{"gene":"MMP7","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1989,"finding":"MMP7 (PUMP-1) is a latent secreted metalloproteinase that, despite lacking the hemopexin-like domain of classical collagenases, is activated by organomercurial compounds (APMA) and degrades casein, type I/III/IV/V gelatins, fibronectin, and can activate latent collagenase in vitro. Active forms of 21,000 and 19,000 Da are generated upon activation. Activity is inhibited by EDTA, 1,10-phenanthroline, and TIMP.","method":"COS cell expression, IgG-Sepharose pulldown, in vitro protease assay, autocleavage assay, inhibitor studies","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in vitro with multiple substrates, inhibitor validation, and autocleavage assay; foundational mechanistic paper replicated by subsequent work","pmids":["2550050"],"is_preprint":false},{"year":2004,"finding":"MMP-7 activates proADAM28s (65 kDa) to produce active 42- and 40-kDa forms. Active ADAM28s then cleaves insulin-like growth factor binding protein-3 (IGFBP-3) in both free and IGF-bound forms; this cleavage is blocked by EDTA, 1,10-phenanthroline, KB-R7785, TIMP-3, and TIMP-4.","method":"In vitro protease assay, recombinant protein incubation, inhibitor studies","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution with recombinant proteins and multiple inhibitor controls in a focused mechanistic study","pmids":["15013428"],"is_preprint":false},{"year":2005,"finding":"MMP-7 promotes invasion of ovarian cancer cells by activating proMMP-2 and proMMP-9. MMP-7 can dissociate MMP-2 from the MMP-2/TIMP-2 complex and activate it in a time-dependent, concentration-dependent manner in vitro. TIMP-2 inhibits both proMMP-2 activation and MMP-7-induced increased invasion.","method":"In vitro progelatinase activation assay, co-immunoprecipitation, Transwell invasion assay, recombinant MMP-7 treatment","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of progelatinase activation, reciprocal inhibitor controls, and functional invasion assay in a single study","pmids":["15523695"],"is_preprint":false},{"year":2008,"finding":"MMP-7 degrades soluble VEGFR-1 (sVEGFR-1/sFlt-1), liberating VEGF165 from the sVEGFR-1 complex and increasing VEGF bioavailability. This degradation abrogates sVEGFR-1 inhibition of VEGFR-2 phosphorylation on endothelial cells and promotes tube formation and migration.","method":"In vitro degradation assay with recombinant proteins, co-immunoprecipitation (HUVECs), tube formation assay, migration assay, VEGFR-2 phosphorylation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical reconstitution of substrate cleavage with multiple orthogonal functional readouts (tube formation, migration, receptor phosphorylation) in a single study","pmids":["18974372"],"is_preprint":false},{"year":2009,"finding":"MMP7 sheds syndecan-1 from lung epithelial cells upon injury; this shedding is absent in Mmp7−/− mice. MMP7-mediated syndecan-1 shedding facilitates wound closure by causing the α2β1 integrin to assume a less active conformation, removing restrictions to cell migration.","method":"Mmp7−/− knockout mouse model, in vitro and in vivo epithelial wound assay, integrin affinity state measurement, syndecan-1 shedding detection","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific phenotypic readout replicated in vitro and in vivo, mechanistic link to integrin conformation established","pmids":["19668337"],"is_preprint":false},{"year":2010,"finding":"MMP7 (matrilysin-1) directly cleaves galectin-3 in vitro, producing three fragments (20.2, 18.9, and 15.5 kDa). Recombinant MMP7 treatment of colonic epithelial T84 cells produces galectin-3 cleavage fragments in the supernatant and inhibits cell migration and wound closure; galectin-3's pro-migratory effect is abrogated by MMP7 co-treatment.","method":"In vitro cleavage assay, N-terminal sequencing, mass spectrometry, Western blotting, in vitro scratch wound assay","journal":"Inflammatory bowel diseases","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with fragment identification by N-terminal sequencing and MS, plus functional cell migration assay in a single study","pmids":["20812334"],"is_preprint":false},{"year":2014,"finding":"MMP7 cleaves purified perlecan/HSPG2 at multiple sites within domain IV in vitro, including when perlecan is decorated with heparan sulfate or embedded in native BM context. MMP7 digestion of perlecan domain IV fragment (Dm IV-3) reverses cell clustering to a cell dispersion phenotype in metastatic PCa cells and increases invasion through perlecan-rich BM extract.","method":"In vitro protease assay with purified perlecan, in silico cleavage prediction, Transwell invasion assay with MMP-7-pre-digested BM extract","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified substrates under multiple conditions plus functional cellular readout in a single focused study","pmids":["24833109"],"is_preprint":false},{"year":2014,"finding":"MMP7 cleaves nucleolin (NCL) at Asp255 to generate a C-terminal truncated form (TNCL, ~55 kDa). TNCL stabilizes MMP9 mRNA (and other oncogenic mRNAs) by binding to their 3'-UTRs, thereby promoting metastasis. This cleavage is induced downstream of EGF receptor pathway activation.","method":"MMP7 in vitro cleavage assay identifying cleavage site, Western blot, mRNA stability assay, 3'-UTR binding, cell invasion assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — identified exact cleavage site in vitro, functional consequence (mRNA stabilization) demonstrated with orthogonal methods","pmids":["24632608"],"is_preprint":false},{"year":2019,"finding":"β-catenin signaling in renal tubular cells drives MMP-7 expression and secretion. Secreted MMP-7 directly degrades nephrin (a key slit diaphragm protein) in a proteolytic-activity-dependent manner in cultured glomeruli and cell-free systems, causing proteinuria and glomerular injury in vivo.","method":"Conditional tubule-specific β-catenin KO mice, MMP-7 genetic ablation (KO mice), ex vivo glomerular incubation with recombinant MMP-7, cell-free nephrin cleavage assay, in vivo MMP-7 infusion/overexpression","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of nephrin cleavage, genetic KO rescue, and in vivo MMP-7 infusion with consistent results across multiple models","pmids":["31743113"],"is_preprint":false},{"year":2018,"finding":"MMP7 cleaves fibronectin aggregates in vitro, producing a prominent 13 kDa EIIIA-containing fragment. MMP7 is upregulated in lysolecithin-induced demyelination (endogenous clearance), whereas proMMP7 levels are substantially reduced in chronic active and inactive MS lesions. IL-4-activated microglia/macrophages are major cellular sources of proMMP7.","method":"In vitro fibronectin aggregate cleavage assay, Western blot, lysolecithin demyelination mouse model, immunostaining of MS lesions, macrophage polarization assays","journal":"Glia","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of fibronectin aggregate cleavage with fragment characterization, corroborated in vivo and in human tissue","pmids":["29600597"],"is_preprint":false},{"year":2011,"finding":"Stat3 signaling enforces MMP7 expression in pancreatic ductal adenocarcinoma (PDA) cells. MMP7 deletion in a Kras-driven mouse model limits tumor size and metastasis, placing MMP7 downstream of Stat3 as a required effector of PDA progression.","method":"Genetic epistasis in Kras-driven mouse PDA model, Stat3 conditional KO, Mmp7 KO mice, tumor size/metastasis quantification","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in a well-controlled in vivo cancer model with multiple KO lines showing consistent pathway placement","pmids":["21481787"],"is_preprint":false},{"year":2004,"finding":"The position of Tcf binding elements (TBEs) relative to the MMP7 transcriptional start site determines whether Lef-1 acts as an activator or repressor of β-catenin-driven MMP7 transcription. Upstream TBEs (human promoter) allow Lef-1 activation, whereas a downstream TBE (mouse promoter) supports Lef-1-mediated repression. TBE sequence affinity for Lef-1 determines potency: high-affinity sites (G·C at 5′/3′ ends) yield up to 115-fold greater β-catenin responsiveness.","method":"Promoter-luciferase reporter assays, TBE mutagenesis, in vitro Lef-1 binding affinity (gel-shift), heterologous promoter constructs","journal":"Molecular carcinogenesis","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with reporter assays and in vitro binding measurements; multiple constructs tested in a single rigorous study","pmids":["15457508"],"is_preprint":false},{"year":2008,"finding":"HER2 overexpression or HRG stimulation upregulates MMP-7 transcription and protein secretion via activated STAT3. STAT3 binds directly to the MMP-7 promoter at a critical STAT3 binding element, as shown by ChIP and promoter mutagenesis. Constitutively active STAT3 is sufficient to drive MMP-7 expression.","method":"Stable HER2/STAT3C overexpression in MCF-7, promoter-luciferase assay, ChIP, STAT3 binding site mutagenesis, RT-PCR, Western blot","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP validates direct STAT3 binding, mutagenesis identifies critical element, supported by constitutively active STAT3 phenocopy","pmids":["18411043"],"is_preprint":false},{"year":2015,"finding":"FOXC1 induces MMP7 expression and MMP7-dependent invasion in basal-like breast cancer cells. Silencing FOXC1 selectively decreases MMP7 without reducing other MMPs; ectopic FOXC1 in non-transformed cells increases MMP7 and invasion in an MMP7-dependent manner.","method":"siRNA knockdown, transient overexpression, Matrigel invasion assay, mRNA/protein expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with invasion phenotype, single lab, two orthogonal methods (siRNA + overexpression)","pmids":["22645147"],"is_preprint":false},{"year":2017,"finding":"FOXC1 directly binds the WNT5A promoter to activate its expression; WNT5A then activates NF-κB signaling to induce MMP7 expression. The FOXC1→WNT5A→NF-κB→MMP7 axis is required for TNBC cell invasiveness in vitro and lung metastasis in vivo (MMP7 overexpression rescues WNT5A-KO metastasis defect).","method":"ChIP (FOXC1 binding to WNT5A promoter), enChIP-MS, WNT5A knockout xenograft model, MMP7 overexpression rescue, NF-κB pathway inhibition","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct promoter binding by ChIP, genetic epistasis in vivo with rescue experiment, multiple orthogonal methods in one study","pmids":["29249801"],"is_preprint":false},{"year":2016,"finding":"MMP7 promotes prostate adenocarcinoma by disrupting the E-cadherin/β-catenin complex to upregulate EMT transcription factors. MMP7 knockout in Pten-null mice limits EMT characteristics, recapitulating the phenotype of IL-17 receptor C/Pten double-KO mice. IL-17 induces MMP7 and EMT in human prostate cancer cells; MMP7 siRNA knockdown inhibits IL-17-induced EMT.","method":"Mmp7/Pten double KO mice, siRNA knockdown, MMP7 inhibitor (Compound III) in vivo, Western blot for E-cadherin/β-catenin","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic double-KO model with in vivo tumor phenotype, pharmacological inhibition, and siRNA knockdown in cell lines providing consistent epistatic placement","pmids":["27375020"],"is_preprint":false},{"year":2010,"finding":"Catecholamine (isoproterenol) stimulation via β2-adrenergic receptor upregulates MMP-7 expression in gastric cancer cells through AP-1 (dominant pathway) and STAT3 transcription factors. STAT3 and c-Jun physically interact and co-occupy the AP-1 site in the MMP-7 promoter; AP-1 site mutation completely abolishes isoproterenol-induced MMP-7 promoter activity, whereas STAT3-site mutation alone does not.","method":"Promoter-luciferase reporter assay, site-directed mutagenesis of AP-1 and STAT3 sites, siRNA knockdown, Co-IP (STAT3/c-Jun interaction), β2-AR antagonist treatment","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis identifies critical promoter element, Co-IP validates physical interaction, multiple orthogonal methods in single study","pmids":["20939893"],"is_preprint":false},{"year":2008,"finding":"Activin A enhances MMP-7 expression via the AP-1 transcription factor (not through Smad2/3). Mutation of the AP-1 binding site in the MMP-7 promoter reduces activity, whereas mutation of the Smad binding site does not. c-Jun is increased in activin A-expressing esophageal carcinoma cells.","method":"Stable transfection of activin βA, promoter-luciferase assay with AP-1 and Smad site mutations, RT-PCR, Northern blot, neutralizing antibody","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — promoter mutagenesis distinguishes AP-1 from Smad dependence, supported by neutralizing antibody; single lab","pmids":["18695873"],"is_preprint":false},{"year":2015,"finding":"FOXC1 promotes MMP7-dependent invasion in TNBC via β-catenin activation of MMP7. Wnt-β-catenin signaling upregulates MMP7 in a PTEN-loss-dependent manner; pharmacological/siRNA attenuation of β-catenin downregulates secreted MMP7 enzymatic activity (casein zymography).","method":"siRNA knockdown of β-catenin, WP inhibitors (XAV939, sulindac sulfide), LY294002 (PTEN mimetic), casein zymography, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic attenuation of pathway with enzymatic readout; single lab, two orthogonal approaches","pmids":["24143235"],"is_preprint":false},{"year":2007,"finding":"Gastrin stimulates MMP-7 promoter-luciferase activity in gastric epithelial cells. MMP-7 secreted by gastric epithelial cells promotes myofibroblast proliferation via MAPK and PI3K pathways; neutralizing antibodies to MMP-7 block this proliferation.","method":"Promoter-luciferase reporter assay, MMP-7 neutralizing antibody, conditioned medium treatment of myofibroblasts, pathway inhibitors (MAPK/PI3K)","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — neutralizing antibody functional rescue plus promoter activity and pathway inhibitor data; single lab","pmids":["17218472"],"is_preprint":false},{"year":2015,"finding":"MMP7 knockdown in PKP3 (Plakophilin3)-deficient cells abolishes in vitro cell migration/invasion and in vivo tumor formation. Increased MMP7 levels upon PKP3 loss are mediated by elevated PRL3 (Phosphatase of Regenerating Liver-3).","method":"shRNA knockdown of MMP7, Transwell migration/invasion assay, mouse xenograft tumor formation, Western blot for PRL3/MMP7","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific phenotypic readout in vitro and in vivo, upstream regulator (PRL3) identified; single lab","pmids":["25875355"],"is_preprint":false},{"year":2016,"finding":"MMP7 physically binds ARF (p14ARF/p19Arf) and co-localizes with it in the nucleus of malignant prostate tumor cells. ARF knockdown markedly reduces MMP7 levels; inducible ARF expression increases MMP7 and decreases E-cadherin. Co-expression of ARF and MMP7 promotes cell migration.","method":"Co-immunoprecipitation, co-localization (nuclear fractionation/immunofluorescence), inducible ARF overexpression, shRNA knockdown, mouse Pten/Trp53/p19Arf triple mutant model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP establishes physical interaction, inducible OE and KD provide reciprocal evidence; nuclear localization tied to functional outcome","pmids":["27356744"],"is_preprint":false},{"year":2018,"finding":"Cortisol induces MMP7 expression in human amnion fibroblasts via AP-1 (c-Fos and c-Jun). ChIP shows enrichment of c-Fos and c-Jun at the AP-1 binding site in the MMP7 promoter following cortisol treatment. MMP7 secreted under cortisol stimulation degrades extracellular COL4A5 (collagen IV α5 chain), which is blocked by anti-MMP-7 antibody.","method":"RNA-sequencing, RT-qPCR, Western blot, ChIP (c-Fos/c-Jun at MMP7 promoter AP-1 site), siRNA knockdown of c-Fos/c-Jun, anti-MMP-7 neutralizing antibody, amnion tissue analysis","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP validates direct AP-1 occupancy, siRNA of both c-Fos and c-Jun attenuates induction, antibody rescue confirms MMP7 as effector; multiple orthogonal methods","pmids":["30303742"],"is_preprint":false},{"year":2015,"finding":"Nicotine increases MMP7 expression in gastric adenocarcinoma cells by enhancing CREB phosphorylation and nuclear translocation. Phosphorylated CREB preferentially binds the -181G allele of the MMP7 promoter relative to -181A (ChIP assay), conferring allele-specific transcriptional upregulation.","method":"Promoter-reporter assay, ChIP (phospho-CREB binding to -181G vs -181A allele), CREB overexpression, Western blot, case-control genotyping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — ChIP distinguishes allele-specific binding, reporter assay confirms functional difference; single lab with two orthogonal methods","pmids":["25847246"],"is_preprint":false},{"year":2009,"finding":"MMP7 promotes resistance to oxaliplatin by shedding Fas receptor from the plasma membrane of resistant colon cancer cells. Inhibition of MMP7 (by 1,10-phenanthroline or siRNA) restores Fas surface levels and re-sensitizes cells to oxaliplatin-induced apoptosis in p53-mutant or p53-null but not p53-wildtype backgrounds.","method":"siRNA knockdown, MMP inhibitor (1,10-phenanthroline), flow cytometry (surface Fas), apoptosis assay, oxaliplatin-resistant cell line models","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and pharmacological inhibition with surface Fas quantification; single lab, two orthogonal inhibition approaches","pmids":["19266094"],"is_preprint":false},{"year":2012,"finding":"LEF-1 directly binds the MMP-7 promoter region (demonstrated by EMSA) and positively regulates MMP-7 transcription. LEF-1 siRNA knockdown in breast cancer cells decreases MMP-7 expression and causes G2/M cell cycle arrest.","method":"EMSA (in vitro DNA-protein binding), siRNA knockdown, RT-PCR, Western blot, cell cycle analysis","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA establishes direct binding, siRNA knockdown confirms functional regulation; single lab","pmids":["22686279"],"is_preprint":false},{"year":2011,"finding":"H2O2-induced MMP-7 expression in colorectal cancer cells is mediated by MAPK signaling through JNK/c-Jun and ERK/c-Fos activation in an AP-1-dependent manner. AP-1 pathway activation is required for H2O2-driven MMP-7 gene transcription and cell invasion.","method":"MAPK inhibitor studies (JNK, ERK, p38), AP-1 reporter assay, siRNA/inhibitor-based pathway dissection, cell invasion assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with AP-1 reporter and invasion readout; single lab, multiple pathway inhibitors","pmids":["21814482"],"is_preprint":false},{"year":2004,"finding":"MMP-7 expression in the kidney is induced during renal injury and closely parallels the expression pattern of Wnt4, consistent with Wnt4-driven regulation of matrilysin expression in tubular injury and progression to tubulointerstitial fibrosis.","method":"Northern blotting, RNase protection assay (RPA), immunohistochemistry, in situ hybridization; expression co-localization in three renal injury mouse models","journal":"Kidney international","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — co-localization by in situ hybridization and immunostaining; no direct functional experiment linking Wnt4 to MMP7 in this paper","pmids":["15149334"],"is_preprint":false},{"year":1996,"finding":"The MMP7 gene (matrilysin) maps to human chromosome 11q21→q22 by somatic cell hybrid analysis and in situ hybridization, placing it within the known cluster of matrix metalloproteinase genes.","method":"Southern blot, PCR analysis of somatic cell hybrids, fluorescence in situ hybridization (FISH)","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent mapping methods (hybrid analysis + FISH) establish chromosomal location","pmids":["8978768"],"is_preprint":false},{"year":2020,"finding":"MMP7 is required for processing pro-α-defensins in Paneth cells via the Mmp7/α-defensin axis; high-fat diet disrupts this axis, and NT deficiency prevents its disruption. NT inhibits DEFA5 (α-defensin 5) expression through atypical PKCτ/λ-mediated suppression of NF-κB signaling in Paneth cells.","method":"NT knockout mice, high-fat diet model, shRNA knockdown (PKCτ), PKC inhibitors, NF-κB reporter, DEFA5 expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and pharmacological intervention establish pathway placement; single lab with multiple approaches","pmids":["32359121"],"is_preprint":false},{"year":2023,"finding":"F. nucleatum infection upregulates MMP7 in colorectal cancer cells via the MAPK(JNK)-AP1 axis, promoting cell migration in vitro.","method":"Wound healing and Transwell migration assays, JNK/AP-1 pathway inhibition, Western blot, gene knockdown","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway inhibitors and knockdown with specific migration readout; single lab","pmids":["37814323"],"is_preprint":false}],"current_model":"MMP7 (matrilysin) is a secreted zinc-dependent endopeptidase that, lacking the hemopexin domain of classical MMPs, is secreted as a ~28 kDa zymogen and activated to ~19–21 kDa active forms; it degrades a broad range of ECM substrates (fibronectin, fibronectin aggregates, gelatins, collagen IV, perlecan, syndecan-1 ectodomain, sVEGFR-1, galectin-3, nephrin, and nucleolin), activates pro-collagenase, proMMP-2/9, and proADAM28s, and its transcription is driven by β-catenin/TCF-Lef, STAT3, AP-1 (c-Jun/c-Fos), CREB, and FOXC1 in context-dependent fashions, placing MMP7 as a downstream effector of Wnt, EGFR/PI3K-Akt, HER2-STAT3, and inflammatory (IL-17, catecholamine/β2-AR) signaling pathways that collectively regulate epithelial repair, inflammatory cell recruitment (via syndecan-1 shedding controlling α2β1 integrin affinity), angiogenesis (via sVEGFR-1 degradation to liberate VEGF), and cancer invasion and metastasis."},"narrative":{"mechanistic_narrative":"MMP7 (matrilysin/PUMP-1) is a secreted zinc-dependent metalloendopeptidase that, despite lacking the hemopexin-like domain of classical collagenases, is produced as a latent zymogen, activated to ~21/19 kDa forms, and degrades a broad range of extracellular substrates including casein, gelatins, fibronectin, and fibronectin aggregates [PMID:2550050, PMID:29600597]. Beyond bulk ECM turnover, MMP7 executes regulatory proteolysis of specific bioactive substrates: it sheds the syndecan-1 ectodomain to lower α2β1 integrin affinity and permit epithelial wound closure [PMID:19668337], cleaves perlecan/HSPG2 domain IV to convert tumor cells from a clustered to a dispersed invasive phenotype [PMID:24833109], degrades soluble VEGFR-1 to liberate VEGF and restore VEGFR-2 signaling and endothelial tube formation [PMID:18974372], and cleaves galectin-3 to suppress epithelial migration [PMID:20812334]. MMP7 also acts as an upstream activator of other proteases, processing proADAM28s, dissociating and activating proMMP-2 from its TIMP-2 complex, and activating latent collagenase [PMID:2550050, PMID:15013428, PMID:15523695]. Its proteolysis extends to cell-surface and intracellular targets controlling cell fate and signaling: shedding of Fas confers oxaliplatin resistance in p53-deficient colon cancer [PMID:19266094], cleavage of nucleolin at Asp255 generates a truncated form that stabilizes oncogenic mRNAs to promote metastasis [PMID:24632608], and disruption of the E-cadherin/β-catenin complex drives EMT [PMID:27375020]. Transcriptionally, MMP7 is a convergent effector of β-catenin/TCF-Lef, STAT3, AP-1 (c-Jun/c-Fos), CREB, and FOXC1 inputs that integrate Wnt, HER2-STAT3, IL-17, β2-adrenergic, and inflammatory signals [PMID:15457508, PMID:18411043, PMID:20939893, PMID:30303742, PMID:25847246, PMID:29249801], positioning it as a required driver of pancreatic, prostate, and breast cancer progression [PMID:21481787, PMID:27375020, PMID:29249801]. In tissue homeostasis and injury it degrades nephrin downstream of tubular β-catenin to cause proteinuria [PMID:31743113] and processes pro-α-defensins in Paneth cells [PMID:32359121].","teleology":[{"year":1989,"claim":"Establishing MMP7 as a bona fide latent metalloproteinase defined its catalytic identity and substrate range despite its atypically minimal domain structure lacking the hemopexin module of classical collagenases.","evidence":"COS-cell expression with in vitro protease and autocleavage assays plus EDTA/phenanthroline/TIMP inhibition","pmids":["2550050"],"confidence":"High","gaps":["In vivo physiological activator not identified","Endogenous tissue substrates inferred only from in vitro casein/gelatin/fibronectin cleavage"]},{"year":2004,"claim":"Showing MMP7 activates proADAM28s and that TCF binding element position dictates Lef-1 activator-versus-repressor behavior established MMP7 both as an upstream protease in a proteolytic cascade and as a context-dependent Wnt/β-catenin transcriptional target.","evidence":"In vitro reconstitution of proADAM28s activation with inhibitor controls; promoter-luciferase reporters with TBE mutagenesis and gel-shift affinity measurement","pmids":["15013428","15457508"],"confidence":"High","gaps":["Physiological relevance of the MMP7→ADAM28s→IGFBP-3 axis in vivo not tested","TBE rules derived from reporter constructs, not native chromatin"]},{"year":2005,"claim":"Demonstrating that MMP7 dissociates and activates proMMP-2 from the MMP-2/TIMP-2 complex placed MMP7 upstream of the gelatinases in driving cancer cell invasion.","evidence":"In vitro progelatinase activation, co-immunoprecipitation, and Transwell invasion with TIMP-2 rescue in ovarian cancer cells","pmids":["15523695"],"confidence":"High","gaps":["Genetic confirmation of the MMP7→MMP-2 axis in vivo absent","Stoichiometry of complex dissociation not resolved"]},{"year":2008,"claim":"Identifying sVEGFR-1 as a substrate and demonstrating HER2/HRG-driven STAT3 promoter occupancy connected MMP7 proteolysis to angiogenic VEGF liberation and to oncogenic transcriptional control.","evidence":"Recombinant degradation assays with tube-formation/migration/VEGFR-2 phosphorylation readouts (Blood); ChIP and promoter mutagenesis with STAT3C phenocopy (MCF-7)","pmids":["18974372","18411043"],"confidence":"High","gaps":["In vivo angiogenic consequence of sVEGFR-1 cleavage not established","Relative contribution of STAT3 versus other promoter inputs context-dependent"]},{"year":2009,"claim":"Knockout evidence that MMP7 sheds syndecan-1 to lower α2β1 integrin affinity defined a non-ECM regulatory proteolysis mechanism enabling epithelial wound closure.","evidence":"Mmp7−/− mice with in vitro/in vivo epithelial wound assays and integrin affinity measurement; recombinant MMP7 Fas-shedding studies in resistant colon cancer","pmids":["19668337","19266094"],"confidence":"High","gaps":["Mechanism by which syndecan-1 shedding alters integrin conformation not structurally defined","Fas-shedding p53-dependence mechanism unresolved (Medium-confidence)"]},{"year":2010,"claim":"Cleavage of galectin-3 and identification of AP-1/STAT3 cooperative promoter occupancy under β2-adrenergic stimulation broadened both the substrate repertoire and the upstream signaling inputs to MMP7.","evidence":"In vitro cleavage with N-terminal sequencing/MS and scratch-wound assay; promoter mutagenesis with STAT3/c-Jun Co-IP and β2-AR antagonist in gastric cancer","pmids":["20812334","20939893"],"confidence":"High","gaps":["In vivo significance of galectin-3 fragments not shown","Whether STAT3 acts only as a c-Jun co-factor at the AP-1 site generalizes beyond gastric cells unknown"]},{"year":2011,"claim":"Genetic epistasis placed MMP7 as a required STAT3-dependent effector of Kras-driven pancreatic cancer progression, moving it from in vitro correlate to in vivo driver.","evidence":"Kras-driven mouse PDA model with Stat3 and Mmp7 conditional KOs and tumor/metastasis quantification","pmids":["21481787"],"confidence":"High","gaps":["Critical MMP7 substrate(s) mediating PDA progression not defined","AP-1-driven H2O2 induction in CRC (Medium) extends but does not confirm pathway breadth"]},{"year":2014,"claim":"Pinpointing MMP7 cleavage of perlecan domain IV and of nucleolin at Asp255 revealed distinct mechanisms—BM remodeling for dispersal versus generation of a truncated RNA-stabilizing fragment—linking MMP7 to invasion and metastasis.","evidence":"In vitro cleavage of purified perlecan with invasion assays; cleavage-site mapping plus mRNA-stability and 3'-UTR binding assays downstream of EGFR","pmids":["24833109","24632608"],"confidence":"High","gaps":["Truncated nucleolin (TNCL) function relies on in vitro cleavage; in vivo abundance not quantified","Full repertoire of TNCL-stabilized mRNAs incomplete"]},{"year":2015,"claim":"Convergent transcriptional studies established FOXC1 (directly and via WNT5A/NF-κB and β-catenin), LEF-1, CREB, and PKP3/PRL3 loss as upstream MMP7 regulators that funnel into invasion programs.","evidence":"siRNA/overexpression with invasion assays, ChIP, EMSA, casein zymography, allele-specific CREB ChIP, and shRNA xenograft models across breast, gastric, and other cancers","pmids":["22645147","24143235","22686279","25847246","25875355"],"confidence":"Medium","gaps":["Most regulatory links are single-lab","Interplay/hierarchy among FOXC1, β-catenin, and NF-κB inputs at the MMP7 locus not unified","Allele-specific CREB regulation (Medium) not independently confirmed"]},{"year":2016,"claim":"Demonstrating MMP7 disrupts the E-cadherin/β-catenin complex to drive IL-17-dependent EMT, and that nuclear MMP7 physically binds ARF, expanded its roles into EMT control and an unexpected nuclear interaction.","evidence":"Mmp7/Pten double-KO mice, IL-17 stimulation with siRNA and inhibitor (prostate cancer); 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hemopexin-like domain of classical collagenases, is activated by organomercurial compounds (APMA) and degrades casein, type I/III/IV/V gelatins, fibronectin, and can activate latent collagenase in vitro. Active forms of 21,000 and 19,000 Da are generated upon activation. Activity is inhibited by EDTA, 1,10-phenanthroline, and TIMP.\",\n      \"method\": \"COS cell expression, IgG-Sepharose pulldown, in vitro protease assay, autocleavage assay, inhibitor studies\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in vitro with multiple substrates, inhibitor validation, and autocleavage assay; foundational mechanistic paper replicated by subsequent work\",\n      \"pmids\": [\"2550050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MMP-7 activates proADAM28s (65 kDa) to produce active 42- and 40-kDa forms. Active ADAM28s then cleaves insulin-like growth factor binding protein-3 (IGFBP-3) in both free and IGF-bound forms; this cleavage is blocked by EDTA, 1,10-phenanthroline, KB-R7785, TIMP-3, and TIMP-4.\",\n      \"method\": \"In vitro protease assay, recombinant protein incubation, inhibitor studies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution with recombinant proteins and multiple inhibitor controls in a focused mechanistic study\",\n      \"pmids\": [\"15013428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MMP-7 promotes invasion of ovarian cancer cells by activating proMMP-2 and proMMP-9. MMP-7 can dissociate MMP-2 from the MMP-2/TIMP-2 complex and activate it in a time-dependent, concentration-dependent manner in vitro. TIMP-2 inhibits both proMMP-2 activation and MMP-7-induced increased invasion.\",\n      \"method\": \"In vitro progelatinase activation assay, co-immunoprecipitation, Transwell invasion assay, recombinant MMP-7 treatment\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of progelatinase activation, reciprocal inhibitor controls, and functional invasion assay in a single study\",\n      \"pmids\": [\"15523695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MMP-7 degrades soluble VEGFR-1 (sVEGFR-1/sFlt-1), liberating VEGF165 from the sVEGFR-1 complex and increasing VEGF bioavailability. This degradation abrogates sVEGFR-1 inhibition of VEGFR-2 phosphorylation on endothelial cells and promotes tube formation and migration.\",\n      \"method\": \"In vitro degradation assay with recombinant proteins, co-immunoprecipitation (HUVECs), tube formation assay, migration assay, VEGFR-2 phosphorylation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical reconstitution of substrate cleavage with multiple orthogonal functional readouts (tube formation, migration, receptor phosphorylation) in a single study\",\n      \"pmids\": [\"18974372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MMP7 sheds syndecan-1 from lung epithelial cells upon injury; this shedding is absent in Mmp7−/− mice. MMP7-mediated syndecan-1 shedding facilitates wound closure by causing the α2β1 integrin to assume a less active conformation, removing restrictions to cell migration.\",\n      \"method\": \"Mmp7−/− knockout mouse model, in vitro and in vivo epithelial wound assay, integrin affinity state measurement, syndecan-1 shedding detection\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific phenotypic readout replicated in vitro and in vivo, mechanistic link to integrin conformation established\",\n      \"pmids\": [\"19668337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MMP7 (matrilysin-1) directly cleaves galectin-3 in vitro, producing three fragments (20.2, 18.9, and 15.5 kDa). Recombinant MMP7 treatment of colonic epithelial T84 cells produces galectin-3 cleavage fragments in the supernatant and inhibits cell migration and wound closure; galectin-3's pro-migratory effect is abrogated by MMP7 co-treatment.\",\n      \"method\": \"In vitro cleavage assay, N-terminal sequencing, mass spectrometry, Western blotting, in vitro scratch wound assay\",\n      \"journal\": \"Inflammatory bowel diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with fragment identification by N-terminal sequencing and MS, plus functional cell migration assay in a single study\",\n      \"pmids\": [\"20812334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MMP7 cleaves purified perlecan/HSPG2 at multiple sites within domain IV in vitro, including when perlecan is decorated with heparan sulfate or embedded in native BM context. MMP7 digestion of perlecan domain IV fragment (Dm IV-3) reverses cell clustering to a cell dispersion phenotype in metastatic PCa cells and increases invasion through perlecan-rich BM extract.\",\n      \"method\": \"In vitro protease assay with purified perlecan, in silico cleavage prediction, Transwell invasion assay with MMP-7-pre-digested BM extract\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified substrates under multiple conditions plus functional cellular readout in a single focused study\",\n      \"pmids\": [\"24833109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MMP7 cleaves nucleolin (NCL) at Asp255 to generate a C-terminal truncated form (TNCL, ~55 kDa). TNCL stabilizes MMP9 mRNA (and other oncogenic mRNAs) by binding to their 3'-UTRs, thereby promoting metastasis. This cleavage is induced downstream of EGF receptor pathway activation.\",\n      \"method\": \"MMP7 in vitro cleavage assay identifying cleavage site, Western blot, mRNA stability assay, 3'-UTR binding, cell invasion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — identified exact cleavage site in vitro, functional consequence (mRNA stabilization) demonstrated with orthogonal methods\",\n      \"pmids\": [\"24632608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"β-catenin signaling in renal tubular cells drives MMP-7 expression and secretion. Secreted MMP-7 directly degrades nephrin (a key slit diaphragm protein) in a proteolytic-activity-dependent manner in cultured glomeruli and cell-free systems, causing proteinuria and glomerular injury in vivo.\",\n      \"method\": \"Conditional tubule-specific β-catenin KO mice, MMP-7 genetic ablation (KO mice), ex vivo glomerular incubation with recombinant MMP-7, cell-free nephrin cleavage assay, in vivo MMP-7 infusion/overexpression\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of nephrin cleavage, genetic KO rescue, and in vivo MMP-7 infusion with consistent results across multiple models\",\n      \"pmids\": [\"31743113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MMP7 cleaves fibronectin aggregates in vitro, producing a prominent 13 kDa EIIIA-containing fragment. MMP7 is upregulated in lysolecithin-induced demyelination (endogenous clearance), whereas proMMP7 levels are substantially reduced in chronic active and inactive MS lesions. IL-4-activated microglia/macrophages are major cellular sources of proMMP7.\",\n      \"method\": \"In vitro fibronectin aggregate cleavage assay, Western blot, lysolecithin demyelination mouse model, immunostaining of MS lesions, macrophage polarization assays\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of fibronectin aggregate cleavage with fragment characterization, corroborated in vivo and in human tissue\",\n      \"pmids\": [\"29600597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Stat3 signaling enforces MMP7 expression in pancreatic ductal adenocarcinoma (PDA) cells. MMP7 deletion in a Kras-driven mouse model limits tumor size and metastasis, placing MMP7 downstream of Stat3 as a required effector of PDA progression.\",\n      \"method\": \"Genetic epistasis in Kras-driven mouse PDA model, Stat3 conditional KO, Mmp7 KO mice, tumor size/metastasis quantification\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in a well-controlled in vivo cancer model with multiple KO lines showing consistent pathway placement\",\n      \"pmids\": [\"21481787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The position of Tcf binding elements (TBEs) relative to the MMP7 transcriptional start site determines whether Lef-1 acts as an activator or repressor of β-catenin-driven MMP7 transcription. Upstream TBEs (human promoter) allow Lef-1 activation, whereas a downstream TBE (mouse promoter) supports Lef-1-mediated repression. TBE sequence affinity for Lef-1 determines potency: high-affinity sites (G·C at 5′/3′ ends) yield up to 115-fold greater β-catenin responsiveness.\",\n      \"method\": \"Promoter-luciferase reporter assays, TBE mutagenesis, in vitro Lef-1 binding affinity (gel-shift), heterologous promoter constructs\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with reporter assays and in vitro binding measurements; multiple constructs tested in a single rigorous study\",\n      \"pmids\": [\"15457508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HER2 overexpression or HRG stimulation upregulates MMP-7 transcription and protein secretion via activated STAT3. STAT3 binds directly to the MMP-7 promoter at a critical STAT3 binding element, as shown by ChIP and promoter mutagenesis. Constitutively active STAT3 is sufficient to drive MMP-7 expression.\",\n      \"method\": \"Stable HER2/STAT3C overexpression in MCF-7, promoter-luciferase assay, ChIP, STAT3 binding site mutagenesis, RT-PCR, Western blot\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP validates direct STAT3 binding, mutagenesis identifies critical element, supported by constitutively active STAT3 phenocopy\",\n      \"pmids\": [\"18411043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FOXC1 induces MMP7 expression and MMP7-dependent invasion in basal-like breast cancer cells. Silencing FOXC1 selectively decreases MMP7 without reducing other MMPs; ectopic FOXC1 in non-transformed cells increases MMP7 and invasion in an MMP7-dependent manner.\",\n      \"method\": \"siRNA knockdown, transient overexpression, Matrigel invasion assay, mRNA/protein expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with invasion phenotype, single lab, two orthogonal methods (siRNA + overexpression)\",\n      \"pmids\": [\"22645147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXC1 directly binds the WNT5A promoter to activate its expression; WNT5A then activates NF-κB signaling to induce MMP7 expression. The FOXC1→WNT5A→NF-κB→MMP7 axis is required for TNBC cell invasiveness in vitro and lung metastasis in vivo (MMP7 overexpression rescues WNT5A-KO metastasis defect).\",\n      \"method\": \"ChIP (FOXC1 binding to WNT5A promoter), enChIP-MS, WNT5A knockout xenograft model, MMP7 overexpression rescue, NF-κB pathway inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct promoter binding by ChIP, genetic epistasis in vivo with rescue experiment, multiple orthogonal methods in one study\",\n      \"pmids\": [\"29249801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MMP7 promotes prostate adenocarcinoma by disrupting the E-cadherin/β-catenin complex to upregulate EMT transcription factors. MMP7 knockout in Pten-null mice limits EMT characteristics, recapitulating the phenotype of IL-17 receptor C/Pten double-KO mice. IL-17 induces MMP7 and EMT in human prostate cancer cells; MMP7 siRNA knockdown inhibits IL-17-induced EMT.\",\n      \"method\": \"Mmp7/Pten double KO mice, siRNA knockdown, MMP7 inhibitor (Compound III) in vivo, Western blot for E-cadherin/β-catenin\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic double-KO model with in vivo tumor phenotype, pharmacological inhibition, and siRNA knockdown in cell lines providing consistent epistatic placement\",\n      \"pmids\": [\"27375020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Catecholamine (isoproterenol) stimulation via β2-adrenergic receptor upregulates MMP-7 expression in gastric cancer cells through AP-1 (dominant pathway) and STAT3 transcription factors. STAT3 and c-Jun physically interact and co-occupy the AP-1 site in the MMP-7 promoter; AP-1 site mutation completely abolishes isoproterenol-induced MMP-7 promoter activity, whereas STAT3-site mutation alone does not.\",\n      \"method\": \"Promoter-luciferase reporter assay, site-directed mutagenesis of AP-1 and STAT3 sites, siRNA knockdown, Co-IP (STAT3/c-Jun interaction), β2-AR antagonist treatment\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis identifies critical promoter element, Co-IP validates physical interaction, multiple orthogonal methods in single study\",\n      \"pmids\": [\"20939893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Activin A enhances MMP-7 expression via the AP-1 transcription factor (not through Smad2/3). Mutation of the AP-1 binding site in the MMP-7 promoter reduces activity, whereas mutation of the Smad binding site does not. c-Jun is increased in activin A-expressing esophageal carcinoma cells.\",\n      \"method\": \"Stable transfection of activin βA, promoter-luciferase assay with AP-1 and Smad site mutations, RT-PCR, Northern blot, neutralizing antibody\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — promoter mutagenesis distinguishes AP-1 from Smad dependence, supported by neutralizing antibody; single lab\",\n      \"pmids\": [\"18695873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FOXC1 promotes MMP7-dependent invasion in TNBC via β-catenin activation of MMP7. Wnt-β-catenin signaling upregulates MMP7 in a PTEN-loss-dependent manner; pharmacological/siRNA attenuation of β-catenin downregulates secreted MMP7 enzymatic activity (casein zymography).\",\n      \"method\": \"siRNA knockdown of β-catenin, WP inhibitors (XAV939, sulindac sulfide), LY294002 (PTEN mimetic), casein zymography, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic attenuation of pathway with enzymatic readout; single lab, two orthogonal approaches\",\n      \"pmids\": [\"24143235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Gastrin stimulates MMP-7 promoter-luciferase activity in gastric epithelial cells. MMP-7 secreted by gastric epithelial cells promotes myofibroblast proliferation via MAPK and PI3K pathways; neutralizing antibodies to MMP-7 block this proliferation.\",\n      \"method\": \"Promoter-luciferase reporter assay, MMP-7 neutralizing antibody, conditioned medium treatment of myofibroblasts, pathway inhibitors (MAPK/PI3K)\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — neutralizing antibody functional rescue plus promoter activity and pathway inhibitor data; single lab\",\n      \"pmids\": [\"17218472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MMP7 knockdown in PKP3 (Plakophilin3)-deficient cells abolishes in vitro cell migration/invasion and in vivo tumor formation. Increased MMP7 levels upon PKP3 loss are mediated by elevated PRL3 (Phosphatase of Regenerating Liver-3).\",\n      \"method\": \"shRNA knockdown of MMP7, Transwell migration/invasion assay, mouse xenograft tumor formation, Western blot for PRL3/MMP7\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific phenotypic readout in vitro and in vivo, upstream regulator (PRL3) identified; single lab\",\n      \"pmids\": [\"25875355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MMP7 physically binds ARF (p14ARF/p19Arf) and co-localizes with it in the nucleus of malignant prostate tumor cells. ARF knockdown markedly reduces MMP7 levels; inducible ARF expression increases MMP7 and decreases E-cadherin. Co-expression of ARF and MMP7 promotes cell migration.\",\n      \"method\": \"Co-immunoprecipitation, co-localization (nuclear fractionation/immunofluorescence), inducible ARF overexpression, shRNA knockdown, mouse Pten/Trp53/p19Arf triple mutant model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP establishes physical interaction, inducible OE and KD provide reciprocal evidence; nuclear localization tied to functional outcome\",\n      \"pmids\": [\"27356744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cortisol induces MMP7 expression in human amnion fibroblasts via AP-1 (c-Fos and c-Jun). ChIP shows enrichment of c-Fos and c-Jun at the AP-1 binding site in the MMP7 promoter following cortisol treatment. MMP7 secreted under cortisol stimulation degrades extracellular COL4A5 (collagen IV α5 chain), which is blocked by anti-MMP-7 antibody.\",\n      \"method\": \"RNA-sequencing, RT-qPCR, Western blot, ChIP (c-Fos/c-Jun at MMP7 promoter AP-1 site), siRNA knockdown of c-Fos/c-Jun, anti-MMP-7 neutralizing antibody, amnion tissue analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP validates direct AP-1 occupancy, siRNA of both c-Fos and c-Jun attenuates induction, antibody rescue confirms MMP7 as effector; multiple orthogonal methods\",\n      \"pmids\": [\"30303742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nicotine increases MMP7 expression in gastric adenocarcinoma cells by enhancing CREB phosphorylation and nuclear translocation. Phosphorylated CREB preferentially binds the -181G allele of the MMP7 promoter relative to -181A (ChIP assay), conferring allele-specific transcriptional upregulation.\",\n      \"method\": \"Promoter-reporter assay, ChIP (phospho-CREB binding to -181G vs -181A allele), CREB overexpression, Western blot, case-control genotyping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP distinguishes allele-specific binding, reporter assay confirms functional difference; single lab with two orthogonal methods\",\n      \"pmids\": [\"25847246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MMP7 promotes resistance to oxaliplatin by shedding Fas receptor from the plasma membrane of resistant colon cancer cells. Inhibition of MMP7 (by 1,10-phenanthroline or siRNA) restores Fas surface levels and re-sensitizes cells to oxaliplatin-induced apoptosis in p53-mutant or p53-null but not p53-wildtype backgrounds.\",\n      \"method\": \"siRNA knockdown, MMP inhibitor (1,10-phenanthroline), flow cytometry (surface Fas), apoptosis assay, oxaliplatin-resistant cell line models\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and pharmacological inhibition with surface Fas quantification; single lab, two orthogonal inhibition approaches\",\n      \"pmids\": [\"19266094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LEF-1 directly binds the MMP-7 promoter region (demonstrated by EMSA) and positively regulates MMP-7 transcription. LEF-1 siRNA knockdown in breast cancer cells decreases MMP-7 expression and causes G2/M cell cycle arrest.\",\n      \"method\": \"EMSA (in vitro DNA-protein binding), siRNA knockdown, RT-PCR, Western blot, cell cycle analysis\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA establishes direct binding, siRNA knockdown confirms functional regulation; single lab\",\n      \"pmids\": [\"22686279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"H2O2-induced MMP-7 expression in colorectal cancer cells is mediated by MAPK signaling through JNK/c-Jun and ERK/c-Fos activation in an AP-1-dependent manner. AP-1 pathway activation is required for H2O2-driven MMP-7 gene transcription and cell invasion.\",\n      \"method\": \"MAPK inhibitor studies (JNK, ERK, p38), AP-1 reporter assay, siRNA/inhibitor-based pathway dissection, cell invasion assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with AP-1 reporter and invasion readout; single lab, multiple pathway inhibitors\",\n      \"pmids\": [\"21814482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MMP-7 expression in the kidney is induced during renal injury and closely parallels the expression pattern of Wnt4, consistent with Wnt4-driven regulation of matrilysin expression in tubular injury and progression to tubulointerstitial fibrosis.\",\n      \"method\": \"Northern blotting, RNase protection assay (RPA), immunohistochemistry, in situ hybridization; expression co-localization in three renal injury mouse models\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization by in situ hybridization and immunostaining; no direct functional experiment linking Wnt4 to MMP7 in this paper\",\n      \"pmids\": [\"15149334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The MMP7 gene (matrilysin) maps to human chromosome 11q21→q22 by somatic cell hybrid analysis and in situ hybridization, placing it within the known cluster of matrix metalloproteinase genes.\",\n      \"method\": \"Southern blot, PCR analysis of somatic cell hybrids, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent mapping methods (hybrid analysis + FISH) establish chromosomal location\",\n      \"pmids\": [\"8978768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MMP7 is required for processing pro-α-defensins in Paneth cells via the Mmp7/α-defensin axis; high-fat diet disrupts this axis, and NT deficiency prevents its disruption. NT inhibits DEFA5 (α-defensin 5) expression through atypical PKCτ/λ-mediated suppression of NF-κB signaling in Paneth cells.\",\n      \"method\": \"NT knockout mice, high-fat diet model, shRNA knockdown (PKCτ), PKC inhibitors, NF-κB reporter, DEFA5 expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and pharmacological intervention establish pathway placement; single lab with multiple approaches\",\n      \"pmids\": [\"32359121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"F. nucleatum infection upregulates MMP7 in colorectal cancer cells via the MAPK(JNK)-AP1 axis, promoting cell migration in vitro.\",\n      \"method\": \"Wound healing and Transwell migration assays, JNK/AP-1 pathway inhibition, Western blot, gene knockdown\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway inhibitors and knockdown with specific migration readout; single lab\",\n      \"pmids\": [\"37814323\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MMP7 (matrilysin) is a secreted zinc-dependent endopeptidase that, lacking the hemopexin domain of classical MMPs, is secreted as a ~28 kDa zymogen and activated to ~19–21 kDa active forms; it degrades a broad range of ECM substrates (fibronectin, fibronectin aggregates, gelatins, collagen IV, perlecan, syndecan-1 ectodomain, sVEGFR-1, galectin-3, nephrin, and nucleolin), activates pro-collagenase, proMMP-2/9, and proADAM28s, and its transcription is driven by β-catenin/TCF-Lef, STAT3, AP-1 (c-Jun/c-Fos), CREB, and FOXC1 in context-dependent fashions, placing MMP7 as a downstream effector of Wnt, EGFR/PI3K-Akt, HER2-STAT3, and inflammatory (IL-17, catecholamine/β2-AR) signaling pathways that collectively regulate epithelial repair, inflammatory cell recruitment (via syndecan-1 shedding controlling α2β1 integrin affinity), angiogenesis (via sVEGFR-1 degradation to liberate VEGF), and cancer invasion and metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MMP7 (matrilysin/PUMP-1) is a secreted zinc-dependent metalloendopeptidase that, despite lacking the hemopexin-like domain of classical collagenases, is produced as a latent zymogen, activated to ~21/19 kDa forms, and degrades a broad range of extracellular substrates including casein, gelatins, fibronectin, and fibronectin aggregates [#0, #9]. Beyond bulk ECM turnover, MMP7 executes regulatory proteolysis of specific bioactive substrates: it sheds the syndecan-1 ectodomain to lower α2β1 integrin affinity and permit epithelial wound closure [#4], cleaves perlecan/HSPG2 domain IV to convert tumor cells from a clustered to a dispersed invasive phenotype [#6], degrades soluble VEGFR-1 to liberate VEGF and restore VEGFR-2 signaling and endothelial tube formation [#3], and cleaves galectin-3 to suppress epithelial migration [#5]. MMP7 also acts as an upstream activator of other proteases, processing proADAM28s, dissociating and activating proMMP-2 from its TIMP-2 complex, and activating latent collagenase [#0, #1, #2]. Its proteolysis extends to cell-surface and intracellular targets controlling cell fate and signaling: shedding of Fas confers oxaliplatin resistance in p53-deficient colon cancer [#24], cleavage of nucleolin at Asp255 generates a truncated form that stabilizes oncogenic mRNAs to promote metastasis [#7], and disruption of the E-cadherin/β-catenin complex drives EMT [#15]. Transcriptionally, MMP7 is a convergent effector of β-catenin/TCF-Lef, STAT3, AP-1 (c-Jun/c-Fos), CREB, and FOXC1 inputs that integrate Wnt, HER2-STAT3, IL-17, β2-adrenergic, and inflammatory signals [#11, #12, #16, #22, #23, #14], positioning it as a required driver of pancreatic, prostate, and breast cancer progression [#10, #15, #14]. In tissue homeostasis and injury it degrades nephrin downstream of tubular β-catenin to cause proteinuria [#8] and processes pro-α-defensins in Paneth cells [#29].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing MMP7 as a bona fide latent metalloproteinase defined its catalytic identity and substrate range despite its atypically minimal domain structure lacking the hemopexin module of classical collagenases.\",\n      \"evidence\": \"COS-cell expression with in vitro protease and autocleavage assays plus EDTA/phenanthroline/TIMP inhibition\",\n      \"pmids\": [\"2550050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological activator not identified\", \"Endogenous tissue substrates inferred only from in vitro casein/gelatin/fibronectin cleavage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing MMP7 activates proADAM28s and that TCF binding element position dictates Lef-1 activator-versus-repressor behavior established MMP7 both as an upstream protease in a proteolytic cascade and as a context-dependent Wnt/β-catenin transcriptional target.\",\n      \"evidence\": \"In vitro reconstitution of proADAM28s activation with inhibitor controls; promoter-luciferase reporters with TBE mutagenesis and gel-shift affinity measurement\",\n      \"pmids\": [\"15013428\", \"15457508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of the MMP7→ADAM28s→IGFBP-3 axis in vivo not tested\", \"TBE rules derived from reporter constructs, not native chromatin\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that MMP7 dissociates and activates proMMP-2 from the MMP-2/TIMP-2 complex placed MMP7 upstream of the gelatinases in driving cancer cell invasion.\",\n      \"evidence\": \"In vitro progelatinase activation, co-immunoprecipitation, and Transwell invasion with TIMP-2 rescue in ovarian cancer cells\",\n      \"pmids\": [\"15523695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genetic confirmation of the MMP7→MMP-2 axis in vivo absent\", \"Stoichiometry of complex dissociation not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying sVEGFR-1 as a substrate and demonstrating HER2/HRG-driven STAT3 promoter occupancy connected MMP7 proteolysis to angiogenic VEGF liberation and to oncogenic transcriptional control.\",\n      \"evidence\": \"Recombinant degradation assays with tube-formation/migration/VEGFR-2 phosphorylation readouts (Blood); ChIP and promoter mutagenesis with STAT3C phenocopy (MCF-7)\",\n      \"pmids\": [\"18974372\", \"18411043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo angiogenic consequence of sVEGFR-1 cleavage not established\", \"Relative contribution of STAT3 versus other promoter inputs context-dependent\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Knockout evidence that MMP7 sheds syndecan-1 to lower α2β1 integrin affinity defined a non-ECM regulatory proteolysis mechanism enabling epithelial wound closure.\",\n      \"evidence\": \"Mmp7−/− mice with in vitro/in vivo epithelial wound assays and integrin affinity measurement; recombinant MMP7 Fas-shedding studies in resistant colon cancer\",\n      \"pmids\": [\"19668337\", \"19266094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which syndecan-1 shedding alters integrin conformation not structurally defined\", \"Fas-shedding p53-dependence mechanism unresolved (Medium-confidence)\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Cleavage of galectin-3 and identification of AP-1/STAT3 cooperative promoter occupancy under β2-adrenergic stimulation broadened both the substrate repertoire and the upstream signaling inputs to MMP7.\",\n      \"evidence\": \"In vitro cleavage with N-terminal sequencing/MS and scratch-wound assay; promoter mutagenesis with STAT3/c-Jun Co-IP and β2-AR antagonist in gastric cancer\",\n      \"pmids\": [\"20812334\", \"20939893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of galectin-3 fragments not shown\", \"Whether STAT3 acts only as a c-Jun co-factor at the AP-1 site generalizes beyond gastric cells unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic epistasis placed MMP7 as a required STAT3-dependent effector of Kras-driven pancreatic cancer progression, moving it from in vitro correlate to in vivo driver.\",\n      \"evidence\": \"Kras-driven mouse PDA model with Stat3 and Mmp7 conditional KOs and tumor/metastasis quantification\",\n      \"pmids\": [\"21481787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Critical MMP7 substrate(s) mediating PDA progression not defined\", \"AP-1-driven H2O2 induction in CRC (Medium) extends but does not confirm pathway breadth\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Pinpointing MMP7 cleavage of perlecan domain IV and of nucleolin at Asp255 revealed distinct mechanisms—BM remodeling for dispersal versus generation of a truncated RNA-stabilizing fragment—linking MMP7 to invasion and metastasis.\",\n      \"evidence\": \"In vitro cleavage of purified perlecan with invasion assays; cleavage-site mapping plus mRNA-stability and 3'-UTR binding assays downstream of EGFR\",\n      \"pmids\": [\"24833109\", \"24632608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Truncated nucleolin (TNCL) function relies on in vitro cleavage; in vivo abundance not quantified\", \"Full repertoire of TNCL-stabilized mRNAs incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Convergent transcriptional studies established FOXC1 (directly and via WNT5A/NF-κB and β-catenin), LEF-1, CREB, and PKP3/PRL3 loss as upstream MMP7 regulators that funnel into invasion programs.\",\n      \"evidence\": \"siRNA/overexpression with invasion assays, ChIP, EMSA, casein zymography, allele-specific CREB ChIP, and shRNA xenograft models across breast, gastric, and other cancers\",\n      \"pmids\": [\"22645147\", \"24143235\", \"22686279\", \"25847246\", \"25875355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most regulatory links are single-lab\", \"Interplay/hierarchy among FOXC1, β-catenin, and NF-κB inputs at the MMP7 locus not unified\", \"Allele-specific CREB regulation (Medium) not independently confirmed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating MMP7 disrupts the E-cadherin/β-catenin complex to drive IL-17-dependent EMT, and that nuclear MMP7 physically binds ARF, expanded its roles into EMT control and an unexpected nuclear interaction.\",\n      \"evidence\": \"Mmp7/Pten double-KO mice, IL-17 stimulation with siRNA and inhibitor (prostate cancer); Co-IP and nuclear co-localization with ARF gain/loss-of-function\",\n      \"pmids\": [\"27375020\", \"27356744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear MMP7-ARF mechanism (Medium) lacks reciprocal validation and catalytic requirement is unclear\", \"How a secreted protease accesses the nucleus unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying MMP7 cleavage of fibronectin aggregates in demyelination and cortisol/AP-1-driven COL4A5 degradation in amnion connected MMP7 to lesion clearance and tissue remodeling in non-cancer contexts.\",\n      \"evidence\": \"In vitro fibronectin-aggregate cleavage with lysolecithin demyelination model and MS lesion staining; RNA-seq, ChIP of c-Fos/c-Jun, siRNA, and neutralizing antibody in amnion fibroblasts\",\n      \"pmids\": [\"29600597\", \"30303742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal contribution of MMP7 to remyelination outcomes not demonstrated by genetic loss-of-function\", \"Physiological role of amnion COL4A5 degradation in membrane rupture not directly tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing tubular β-catenin drives MMP7 secretion that directly cleaves nephrin established a defined β-catenin→MMP7→nephrin axis causing proteinuria and glomerular injury.\",\n      \"evidence\": \"Tubule-specific β-catenin KO, Mmp7 KO, ex vivo glomerular and cell-free nephrin cleavage assays, and in vivo MMP7 infusion/overexpression\",\n      \"pmids\": [\"31743113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether nephrin cleavage is the sole mediator of injury not isolated\", \"Earlier Wnt4/MMP7 co-localization (Low) provides only correlative upstream context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placing MMP7 in the Paneth-cell Mmp7/α-defensin axis disrupted by high-fat diet extended its physiological role to innate antimicrobial peptide processing.\",\n      \"evidence\": \"NT knockout mice, high-fat diet model, PKCτ shRNA/inhibitors, and NF-κB/DEFA5 readouts\",\n      \"pmids\": [\"32359121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MMP7 cleavage of pro-α-defensins not reconstituted in this study\", \"Single-lab pathway placement\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linking F. nucleatum infection to MMP7 induction via JNK-AP1 added a microbial inflammatory input to the AP-1 transcriptional control of MMP7 in colorectal cancer.\",\n      \"evidence\": \"Wound-healing/Transwell migration with JNK/AP-1 inhibition and knockdown\",\n      \"pmids\": [\"37814323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation\", \"Direct AP-1 occupancy at MMP7 promoter not shown in this context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MMP7 zymogen activation is controlled in vivo, which of its many substrates dominate in each tissue context, and the structural/mechanistic basis of its reported nuclear ARF interaction remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo physiological pro-MMP7 activator identified\", \"Tissue-specific dominant substrate not deconvoluted from the broad in vitro repertoire\", \"Mechanism of secreted-protease nuclear access and ARF binding undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 6, 7, 8, 9]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 7, 8, 22, 24]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 3, 4, 8, 22]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 4, 6, 9, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 15, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 12, 16, 18, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ADAM28\", \"MMP2\", \"TIMP2\", \"FLT1\", \"LGALS3\", \"HSPG2\", \"NCL\", \"ARF\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}