erlotinib and Palbociclib Combination Therapy.","date":"2018","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/30504427","citation_count":39,"is_preprint":false},{"pmid":"10471807","id":"PMC_10471807","title":"Human membrane type-4 matrix metalloproteinase (MT4-MMP) is encoded by a novel major transcript: isolation of complementary DNA clones for human and mouse mt4-mmp transcripts.","date":"1999","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10471807","citation_count":38,"is_preprint":false},{"pmid":"29500407","id":"PMC_29500407","title":"MT4-MMP deficiency increases patrolling monocyte recruitment to early lesions and accelerates atherosclerosis.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29500407","citation_count":36,"is_preprint":false},{"pmid":"25320013","id":"PMC_25320013","title":"EGFR activation and signaling in cancer cells are enhanced by the membrane-bound metalloprotease MT4-MMP.","date":"2014","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25320013","citation_count":36,"is_preprint":false},{"pmid":"17825051","id":"PMC_17825051","title":"Establishment of an MT4-MMP-deficient mouse strain representing an efficient tracking system for MT4-MMP/MMP-17 expression in vivo using beta-galactosidase.","date":"2007","source":"Genes to cells : devoted to molecular & cellular 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/31813546","citation_count":18,"is_preprint":false},{"pmid":"21225300","id":"PMC_21225300","title":"Isolation and characterization of a new bacteriophage MMP17 from Meiothermus.","date":"2011","source":"Extremophiles : life under extreme conditions","url":"https://pubmed.ncbi.nlm.nih.gov/21225300","citation_count":15,"is_preprint":false},{"pmid":"32843096","id":"PMC_32843096","title":"MMPphg from the thermophilic Meiothermus bacteriophage MMP17 as a potential antimicrobial agent against both Gram-negative and Gram-positive bacteria.","date":"2020","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/32843096","citation_count":15,"is_preprint":false},{"pmid":"26663028","id":"PMC_26663028","title":"Dynamics of internalization and recycling of the prometastatic membrane type 4 matrix metalloproteinase (MT4-MMP) in breast cancer cells.","date":"2016","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/26663028","citation_count":15,"is_preprint":false},{"pmid":"28926609","id":"PMC_28926609","title":"Developmental expression of membrane type 4-matrix metalloproteinase (Mt4-mmp/Mmp17) in the mouse embryo.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28926609","citation_count":13,"is_preprint":false},{"pmid":"16686598","id":"PMC_16686598","title":"MT1-MMP hemopexin domain exchange with MT4-MMP blocks enzyme maturation and trafficking to the plasma membrane in MCF7 cells.","date":"2006","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/16686598","citation_count":12,"is_preprint":false},{"pmid":"21347258","id":"PMC_21347258","title":"Membrane-type 4 matrix metalloproteinase (MT4-MMP) modulates water homeostasis in mice.","date":"2011","source":"PloS 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pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28531887","citation_count":7,"is_preprint":false},{"pmid":"38571554","id":"PMC_38571554","title":"SH3GL2 and MMP17 as lung adenocarcinoma biomarkers: a machine-learning based approach.","date":"2024","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/38571554","citation_count":4,"is_preprint":false},{"pmid":"38158115","id":"PMC_38158115","title":"Doxycycline hydrochloride inhibits the progress of malignant rhabdoid tumor of kidney by targeting MMP17 and MMP1 through PI3K-Akt signaling pathway.","date":"2023","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38158115","citation_count":3,"is_preprint":false},{"pmid":"39062041","id":"PMC_39062041","title":"CCZ1 Accelerates the Progression of Cervical Squamous Cell Carcinoma by Promoting MMP2/MMP17 Expression.","date":"2024","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/39062041","citation_count":2,"is_preprint":false},{"pmid":"39747260","id":"PMC_39747260","title":"Plasma concentration of MMP-17 is elevated in boys with cryptorchidism and correlates with HSP-70.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39747260","citation_count":2,"is_preprint":false},{"pmid":"30792164","id":"PMC_30792164","title":"MT4-MMP Modulates the Expression of miRNAs in Breast Cancer Cells.","date":"2019","source":"Archives of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/30792164","citation_count":1,"is_preprint":false},{"pmid":"36733691","id":"PMC_36733691","title":"The Relationship Between MMP17 Variants and Ischemic Stroke Risk in the Population from Shaanxi Province in China.","date":"2023","source":"Pharmacogenomics and personalized 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\"finding\": \"MT4-MMP (MMP17) is a GPI-anchored proteinase — the first GPI-anchored member of the MMP family. [3H]ethanolamine labeling incorporated into the GPI unit in a sequence-dependent manner, and phosphatidylinositol-specific phospholipase C treatment released MT4-MMP from the cell surface of transfected cells. MT4-MMP is also shed from the cell surface by an endogenous metalloproteinase.\",\n      \"method\": \"Metabolic labeling with [3H]ethanolamine, PI-PLC treatment of transfected cells, cell surface release assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical reconstitution with two orthogonal methods (metabolic labeling + PI-PLC cleavage) in transfected cells, foundational finding\",\n      \"pmids\": [\"10567400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mouse MT4-MMP catalytic domain has TNF-alpha convertase activity: it efficiently cleaves a peptide spanning the pro-TNFα cleavage site, cleaves a GST-pro-TNFα fusion protein in vitro, and sheds pro-TNFα when co-transfected in COS-7 cells. However, it does not activate pro-MMP2 and shows very limited activity against ECM components except fibrinogen and fibrin. Catalytic activity is inhibited by TIMP-1, -2, and -3.\",\n      \"method\": \"E. coli expression/refolding of recombinant catalytic domain, synthetic peptide cleavage assay, GST-fusion protein cleavage, co-transfection shedding assay in COS-7 cells, TIMP inhibition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro and cell-based assays with recombinant protein and mutagenesis-compatible controls, replicated in cell-based system\",\n      \"pmids\": [\"10799478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The originally reported human MT4-MMP cDNA (Puente et al. 1996) lacked the full ORF and failed to express protein. A new major transcript with an extended open reading frame was identified by 5' RACE and encodes 67 and 71 kDa translation products — the functional MT4-MMP protein.\",\n      \"method\": \"5' RACE, cDNA cloning, protein expression in transfected cells (Western blot)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 5' RACE plus expression validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"10471807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MT4-MMP expressed in COS-7 cells localizes to the cell surface but does not activate pro-MMP2, distinguishing it functionally from MT1-, MT2-, and MT3-MMP.\",\n      \"method\": \"COS-7 cell transfection, cell-surface expression assay, pro-MMP2 activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cell-based assay with clear negative result for pro-MMP2 activation, single lab\",\n      \"pmids\": [\"10799478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The hemopexin domain of MT4-MMP, when substituted into MT1-MMP chimeras, blocks propeptide processing, prevents trafficking to the plasma membrane (retained in ER), and abolishes pro-MMP2 activation and gelatin degradation. The MT4-MMP hemopexin domain therefore carries an intrinsic inhibitory signal for enzyme maturation and trafficking.\",\n      \"method\": \"MT1-MT4-MMP chimera construction, cell-surface biotinylation, indirect immunofluorescence, pro-MMP2 activation assay, gelatin degradation assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain-swap mutagenesis with multiple orthogonal readouts (surface biotinylation, immunofluorescence, functional activity assays), single lab\",\n      \"pmids\": [\"16686598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In vivo, MT4-MMP is expressed primarily in cerebrum, lung, spleen, intestine and uterus; specifically in neurons (cerebrum), smooth muscle cells (intestine, uterus), and macrophages (lung alveolar/intraperitoneal space). LPS-induced TNF-α release from MT4-MMP-null macrophages was not different from wild-type, and MT4-MMP mRNA was repressed by LPS stimulation — arguing against a dominant role as a TNFα sheddase in macrophages in vivo.\",\n      \"method\": \"MT4-MMP KO mouse with LacZ reporter, β-galactosidase staining, RT-PCR, TNF-α release assay from macrophages\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic reporter model plus functional macrophage assay, single lab\",\n      \"pmids\": [\"17825051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MT4-MMP is required for IL-1-induced aggrecanolysis in bovine cartilage explants. Blocking GPI-anchor synthesis with mannosamine (inhibiting MT4-MMP membrane anchoring) blocked IL-1-mediated aggrecan cleavage, MT4-MMP induction, and ADAMTS4 processing (p68→p53 conversion and release). This supports MT4-MMP-mediated processing of resident ADAMTS4 as the mechanism of aggrecanolysis.\",\n      \"method\": \"Bovine cartilage explant treatment with IL-1, Western blot for aggrecan fragments, MT4-MMP, and ADAMTS4, mannosamine GPI-anchor inhibition, esculetin MMP inhibition\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition of GPI anchoring combined with Western blot readouts, indirect evidence for MT4-MMP→ADAMTS4 axis, single lab\",\n      \"pmids\": [\"15780640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The proteolytic activity of MT4-MMP is required for its pro-angiogenic and pro-metastatic effects in breast cancer. Glutamic acid 249→Alanine active-site mutation abolished the MT4-MMP-induced angiogenic switch, tumor growth acceleration, and lung colonization. Tumor-derived (not host-derived) MT4-MMP drives angiogenesis; MT4-MMP-deficient host mice were unaffected.\",\n      \"method\": \"Site-directed mutagenesis (E249A), subcutaneous tumor implantation in RAG1-deficient mice, MT4-MMP-null mouse host experiments, tumor growth and lung colonization assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis combined with in vivo genetic loss-of-function model and multiple tumor biology readouts, single lab\",\n      \"pmids\": [\"22262494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MT4-MMP directly associates with EGFR at the cell surface and enhances EGFR phosphorylation in response to TGFα and EGF, driving cancer cell proliferation through CDK4 activation and retinoblastoma protein inactivation. These effects on proliferation and EGFR activation do not require MT4-MMP metalloprotease activity.\",\n      \"method\": \"Co-immunoprecipitation, EGFR phosphorylation assays, cell proliferation assays, CDK4/Rb pathway analysis, catalytic mutant comparison\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional signaling assays and catalytic mutant used to dissect mechanism, single lab\",\n      \"pmids\": [\"25320013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MMP17/MT4-MMP cleaves osteopontin, and this cleavage regulates vascular smooth muscle cell maturation via c-Jun N-terminal kinase (JNK) signaling during aorta wall development. Loss of Mmp17 in mice results in dysfunctional VSMCs and altered ECM, leading to increased susceptibility to angiotensin-II-induced thoracic aortic aneurysm. Re-expression of catalytically active Mmp17 or the N-terminal osteopontin fragment rescued part of the vessel-wall phenotype.\",\n      \"method\": \"Mmp17 knockout mouse model, angiotensin-II-induced aneurysm model, lentiviral re-expression of active Mmp17 or osteopontin fragment, JNK signaling analysis, human patient mutation (R373H) blocking expression\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic KO model combined with rescue experiments (catalytically active enzyme and substrate fragment), human mutation validation, multiple orthogonal readouts\",\n      \"pmids\": [\"25963716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MT4-MMP forms homophilic complexes (oligomers and dimers) at the cell surface. It is internalized via the clathrin-independent carriers/GPI-enriched early endosomal compartments (CLIC/GEEC) pathway into early endosomes, where it is either autodegraded or recycled to the cell surface. Internalization was reduced by CDC42 or RhoA siRNA silencing but not by caveolin-1 or clathrin pathway inhibitors.\",\n      \"method\": \"Co-immunoprecipitation of FLAG- and Myc-tagged MT4-MMP, reducing/non-reducing immunoblotting, antibody feeding assay with confocal microscopy, cell surface biotinylation/Western blot, siRNA knockdown of CDC42/RhoA/caveolin-1\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal trafficking assays with genetic perturbations, single lab\",\n      \"pmids\": [\"26663028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MT4-MMP in melanoma cells is processed by furin cleavage in the Golgi apparatus. The 69 kDa form is the intracellular precursor and the 58 kDa form is the mature protein present at the cell membrane. Asn318 was identified as the single N-glycosylation site of MT4-MMP.\",\n      \"method\": \"Iodixanol gradient organelle fractionation, glycosidase treatment, site-directed mutagenesis of N-glycosylation sites, Western blotting\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of glycosylation site combined with fractionation and enzymatic deglycosylation, single lab\",\n      \"pmids\": [\"28531887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MT4-MMP deficiency in mice increases adhesion of patrolling monocytes to inflamed endothelia, elevates Mafb+AIM+ macrophage accumulation at early atherosclerotic lesions, and accelerates atherosclerosis. MT4-MMP-null Mafb+AIM+ macrophages show higher AIM and CD36 expression, increased resistance to apoptosis, and avid acLDL binding. CCR5 inhibition blocks the enhanced recruitment of MT4-MMP-null patrolling monocytes and alleviates atherosclerosis acceleration.\",\n      \"method\": \"MT4-MMP KO mouse crossed to atherosclerosis model, intravital microscopy, flow cytometry, peritoneal macrophage functional assays (apoptosis, acLDL binding), CCR5 inhibitor treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model with multiple orthogonal cellular assays, pharmacological rescue, in vivo imaging, published in high-quality journal\",\n      \"pmids\": [\"29500407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MT4-MMP promotes invadopodia formation and amoeboid-like cell movement in head and neck cancer cells. Mechanistically, MT4-MMP binds Tks5 and PDGFRα, leading to Src activation (invadopodia), and stimulates Rho and Cdc42 GTPases (amoeboid movement). MT4-MMP expression increased gelatin degradation in 3D assays.\",\n      \"method\": \"MT4-MMP overexpression in FaDu cells, 3D collagen/gelatin invasion assays, co-immunoprecipitation of MT4-MMP with Tks5 and PDGFRα, Src/Rho/Cdc42 activity assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP binding data combined with functional invasion assays and signaling readouts, single lab\",\n      \"pmids\": [\"31813546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MMP17, exclusively expressed by smooth muscle cells in the intestine, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. MMP17 affects intestinal epithelial reprogramming indirectly by cleaving the matricellular protein PERIOSTIN, and smooth muscle-derived MMP17 promotes BMP antagonist supply essential for intestinal stem cell maintenance and YAP activity.\",\n      \"method\": \"Mmp17 KO mouse, intestinal injury models (inflammation, irradiation), intestinal organoid assays, PERIOSTIN cleavage assay, YAP activity analysis, single-cell/cell-type-specific expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with multiple injury models, substrate cleavage evidence, organoid functional assays, published in high-quality journal\",\n      \"pmids\": [\"34795242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MMP17 expressed in smooth muscle cells and lamina propria macrophages of the intestine extrinsically regulates goblet cell maturation. Mmp17 KO mice show elevated goblet-cell-associated genes (CLCA1, RELM-β) and increased resistance to low-dose Trichuris muris helminth infection. The mechanism does not appear to involve NOTCH pathway changes or altered cytokine levels.\",\n      \"method\": \"Mmp17 KO mouse, helminth (T. muris) infection model, Citrobacter rodentium infection model, gene/protein expression analysis of goblet cell markers\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with two infection models and molecular readouts, single lab, mechanism incompletely defined\",\n      \"pmids\": [\"37869014\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MMP17 (MT4-MMP) is a GPI-anchored, cell-surface matrix metalloproteinase that is processed by furin in the Golgi, forms homophilic complexes, and internalizes via a clathrin-independent/CDC42-RhoA-dependent pathway; its catalytic activity cleaves substrates including pro-TNFα, fibrinogen/fibrin, osteopontin, and PERIOSTIN, while its non-catalytic scaffold function enhances EGFR signaling through direct physical association, collectively regulating vascular smooth muscle cell maturation (via osteopontin-JNK signaling), intestinal stem cell niche maintenance and epithelial repair (via PERIOSTIN cleavage), monocyte/macrophage behavior in atherosclerosis (via CCR5-dependent patrolling monocyte recruitment), and tumor angiogenesis and metastasis (requiring proteolytic activity in tumor cells).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MMP17 (MT4-MMP) is a GPI-anchored, cell-surface matrix metalloproteinase that regulates tissue remodeling and stem-cell niche function through both proteolytic and non-catalytic scaffolding activities [#0, #9, #14]. It is the first GPI-anchored MMP, attached to the membrane via a sequence-dependent GPI unit and releasable by PI-PLC, and is also shed by an endogenous metalloproteinase [#0]. The enzyme matures through furin cleavage in the Golgi to a membrane-resident form, carries a single N-glycosylation site at Asn318, and its hemopexin domain harbors an intrinsic inhibitory signal that restrains trafficking and enzyme maturation [#11, #4]. At the surface it forms homophilic oligomers and is internalized by a clathrin-independent, CDC42/RhoA-dependent CLIC/GEEC route into early endosomes for autodegradation or recycling [#10]. Catalytically, MT4-MMP has TNFα-convertase activity and a narrow ECM substrate range limited largely to fibrinogen/fibrin, and notably does not activate pro-MMP2, distinguishing it from other membrane-type MMPs; its activity is inhibited by TIMP-1, -2, and -3 [#1, #3]. Its physiological substrates include osteopontin, whose cleavage controls vascular smooth muscle cell maturation via JNK signaling such that loss of Mmp17 produces dysfunctional VSMCs and susceptibility to angiotensin-II-induced thoracic aortic aneurysm, and PERIOSTIN, whose cleavage by smooth-muscle-derived MMP17 supports BMP-antagonist supply, intestinal stem cell maintenance, YAP activity, and epithelial repair after injury [#9, #14]. A human R373H mutation that blocks MMP17 expression links the gene to the aortic vessel-wall phenotype [#9]. Independently of proteolysis, MT4-MMP directly associates with EGFR to enhance EGFR phosphorylation and drive proliferation through CDK4/Rb [#8]. In disease, tumor-derived (not host) MT4-MMP requires its catalytic activity to drive the angiogenic switch and metastasis, and it deficiency accelerates atherosclerosis through CCR5-dependent patrolling-monocyte recruitment [#7, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the unique membrane attachment mode of MT4-MMP, defining it as the first GPI-anchored MMP rather than a transmembrane membrane-type MMP.\",\n      \"evidence\": \"[3H]ethanolamine metabolic labeling and PI-PLC release in transfected cells\",\n      \"pmids\": [\"10567400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which endogenous metalloproteinase sheds MT4-MMP\", \"Functional consequences of GPI anchoring vs shedding not addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved the discrepancy in the original cDNA by identifying the true full-length ORF, enabling expression of functional MT4-MMP protein.\",\n      \"evidence\": \"5' RACE and cDNA cloning with expression validation by Western blot\",\n      \"pmids\": [\"10471807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not characterize protein function\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the catalytic specificity of MT4-MMP, showing TNFα-convertase activity and a narrow ECM substrate range while ruling out pro-MMP2 activation, separating it functionally from MT1/2/3-MMP.\",\n      \"evidence\": \"Recombinant catalytic domain peptide/fusion cleavage, COS-7 shedding assay, TIMP inhibition, and pro-MMP2 activation assay\",\n      \"pmids\": [\"10799478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro TNFα cleavage not shown to be physiologically dominant\", \"Full physiological substrate repertoire unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Implicated MT4-MMP in cartilage catabolism by linking its GPI-anchored activity to ADAMTS4 processing and IL-1-induced aggrecanolysis.\",\n      \"evidence\": \"Bovine cartilage explants with mannosamine GPI-inhibition and Western blots for aggrecan, MT4-MMP, and ADAMTS4\",\n      \"pmids\": [\"15780640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological inhibition is indirect for MT4-MMP function\", \"Direct MT4-MMP cleavage of ADAMTS4 not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Located an intrinsic maturation/trafficking control within the hemopexin domain, explaining why MT4-MMP behaves differently from other MT-MMPs.\",\n      \"evidence\": \"MT1/MT4-MMP domain-swap chimeras with surface biotinylation, immunofluorescence, and activity assays\",\n      \"pmids\": [\"16686598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of the inhibitory signal undefined\", \"Studied in chimeric context rather than native protein\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped in vivo expression and challenged the TNFα-sheddase model by showing normal LPS-induced TNFα release in MT4-MMP-null macrophages.\",\n      \"evidence\": \"MT4-MMP KO/LacZ reporter mouse, β-gal staining, RT-PCR, and macrophage TNFα release assay\",\n      \"pmids\": [\"17825051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not exclude TNFα cleavage in other contexts\", \"Did not identify the dominant in vivo substrate\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that catalytic activity of tumor-derived MT4-MMP is required for angiogenesis and metastasis, isolating a proteolysis-dependent oncogenic function.\",\n      \"evidence\": \"E249A active-site mutant, subcutaneous tumors in RAG1-deficient and MT4-MMP-null host mice, tumor growth and lung colonization assays\",\n      \"pmids\": [\"22262494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pro-angiogenic substrate not identified\", \"Mechanism of the angiogenic switch unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Uncovered a non-catalytic scaffold function whereby MT4-MMP physically associates with EGFR to amplify signaling and proliferation.\",\n      \"evidence\": \"Co-IP, EGFR phosphorylation and proliferation assays, CDK4/Rb analysis, and catalytic mutant comparison\",\n      \"pmids\": [\"25320013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect EGFR binding not structurally defined\", \"Single lab without reciprocal validation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified osteopontin as a physiological substrate linking MT4-MMP proteolysis to VSMC maturation and aortic wall integrity, with a human mutation tying the gene to aneurysm susceptibility.\",\n      \"evidence\": \"Mmp17 KO mice, angiotensin-II aneurysm model, rescue with active enzyme or osteopontin fragment, JNK analysis, and human R373H mutation\",\n      \"pmids\": [\"25963716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical osteopontin cleavage site mapping not detailed\", \"How JNK output is set by the osteopontin fragment unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined MT4-MMP surface oligomerization and its clathrin-independent CDC42/RhoA-dependent internalization and recycling itinerary.\",\n      \"evidence\": \"Co-IP of differentially tagged MT4-MMP, reducing/non-reducing blots, antibody-feeding confocal assays, biotinylation, and CDC42/RhoA/caveolin-1 siRNA\",\n      \"pmids\": [\"26663028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional purpose of homophilic complexes unclear\", \"Trafficking studied in cell lines only\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established the biosynthetic maturation pathway, showing furin cleavage in the Golgi yields the mature membrane form and identifying Asn318 as the sole N-glycosylation site.\",\n      \"evidence\": \"Iodixanol organelle fractionation, glycosidase treatment, and N-glycosylation site mutagenesis in melanoma cells\",\n      \"pmids\": [\"28531887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of glycosylation not tested\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a vasculoprotective role in atherosclerosis, with MT4-MMP loss accelerating disease via CCR5-dependent patrolling-monocyte recruitment.\",\n      \"evidence\": \"MT4-MMP KO crossed to atherosclerosis model, intravital microscopy, flow cytometry, macrophage functional assays, and CCR5 inhibitor rescue\",\n      \"pmids\": [\"29500407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct MT4-MMP substrate controlling monocyte adhesion not identified\", \"Catalytic vs scaffold dependence not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected MT4-MMP to invasive cancer cell motility through binding Tks5 and PDGFRα to activate Src and Rho/Cdc42.\",\n      \"evidence\": \"Overexpression in FaDu cells, 3D invasion assays, co-IP with Tks5 and PDGFRα, and Src/Rho/Cdc42 activity assays\",\n      \"pmids\": [\"31813546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression system may not reflect endogenous behavior\", \"Direct vs indirect partner binding not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified PERIOSTIN cleavage by smooth-muscle MMP17 as the niche signal supporting BMP antagonism, intestinal stem cell maintenance, and epithelial repair.\",\n      \"evidence\": \"Mmp17 KO mice, inflammation/irradiation injury models, organoid assays, PERIOSTIN cleavage assay, and YAP analysis\",\n      \"pmids\": [\"34795242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise BMP-antagonist link to periostin fragment incompletely mapped\", \"Cleavage site on periostin not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended MMP17's niche-regulatory role to goblet cell maturation and anti-helminth resistance, while excluding NOTCH and cytokine changes as mechanism.\",\n      \"evidence\": \"Mmp17 KO mice, T. muris and C. rodentium infection models, and goblet cell marker expression analysis\",\n      \"pmids\": [\"37869014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effector substrate driving goblet cell phenotype unknown\", \"Mechanism remains incompletely defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MT4-MMP's catalytic and non-catalytic (EGFR-scaffold) functions are coordinated across tissues, and which substrate cleavages drive each in vivo phenotype, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking proteolysis-dependent and scaffold functions\", \"Substrates underlying monocyte and goblet cell phenotypes unidentified\", \"No structural model of substrate or EGFR engagement\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 9, 14]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 11]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EGFR\", \"Tks5\", \"PDGFRA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":9,"faith_pct":88.88888888888889}}