{"gene":"MMP17","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":1999,"finding":"MT4-MMP (MMP17) is anchored to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor, making it the first GPI-anchored proteinase in the MMP family. This was demonstrated by [3H]ethanolamine labeling of the GPI unit in a sequence-dependent manner and release from the cell surface by phosphatidylinositol-specific phospholipase C treatment. MT4-MMP is also shed from the cell surface by an endogenous metalloproteinase.","method":"Radiolabeling ([3H]ethanolamine incorporation), phosphatidylinositol-specific phospholipase C treatment, cell surface shedding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical reconstitution with multiple orthogonal methods confirming GPI anchor","pmids":["10567400"],"is_preprint":false},{"year":2000,"finding":"Mouse MT4-MMP (MMP17) expressed at the cell surface does not activate pro-MMP2. The recombinant catalytic domain, refolded from E. coli inclusion bodies, is inhibited by TIMP-1, -2, and -3, is poorly active against ECM components except fibrinogen and fibrin, and efficiently cleaves a pro-TNFα cleavage-site peptide and a GST-pro-TNFα fusion protein. MT4-MMP also sheds pro-TNFα when co-transfected in COS-7 cells, demonstrating TNFα convertase activity.","method":"Recombinant protein expression and refolding, synthetic peptide assays, GST-fusion protein cleavage, co-transfection shedding assay in COS-7 cells, TIMP inhibition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assays with recombinant protein and cell-based shedding assay, replicated across substrates","pmids":["10799478"],"is_preprint":false},{"year":1999,"finding":"The functional human MT4-MMP (MMP17) is encoded by a major transcript with an extended open reading frame producing 67 and 71 kDa translation products; the previously reported minor transcript failed to express protein.","method":"5' RACE, cDNA cloning, expression in cells with Western blot","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 — direct molecular identification of functional transcript with protein expression confirmation","pmids":["10471807"],"is_preprint":false},{"year":2005,"finding":"MT4-MMP is involved in IL-1-induced aggrecanolysis in bovine cartilage. IL-1 treatment increases MT4-MMP abundance in tissue and medium, and blockade of GPI anchor synthesis with mannosamine inhibits both MT4-MMP increase and aggrecan cleavage. The data support MT4-MMP-mediated processing of ADAMTS4 (conversion of p68 to p53) and its release from the cell surface as a mechanism of aggrecanolysis.","method":"Western blot analysis of aggrecan fragments and MT4-MMP/ADAMTS4 species, pharmacological inhibition (mannosamine, esculetin), real-time PCR in cartilage explants","journal":"Osteoarthritis and cartilage","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in tissue model but indirect (inhibitor-based) evidence for MT4-MMP as the active agent","pmids":["15780640"],"is_preprint":false},{"year":2006,"finding":"The hemopexin domain of MT4-MMP prevents proper maturation, processing, and trafficking to the plasma membrane when substituted into MT1-MMP chimeras. MT1-MMP chimeras bearing the MT4-MMP hemopexin domain are retained in the endoplasmic reticulum, fail to undergo propeptide processing, and cannot activate pro-MMP2 or degrade gelatin.","method":"Domain-swap chimera construction, cell surface biotinylation, indirect immunofluorescence, pro-MMP2 activation assay, gelatin degradation assay, propeptide-specific antibody Western blot","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods with domain-swap mutagenesis and functional rescue","pmids":["16686598"],"is_preprint":false},{"year":2007,"finding":"MT4-MMP is expressed primarily in cerebrum, lung, spleen, intestine and uterus in vivo, with expression in neurons, intestinal/uterine smooth muscle cells, and alveolar/intraperitoneal macrophages. MT4-MMP-null mice have normal growth and fertility. LPS-induced TNFα release from MT4-MMP-null macrophages was not different from wild-type, suggesting MT4-MMP is not the primary TNFα sheddase in macrophages.","method":"LacZ reporter knock-in mouse model, LacZ staining, RT-PCR tissue distribution, LPS-stimulated macrophage TNFα release assay","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function model with in vivo reporter and functional cellular assays","pmids":["17825051"],"is_preprint":false},{"year":2009,"finding":"MT4-MMP expression in breast cancer cells promotes lung metastasis by increasing tumor vascular permeability: it induces blood vessel enlargement and detachment of mural cells from the vascular tree, facilitating tumor cell intravasation (not extravasation or lymph node colonization).","method":"Experimental (intravenous) and spontaneous (subcutaneous) lung metastasis models, ultrastructural and fluorescent microscopy, computer-assisted quantification of vessel morphology, intravasation assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — defined cellular phenotype with imaging evidence but no direct molecular mechanism for mural cell detachment","pmids":["19426156"],"is_preprint":false},{"year":2012,"finding":"The proteolytic activity of MT4-MMP is required for its pro-angiogenic and pro-metastatic effects. Catalytic inactivation (E249A mutation in the active site) abrogates the angiogenic switch, tumor growth acceleration, and lung colonization driven by tumor cell-derived MT4-MMP. Host (stromal)-derived MT4-MMP does not contribute to the angiogenic response.","method":"Site-directed mutagenesis (E249A), subcutaneous tumor implantation in RAG1-deficient mice, MT4-MMP-deficient mouse host experiments, angiogenesis quantification","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 1-2 — active site mutagenesis combined with genetic host KO model and functional tumor assays","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 via CDK4 activation and retinoblastoma protein inactivation. These effects on EGFR activation do not require MT4-MMP metalloprotease activity.","method":"Co-immunoprecipitation, phosphorylation assays, proliferation assays, CDK4/Rb signaling analysis, metalloprotease-inactive mutant comparison","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP showing direct association plus functional assays, but mechanistic details of the non-proteolytic EGFR interaction are incomplete","pmids":["25320013"],"is_preprint":false},{"year":2015,"finding":"MMP17 proteolytic activity regulates vascular smooth muscle cell maturation in the arterial wall via cleavage of osteopontin, generating an N-terminal osteopontin fragment that activates c-Jun N-terminal kinase (JNK) signaling. Loss of Mmp17 leads to dysfunctional vascular smooth muscle cells, altered extracellular matrix, and increased susceptibility to angiotensin-II-induced thoracic aortic aneurysm. Re-expression of catalytically active Mmp17 or the N-terminal osteopontin fragment partially rescues the vessel-wall phenotype.","method":"Mmp17 knock-out mouse model, angiotensin-II aneurysm model, lentiviral re-expression of active Mmp17 and osteopontin fragment, JNK signaling analysis, mass spectrometry proteomics, human patient missense mutation (R373H) functional analysis","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO, catalytically active rescue, substrate identification, downstream signaling pathway defined; strong and multiple orthogonal methods","pmids":["25963716"],"is_preprint":false},{"year":2016,"finding":"MT4-MMP forms homophilic dimeric and oligomeric complexes at the cell surface and 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 requires CDC42 and RhoA, but not caveolin-1 or clathrin pathways.","method":"Co-immunoprecipitation with FLAG/Myc-tagged MT4-MMP, non-reducing/reducing immunoblotting, antibody-feeding internalization assay, confocal microscopy, cell surface biotinylation, siRNA knockdown of CDC42, RhoA, caveolin-1, pharmacological inhibitors","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, live cell trafficking, siRNA knockdown, pharmacological inhibition) in a single study","pmids":["26663028"],"is_preprint":false},{"year":2017,"finding":"MT4-MMP in melanoma cells exists in three forms (45, 58, and 69 kDa): the 58 kDa form is the mature cell membrane protein, and the 69 kDa form is its intracellular precursor processed by furin cleavage in the Golgi apparatus. Asn318 is the single N-glycosylation site of MT4-MMP.","method":"Western blotting, iodixanol density gradient organelle fractionation, glucosidase treatment, site-directed mutagenesis of N-glycosylation sites, quantitative PCR","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — organelle fractionation plus mutagenesis identifying glycosylation site and processing pathway","pmids":["28531887"],"is_preprint":false},{"year":2019,"finding":"MT4-MMP promotes invadopodia formation and amoeboid cell movement in head and neck cancer cells. Mechanistically, MT4-MMP binds Tks5 and PDGFRα to activate Src, driving invadopodia formation, and stimulates small GTPases RhoA and Cdc42 to promote amoeboid-like movement on collagen gel.","method":"MT4-MMP overexpression in FaDu cells, 3D invadopodia assay, gelatin degradation assay, collagen gel motility assay, co-immunoprecipitation (MT4-MMP with Tks5 and PDGFRα), Src activation assay, Rho/Cdc42 activation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP combined with functional 3D assays, but single lab and limited mechanistic depth","pmids":["31813546"],"is_preprint":false},{"year":2021,"finding":"MMP17 is exclusively expressed by intestinal smooth muscle cells and is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Mechanistically, MMP17 cleaves the matricellular protein PERIOSTIN (and possibly other diffusible factors), indirectly modulating epithelial reprogramming including YAP activity. Smooth muscle cells are identified as major suppliers of BMP antagonists essential for intestinal stem cell niche maintenance.","method":"Mmp17 knockout mice, inflammation and irradiation injury models, single-cell RNA sequencing, proteomics (PERIOSTIN cleavage), YAP activity assays, organoid culture experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO model with injury assays, substrate identification, and signaling pathway analysis using multiple orthogonal methods","pmids":["34795242"],"is_preprint":false},{"year":2018,"finding":"MT4-MMP deficiency in mice results in increased adherence of macrophages to inflamed peritonea, higher numbers of patrolling monocytes crawling on inflamed endothelia, and accumulation of Mafb+AIM+ macrophages at atherosclerotic lesions. MT4-MMP-null Mafb+AIM+ macrophages express higher AIM and scavenger receptor CD36, are more resistant to apoptosis, and bind acLDL more avidly. CCR5 inhibition alleviates enhanced recruitment of MT4-MMP-null patrolling monocytes, blocking atherosclerosis acceleration.","method":"MT4-MMP-deficient mice crossed to atherosclerosis model, intravital microscopy, flow cytometry, macrophage adhesion and apoptosis assays, acLDL binding assay, CCR5 inhibitor treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO mouse model with multiple orthogonal cellular and in vivo functional readouts","pmids":["29500407"],"is_preprint":false},{"year":2023,"finding":"MMP17 expressed by smooth muscle cells and lamina propria macrophages in the intestine extrinsically regulates goblet cell maturation. Mmp17 knockout mice show elevated goblet cell effector gene expression (CLCA1, RELM-β) and increased resistance to low-dose Trichuris muris helminth infection, without changes in NOTCH pathway activity or specific cytokine levels.","method":"Mmp17 knockout mice, Trichuris muris and Citrobacter rodentium infection models, gene and protein expression analysis, single-cell RNA sequencing, NOTCH pathway analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined infection model phenotype, but molecular mechanism of goblet cell regulation is not fully resolved","pmids":["37869014"],"is_preprint":false}],"current_model":"MMP17 (MT4-MMP) is a GPI-anchored membrane metalloproteinase that cleaves substrates including pro-TNFα, fibrinogen/fibrin, osteopontin (generating a JNK-activating N-terminal fragment to regulate vascular smooth muscle cell maturation), PERIOSTIN (modulating intestinal epithelial regeneration), and ADAMTS4 (contributing to cartilage aggrecanolysis); it forms homophilic surface complexes, is internalized via the CLIC/GEEC pathway in a CDC42/RhoA-dependent manner, activates EGFR signaling and Src/Tks5/PDGFRα complexes non-proteolytically to drive cancer cell proliferation and invasion, and its GPI anchor, furin-mediated Golgi processing, and hemopexin domain each govern distinct aspects of its trafficking, maturation, and inability to activate pro-MMP2."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing MMP17 as the first GPI-anchored MMP resolved how a membrane metalloproteinase could be tethered without a transmembrane domain, revealing a novel mode of surface presentation and shedding.","evidence":"[3H]ethanolamine radiolabeling and PI-PLC release from cell surface","pmids":["10567400"],"confidence":"High","gaps":["Identity of the endogenous metalloproteinase responsible for MMP17 shedding was not determined","Functional consequences of GPI anchoring versus transmembrane anchoring were not compared"]},{"year":2000,"claim":"Defining the substrate profile revealed that MMP17 is a poor ECM protease but an efficient pro-TNFα sheddase and fibrinogen/fibrin protease, distinguishing it functionally from transmembrane MT-MMPs that activate pro-MMP2.","evidence":"Recombinant catalytic domain assays against ECM substrates, GST-pro-TNFα cleavage, and COS-7 co-transfection shedding assay","pmids":["10799478"],"confidence":"High","gaps":["In vivo relevance of TNFα shedding by MMP17 was not tested","Full substrate repertoire remained uncharacterized"]},{"year":2005,"claim":"Linking MMP17 to cartilage aggrecanolysis via ADAMTS4 processing revealed a new indirect mechanism by which a GPI-anchored MMP can regulate ECM turnover.","evidence":"IL-1-treated bovine cartilage explants with mannosamine inhibition of GPI anchor synthesis, Western blot of ADAMTS4 processing","pmids":["15780640"],"confidence":"Medium","gaps":["Evidence for MMP17 as the responsible GPI-anchored protease is indirect (pharmacological inhibitor affects all GPI-anchored proteins)","Direct cleavage of ADAMTS4 by MMP17 was not reconstituted in vitro"]},{"year":2006,"claim":"Domain-swap experiments showed that the hemopexin domain of MMP17 prevents ER-to-surface maturation when placed in MT1-MMP, explaining why MMP17 cannot activate pro-MMP2 and establishing that domain-specific features dictate its trafficking fate.","evidence":"MT1-MMP/MT4-MMP hemopexin domain chimeras assayed for surface biotinylation, propeptide processing, and pro-MMP2 activation","pmids":["16686598"],"confidence":"High","gaps":["Structural basis for ER retention by the MMP17 hemopexin domain was not resolved","Whether hemopexin domain also governs substrate selectivity was not tested"]},{"year":2007,"claim":"Generation of MMP17-null mice revealed its tissue expression pattern (neurons, smooth muscle, macrophages) and showed that it is dispensable for TNFα shedding in macrophages, redirecting the search for its physiological substrates.","evidence":"LacZ knock-in reporter mouse, LPS-stimulated macrophage TNFα release assay","pmids":["17825051"],"confidence":"High","gaps":["Physiological substrates in smooth muscle and neurons remained unidentified","Compensatory mechanisms by other sheddases were not excluded"]},{"year":2009,"claim":"Demonstrating that MMP17 promotes lung metastasis by increasing tumor vascular permeability and mural cell detachment identified a specific pro-metastatic mechanism distinct from direct ECM degradation.","evidence":"Spontaneous and experimental lung metastasis models with ultrastructural vessel analysis","pmids":["19426156"],"confidence":"Medium","gaps":["Molecular substrate responsible for mural cell detachment was not identified","Contribution of proteolytic versus non-proteolytic activity was not distinguished"]},{"year":2012,"claim":"Active-site mutagenesis (E249A) established that proteolytic activity is required for MMP17-driven angiogenesis and metastasis, and host-derived MMP17 is dispensable, pinpointing tumor-cell-intrinsic catalysis as the driver.","evidence":"E249A catalytic-dead mutant in subcutaneous tumor models and MMP17-deficient hosts (RAG1−/− mice)","pmids":["22262494"],"confidence":"High","gaps":["The pro-angiogenic substrate cleaved by tumor-derived MMP17 was not identified","Whether the non-proteolytic EGFR mechanism contributes to angiogenesis was not tested"]},{"year":2014,"claim":"Discovery that MMP17 associates with EGFR and enhances its phosphorylation independently of catalytic activity revealed a non-proteolytic signaling function, expanding MMP17's role beyond substrate cleavage.","evidence":"Co-immunoprecipitation of MMP17–EGFR, proliferation and CDK4/Rb pathway analysis with catalytically inactive mutant","pmids":["25320013"],"confidence":"Medium","gaps":["Structural basis of MMP17–EGFR interaction is unknown","Whether GPI-anchor microdomain co-localization drives the interaction was not tested","In vivo relevance of non-proteolytic EGFR activation was not assessed"]},{"year":2015,"claim":"Identification of osteopontin as a physiological MMP17 substrate whose N-terminal cleavage fragment activates JNK signaling resolved the mechanism by which MMP17 regulates vascular smooth muscle cell maturation and protects against aortic aneurysm.","evidence":"Mmp17 KO mouse, angiotensin-II aneurysm model, lentiviral re-expression of catalytically active MMP17 and OPN N-terminal fragment, mass spectrometry, human R373H mutation analysis","pmids":["25963716"],"confidence":"High","gaps":["How the OPN N-terminal fragment specifically activates JNK is mechanistically unresolved","Whether the human R373H variant causes clinical aortic disease was not established in a family study"]},{"year":2016,"claim":"Elucidating MMP17 homophilic complex formation and CLIC/GEEC-mediated internalization dependent on CDC42/RhoA defined the trafficking itinerary of this GPI-anchored protease and explained how surface levels are regulated.","evidence":"Co-IP of tagged MMP17 constructs, antibody-feeding internalization assay, siRNA knockdown of CDC42/RhoA/caveolin-1","pmids":["26663028"],"confidence":"High","gaps":["Functional consequence of homophilic oligomerization for catalytic activity was not determined","Whether oligomerization state governs internalization rate is unknown"]},{"year":2017,"claim":"Mapping the biosynthetic pathway showed furin-dependent Golgi processing of the 69 kDa precursor to the 58 kDa mature form, with Asn318 as the sole N-glycosylation site, clarifying MMP17 maturation steps.","evidence":"Organelle fractionation, glycosidase treatment, N-glycosylation site mutagenesis in melanoma cells","pmids":["28531887"],"confidence":"Medium","gaps":["Role of N-glycosylation at Asn318 in folding, trafficking, or catalysis was not functionally tested","Identity of the 45 kDa species (degradation product vs. alternatively processed form) was not resolved"]},{"year":2018,"claim":"MMP17 deficiency enhanced patrolling monocyte recruitment and Mafb+AIM+ macrophage accumulation at atherosclerotic lesions, identifying MMP17 as a regulator of myeloid cell adhesion and atherogenesis.","evidence":"MMP17-KO mice crossed to atherosclerosis model, intravital microscopy, flow cytometry, CCR5 inhibitor rescue","pmids":["29500407"],"confidence":"High","gaps":["The substrate cleaved by MMP17 to regulate monocyte/macrophage adhesion is unknown","Whether macrophage-intrinsic or smooth-muscle-derived MMP17 is responsible was not resolved"]},{"year":2019,"claim":"MMP17 was shown to form complexes with Tks5 and PDGFRα to activate Src, promoting invadopodia and amoeboid movement, revealing a second non-proteolytic scaffolding function in cancer invasion.","evidence":"Co-IP of MMP17 with Tks5/PDGFRα, 3D invadopodia and collagen gel motility assays in FaDu head and neck cancer cells","pmids":["31813546"],"confidence":"Medium","gaps":["Whether this scaffolding function requires the GPI anchor or hemopexin domain is untested","Single lab finding without independent replication","Contribution of proteolytic versus scaffolding activity was not separated"]},{"year":2021,"claim":"Identification of PERIOSTIN as an MMP17 substrate in intestinal smooth muscle cells established a paracrine mechanism by which mesenchymal cells regulate epithelial regeneration and YAP activity after injury.","evidence":"Mmp17 KO mice with colitis and irradiation injury models, proteomics, organoid culture, single-cell RNA-seq","pmids":["34795242"],"confidence":"High","gaps":["Direct cleavage site on PERIOSTIN and identity of active fragments were not fully characterized","Whether other diffusible substrates contribute to the epithelial phenotype is unresolved"]},{"year":2023,"claim":"MMP17 was found to extrinsically regulate goblet cell maturation, with knockout mice showing enhanced goblet cell effector expression and helminth resistance, extending MMP17's intestinal role beyond epithelial repair to mucosal immunity.","evidence":"Mmp17 KO mice with Trichuris muris and Citrobacter rodentium infection models, gene/protein expression, single-cell RNA-seq","pmids":["37869014"],"confidence":"Medium","gaps":["Molecular target through which MMP17 regulates goblet cell maturation is unidentified","Whether the phenotype is a direct consequence of PERIOSTIN cleavage or involves distinct substrates is unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis for MMP17's non-proteolytic signaling interactions (EGFR, Tks5/PDGFRα), the substrates responsible for its roles in atherosclerosis and goblet cell regulation, and whether its proteolytic and scaffolding functions are segregated by tissue or context.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of MMP17 exists","Substrate responsible for myeloid/vascular adhesion phenotype is unknown","Relative in vivo contributions of proteolytic versus non-proteolytic functions remain unseparated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3,7,9,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,10,11]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[10]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,9,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,7,8]}],"complexes":[],"partners":["EGFR","TKS5","PDGFRA","ADAMTS4","SPP1"],"other_free_text":[]},"mechanistic_narrative":"MMP17 (MT4-MMP) is a GPI-anchored membrane-type matrix metalloproteinase that functions in vascular smooth muscle cell maturation, intestinal epithelial repair, and immune cell regulation, with additional non-proteolytic roles in cancer cell signaling. As the only GPI-anchored MMP family member, it is processed by furin in the Golgi, N-glycosylated at Asn318, and trafficked to the plasma membrane where it forms homophilic complexes and is internalized via the CDC42/RhoA-dependent CLIC/GEEC pathway [PMID:10567400, PMID:28531887, PMID:26663028]. Its proteolytic substrates include osteopontin—whose MMP17-generated N-terminal fragment activates JNK signaling to drive vascular smooth muscle cell maturation and protect against aortic aneurysm—PERIOSTIN in intestinal epithelial regeneration, pro-TNFα, fibrinogen/fibrin, and ADAMTS4 [PMID:25963716, PMID:34795242, PMID:10799478, PMID:15780640]. Independent of its catalytic activity, MMP17 associates with EGFR to enhance receptor phosphorylation and downstream CDK4/Rb signaling, and binds Tks5/PDGFRα to activate Src and promote invadopodia formation [PMID:25320013, PMID:31813546]."},"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":166,"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":113,"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":"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":"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":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":41,"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 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pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28531887","citation_count":6,"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":3,"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 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37869014","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.30.626196","title":"The opposing mechanisms by which miRNAs critically contribute to differential roles of Nrf1 and Nrf2 in modulating the epithelial-mesenchymal transformation of hepatocellular carcinoma","date":"2024-12-01","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.30.626196","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18270,"output_tokens":4392,"usd":0.060345},"stage2":{"model":"claude-opus-4-6","input_tokens":7871,"output_tokens":3773,"usd":0.20052},"total_usd":0.260865,"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\": 1999,\n      \"finding\": \"MT4-MMP (MMP17) is anchored to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor, making it the first GPI-anchored proteinase in the MMP family. This was demonstrated by [3H]ethanolamine labeling of the GPI unit in a sequence-dependent manner and release from the cell surface by phosphatidylinositol-specific phospholipase C treatment. MT4-MMP is also shed from the cell surface by an endogenous metalloproteinase.\",\n      \"method\": \"Radiolabeling ([3H]ethanolamine incorporation), phosphatidylinositol-specific phospholipase C treatment, cell surface shedding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical reconstitution with multiple orthogonal methods confirming GPI anchor\",\n      \"pmids\": [\"10567400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mouse MT4-MMP (MMP17) expressed at the cell surface does not activate pro-MMP2. The recombinant catalytic domain, refolded from E. coli inclusion bodies, is inhibited by TIMP-1, -2, and -3, is poorly active against ECM components except fibrinogen and fibrin, and efficiently cleaves a pro-TNFα cleavage-site peptide and a GST-pro-TNFα fusion protein. MT4-MMP also sheds pro-TNFα when co-transfected in COS-7 cells, demonstrating TNFα convertase activity.\",\n      \"method\": \"Recombinant protein expression and refolding, synthetic peptide assays, GST-fusion protein cleavage, co-transfection shedding assay in COS-7 cells, TIMP inhibition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assays with recombinant protein and cell-based shedding assay, replicated across substrates\",\n      \"pmids\": [\"10799478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The functional human MT4-MMP (MMP17) is encoded by a major transcript with an extended open reading frame producing 67 and 71 kDa translation products; the previously reported minor transcript failed to express protein.\",\n      \"method\": \"5' RACE, cDNA cloning, expression in cells with Western blot\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular identification of functional transcript with protein expression confirmation\",\n      \"pmids\": [\"10471807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MT4-MMP is involved in IL-1-induced aggrecanolysis in bovine cartilage. IL-1 treatment increases MT4-MMP abundance in tissue and medium, and blockade of GPI anchor synthesis with mannosamine inhibits both MT4-MMP increase and aggrecan cleavage. The data support MT4-MMP-mediated processing of ADAMTS4 (conversion of p68 to p53) and its release from the cell surface as a mechanism of aggrecanolysis.\",\n      \"method\": \"Western blot analysis of aggrecan fragments and MT4-MMP/ADAMTS4 species, pharmacological inhibition (mannosamine, esculetin), real-time PCR in cartilage explants\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in tissue model but indirect (inhibitor-based) evidence for MT4-MMP as the active agent\",\n      \"pmids\": [\"15780640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The hemopexin domain of MT4-MMP prevents proper maturation, processing, and trafficking to the plasma membrane when substituted into MT1-MMP chimeras. MT1-MMP chimeras bearing the MT4-MMP hemopexin domain are retained in the endoplasmic reticulum, fail to undergo propeptide processing, and cannot activate pro-MMP2 or degrade gelatin.\",\n      \"method\": \"Domain-swap chimera construction, cell surface biotinylation, indirect immunofluorescence, pro-MMP2 activation assay, gelatin degradation assay, propeptide-specific antibody Western blot\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods with domain-swap mutagenesis and functional rescue\",\n      \"pmids\": [\"16686598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MT4-MMP is expressed primarily in cerebrum, lung, spleen, intestine and uterus in vivo, with expression in neurons, intestinal/uterine smooth muscle cells, and alveolar/intraperitoneal macrophages. MT4-MMP-null mice have normal growth and fertility. LPS-induced TNFα release from MT4-MMP-null macrophages was not different from wild-type, suggesting MT4-MMP is not the primary TNFα sheddase in macrophages.\",\n      \"method\": \"LacZ reporter knock-in mouse model, LacZ staining, RT-PCR tissue distribution, LPS-stimulated macrophage TNFα release assay\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function model with in vivo reporter and functional cellular assays\",\n      \"pmids\": [\"17825051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MT4-MMP expression in breast cancer cells promotes lung metastasis by increasing tumor vascular permeability: it induces blood vessel enlargement and detachment of mural cells from the vascular tree, facilitating tumor cell intravasation (not extravasation or lymph node colonization).\",\n      \"method\": \"Experimental (intravenous) and spontaneous (subcutaneous) lung metastasis models, ultrastructural and fluorescent microscopy, computer-assisted quantification of vessel morphology, intravasation assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotype with imaging evidence but no direct molecular mechanism for mural cell detachment\",\n      \"pmids\": [\"19426156\"],\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. Catalytic inactivation (E249A mutation in the active site) abrogates the angiogenic switch, tumor growth acceleration, and lung colonization driven by tumor cell-derived MT4-MMP. Host (stromal)-derived MT4-MMP does not contribute to the angiogenic response.\",\n      \"method\": \"Site-directed mutagenesis (E249A), subcutaneous tumor implantation in RAG1-deficient mice, MT4-MMP-deficient mouse host experiments, angiogenesis quantification\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — active site mutagenesis combined with genetic host KO model and functional tumor assays\",\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 via CDK4 activation and retinoblastoma protein inactivation. These effects on EGFR activation do not require MT4-MMP metalloprotease activity.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, proliferation assays, CDK4/Rb signaling analysis, metalloprotease-inactive mutant comparison\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP showing direct association plus functional assays, but mechanistic details of the non-proteolytic EGFR interaction are incomplete\",\n      \"pmids\": [\"25320013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MMP17 proteolytic activity regulates vascular smooth muscle cell maturation in the arterial wall via cleavage of osteopontin, generating an N-terminal osteopontin fragment that activates c-Jun N-terminal kinase (JNK) signaling. Loss of Mmp17 leads to dysfunctional vascular smooth muscle cells, altered extracellular matrix, and increased susceptibility to angiotensin-II-induced thoracic aortic aneurysm. Re-expression of catalytically active Mmp17 or the N-terminal osteopontin fragment partially rescues the vessel-wall phenotype.\",\n      \"method\": \"Mmp17 knock-out mouse model, angiotensin-II aneurysm model, lentiviral re-expression of active Mmp17 and osteopontin fragment, JNK signaling analysis, mass spectrometry proteomics, human patient missense mutation (R373H) functional analysis\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO, catalytically active rescue, substrate identification, downstream signaling pathway defined; strong and multiple orthogonal methods\",\n      \"pmids\": [\"25963716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MT4-MMP forms homophilic dimeric and oligomeric complexes at the cell surface and 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 requires CDC42 and RhoA, but not caveolin-1 or clathrin pathways.\",\n      \"method\": \"Co-immunoprecipitation with FLAG/Myc-tagged MT4-MMP, non-reducing/reducing immunoblotting, antibody-feeding internalization assay, confocal microscopy, cell surface biotinylation, siRNA knockdown of CDC42, RhoA, caveolin-1, pharmacological inhibitors\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, live cell trafficking, siRNA knockdown, pharmacological inhibition) in a single study\",\n      \"pmids\": [\"26663028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MT4-MMP in melanoma cells exists in three forms (45, 58, and 69 kDa): the 58 kDa form is the mature cell membrane protein, and the 69 kDa form is its intracellular precursor processed by furin cleavage in the Golgi apparatus. Asn318 is the single N-glycosylation site of MT4-MMP.\",\n      \"method\": \"Western blotting, iodixanol density gradient organelle fractionation, glucosidase treatment, site-directed mutagenesis of N-glycosylation sites, quantitative PCR\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — organelle fractionation plus mutagenesis identifying glycosylation site and processing pathway\",\n      \"pmids\": [\"28531887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MT4-MMP promotes invadopodia formation and amoeboid cell movement in head and neck cancer cells. Mechanistically, MT4-MMP binds Tks5 and PDGFRα to activate Src, driving invadopodia formation, and stimulates small GTPases RhoA and Cdc42 to promote amoeboid-like movement on collagen gel.\",\n      \"method\": \"MT4-MMP overexpression in FaDu cells, 3D invadopodia assay, gelatin degradation assay, collagen gel motility assay, co-immunoprecipitation (MT4-MMP with Tks5 and PDGFRα), Src activation assay, Rho/Cdc42 activation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP combined with functional 3D assays, but single lab and limited mechanistic depth\",\n      \"pmids\": [\"31813546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MMP17 is exclusively expressed by intestinal smooth muscle cells and is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Mechanistically, MMP17 cleaves the matricellular protein PERIOSTIN (and possibly other diffusible factors), indirectly modulating epithelial reprogramming including YAP activity. Smooth muscle cells are identified as major suppliers of BMP antagonists essential for intestinal stem cell niche maintenance.\",\n      \"method\": \"Mmp17 knockout mice, inflammation and irradiation injury models, single-cell RNA sequencing, proteomics (PERIOSTIN cleavage), YAP activity assays, organoid culture experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO model with injury assays, substrate identification, and signaling pathway analysis using multiple orthogonal methods\",\n      \"pmids\": [\"34795242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MT4-MMP deficiency in mice results in increased adherence of macrophages to inflamed peritonea, higher numbers of patrolling monocytes crawling on inflamed endothelia, and accumulation of Mafb+AIM+ macrophages at atherosclerotic lesions. MT4-MMP-null Mafb+AIM+ macrophages express higher AIM and scavenger receptor CD36, are more resistant to apoptosis, and bind acLDL more avidly. CCR5 inhibition alleviates enhanced recruitment of MT4-MMP-null patrolling monocytes, blocking atherosclerosis acceleration.\",\n      \"method\": \"MT4-MMP-deficient mice crossed to atherosclerosis model, intravital microscopy, flow cytometry, macrophage adhesion and apoptosis assays, acLDL binding assay, CCR5 inhibitor treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO mouse model with multiple orthogonal cellular and in vivo functional readouts\",\n      \"pmids\": [\"29500407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MMP17 expressed by smooth muscle cells and lamina propria macrophages in the intestine extrinsically regulates goblet cell maturation. Mmp17 knockout mice show elevated goblet cell effector gene expression (CLCA1, RELM-β) and increased resistance to low-dose Trichuris muris helminth infection, without changes in NOTCH pathway activity or specific cytokine levels.\",\n      \"method\": \"Mmp17 knockout mice, Trichuris muris and Citrobacter rodentium infection models, gene and protein expression analysis, single-cell RNA sequencing, NOTCH pathway analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined infection model phenotype, but molecular mechanism of goblet cell regulation is not fully resolved\",\n      \"pmids\": [\"37869014\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MMP17 (MT4-MMP) is a GPI-anchored membrane metalloproteinase that cleaves substrates including pro-TNFα, fibrinogen/fibrin, osteopontin (generating a JNK-activating N-terminal fragment to regulate vascular smooth muscle cell maturation), PERIOSTIN (modulating intestinal epithelial regeneration), and ADAMTS4 (contributing to cartilage aggrecanolysis); it forms homophilic surface complexes, is internalized via the CLIC/GEEC pathway in a CDC42/RhoA-dependent manner, activates EGFR signaling and Src/Tks5/PDGFRα complexes non-proteolytically to drive cancer cell proliferation and invasion, and its GPI anchor, furin-mediated Golgi processing, and hemopexin domain each govern distinct aspects of its trafficking, maturation, and inability to activate pro-MMP2.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MMP17 (MT4-MMP) is a GPI-anchored membrane-type matrix metalloproteinase that functions in vascular smooth muscle cell maturation, intestinal epithelial repair, and immune cell regulation, with additional non-proteolytic roles in cancer cell signaling. As the only GPI-anchored MMP family member, it is processed by furin in the Golgi, N-glycosylated at Asn318, and trafficked to the plasma membrane where it forms homophilic complexes and is internalized via the CDC42/RhoA-dependent CLIC/GEEC pathway [PMID:10567400, PMID:28531887, PMID:26663028]. Its proteolytic substrates include osteopontin—whose MMP17-generated N-terminal fragment activates JNK signaling to drive vascular smooth muscle cell maturation and protect against aortic aneurysm—PERIOSTIN in intestinal epithelial regeneration, pro-TNFα, fibrinogen/fibrin, and ADAMTS4 [PMID:25963716, PMID:34795242, PMID:10799478, PMID:15780640]. Independent of its catalytic activity, MMP17 associates with EGFR to enhance receptor phosphorylation and downstream CDK4/Rb signaling, and binds Tks5/PDGFRα to activate Src and promote invadopodia formation [PMID:25320013, PMID:31813546].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing MMP17 as the first GPI-anchored MMP resolved how a membrane metalloproteinase could be tethered without a transmembrane domain, revealing a novel mode of surface presentation and shedding.\",\n      \"evidence\": \"[3H]ethanolamine radiolabeling and PI-PLC release from cell surface\",\n      \"pmids\": [\"10567400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the endogenous metalloproteinase responsible for MMP17 shedding was not determined\", \"Functional consequences of GPI anchoring versus transmembrane anchoring were not compared\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defining the substrate profile revealed that MMP17 is a poor ECM protease but an efficient pro-TNFα sheddase and fibrinogen/fibrin protease, distinguishing it functionally from transmembrane MT-MMPs that activate pro-MMP2.\",\n      \"evidence\": \"Recombinant catalytic domain assays against ECM substrates, GST-pro-TNFα cleavage, and COS-7 co-transfection shedding assay\",\n      \"pmids\": [\"10799478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of TNFα shedding by MMP17 was not tested\", \"Full substrate repertoire remained uncharacterized\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linking MMP17 to cartilage aggrecanolysis via ADAMTS4 processing revealed a new indirect mechanism by which a GPI-anchored MMP can regulate ECM turnover.\",\n      \"evidence\": \"IL-1-treated bovine cartilage explants with mannosamine inhibition of GPI anchor synthesis, Western blot of ADAMTS4 processing\",\n      \"pmids\": [\"15780640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Evidence for MMP17 as the responsible GPI-anchored protease is indirect (pharmacological inhibitor affects all GPI-anchored proteins)\", \"Direct cleavage of ADAMTS4 by MMP17 was not reconstituted in vitro\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Domain-swap experiments showed that the hemopexin domain of MMP17 prevents ER-to-surface maturation when placed in MT1-MMP, explaining why MMP17 cannot activate pro-MMP2 and establishing that domain-specific features dictate its trafficking fate.\",\n      \"evidence\": \"MT1-MMP/MT4-MMP hemopexin domain chimeras assayed for surface biotinylation, propeptide processing, and pro-MMP2 activation\",\n      \"pmids\": [\"16686598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for ER retention by the MMP17 hemopexin domain was not resolved\", \"Whether hemopexin domain also governs substrate selectivity was not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Generation of MMP17-null mice revealed its tissue expression pattern (neurons, smooth muscle, macrophages) and showed that it is dispensable for TNFα shedding in macrophages, redirecting the search for its physiological substrates.\",\n      \"evidence\": \"LacZ knock-in reporter mouse, LPS-stimulated macrophage TNFα release assay\",\n      \"pmids\": [\"17825051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates in smooth muscle and neurons remained unidentified\", \"Compensatory mechanisms by other sheddases were not excluded\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that MMP17 promotes lung metastasis by increasing tumor vascular permeability and mural cell detachment identified a specific pro-metastatic mechanism distinct from direct ECM degradation.\",\n      \"evidence\": \"Spontaneous and experimental lung metastasis models with ultrastructural vessel analysis\",\n      \"pmids\": [\"19426156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrate responsible for mural cell detachment was not identified\", \"Contribution of proteolytic versus non-proteolytic activity was not distinguished\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Active-site mutagenesis (E249A) established that proteolytic activity is required for MMP17-driven angiogenesis and metastasis, and host-derived MMP17 is dispensable, pinpointing tumor-cell-intrinsic catalysis as the driver.\",\n      \"evidence\": \"E249A catalytic-dead mutant in subcutaneous tumor models and MMP17-deficient hosts (RAG1−/− mice)\",\n      \"pmids\": [\"22262494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The pro-angiogenic substrate cleaved by tumor-derived MMP17 was not identified\", \"Whether the non-proteolytic EGFR mechanism contributes to angiogenesis was not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that MMP17 associates with EGFR and enhances its phosphorylation independently of catalytic activity revealed a non-proteolytic signaling function, expanding MMP17's role beyond substrate cleavage.\",\n      \"evidence\": \"Co-immunoprecipitation of MMP17–EGFR, proliferation and CDK4/Rb pathway analysis with catalytically inactive mutant\",\n      \"pmids\": [\"25320013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of MMP17–EGFR interaction is unknown\", \"Whether GPI-anchor microdomain co-localization drives the interaction was not tested\", \"In vivo relevance of non-proteolytic EGFR activation was not assessed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of osteopontin as a physiological MMP17 substrate whose N-terminal cleavage fragment activates JNK signaling resolved the mechanism by which MMP17 regulates vascular smooth muscle cell maturation and protects against aortic aneurysm.\",\n      \"evidence\": \"Mmp17 KO mouse, angiotensin-II aneurysm model, lentiviral re-expression of catalytically active MMP17 and OPN N-terminal fragment, mass spectrometry, human R373H mutation analysis\",\n      \"pmids\": [\"25963716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the OPN N-terminal fragment specifically activates JNK is mechanistically unresolved\", \"Whether the human R373H variant causes clinical aortic disease was not established in a family study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Elucidating MMP17 homophilic complex formation and CLIC/GEEC-mediated internalization dependent on CDC42/RhoA defined the trafficking itinerary of this GPI-anchored protease and explained how surface levels are regulated.\",\n      \"evidence\": \"Co-IP of tagged MMP17 constructs, antibody-feeding internalization assay, siRNA knockdown of CDC42/RhoA/caveolin-1\",\n      \"pmids\": [\"26663028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of homophilic oligomerization for catalytic activity was not determined\", \"Whether oligomerization state governs internalization rate is unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping the biosynthetic pathway showed furin-dependent Golgi processing of the 69 kDa precursor to the 58 kDa mature form, with Asn318 as the sole N-glycosylation site, clarifying MMP17 maturation steps.\",\n      \"evidence\": \"Organelle fractionation, glycosidase treatment, N-glycosylation site mutagenesis in melanoma cells\",\n      \"pmids\": [\"28531887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of N-glycosylation at Asn318 in folding, trafficking, or catalysis was not functionally tested\", \"Identity of the 45 kDa species (degradation product vs. alternatively processed form) was not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"MMP17 deficiency enhanced patrolling monocyte recruitment and Mafb+AIM+ macrophage accumulation at atherosclerotic lesions, identifying MMP17 as a regulator of myeloid cell adhesion and atherogenesis.\",\n      \"evidence\": \"MMP17-KO mice crossed to atherosclerosis model, intravital microscopy, flow cytometry, CCR5 inhibitor rescue\",\n      \"pmids\": [\"29500407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The substrate cleaved by MMP17 to regulate monocyte/macrophage adhesion is unknown\", \"Whether macrophage-intrinsic or smooth-muscle-derived MMP17 is responsible was not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"MMP17 was shown to form complexes with Tks5 and PDGFRα to activate Src, promoting invadopodia and amoeboid movement, revealing a second non-proteolytic scaffolding function in cancer invasion.\",\n      \"evidence\": \"Co-IP of MMP17 with Tks5/PDGFRα, 3D invadopodia and collagen gel motility assays in FaDu head and neck cancer cells\",\n      \"pmids\": [\"31813546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this scaffolding function requires the GPI anchor or hemopexin domain is untested\", \"Single lab finding without independent replication\", \"Contribution of proteolytic versus scaffolding activity was not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of PERIOSTIN as an MMP17 substrate in intestinal smooth muscle cells established a paracrine mechanism by which mesenchymal cells regulate epithelial regeneration and YAP activity after injury.\",\n      \"evidence\": \"Mmp17 KO mice with colitis and irradiation injury models, proteomics, organoid culture, single-cell RNA-seq\",\n      \"pmids\": [\"34795242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cleavage site on PERIOSTIN and identity of active fragments were not fully characterized\", \"Whether other diffusible substrates contribute to the epithelial phenotype is unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"MMP17 was found to extrinsically regulate goblet cell maturation, with knockout mice showing enhanced goblet cell effector expression and helminth resistance, extending MMP17's intestinal role beyond epithelial repair to mucosal immunity.\",\n      \"evidence\": \"Mmp17 KO mice with Trichuris muris and Citrobacter rodentium infection models, gene/protein expression, single-cell RNA-seq\",\n      \"pmids\": [\"37869014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target through which MMP17 regulates goblet cell maturation is unidentified\", \"Whether the phenotype is a direct consequence of PERIOSTIN cleavage or involves distinct substrates is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for MMP17's non-proteolytic signaling interactions (EGFR, Tks5/PDGFRα), the substrates responsible for its roles in atherosclerosis and goblet cell regulation, and whether its proteolytic and scaffolding functions are segregated by tissue or context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of MMP17 exists\", \"Substrate responsible for myeloid/vascular adhesion phenotype is unknown\", \"Relative in vivo contributions of proteolytic versus non-proteolytic functions remain unseparated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3, 7, 9, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 10, 11]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"EGFR\",\n      \"TKS5\",\n      \"PDGFRA\",\n      \"ADAMTS4\",\n      \"SPP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}