{"gene":"MMP1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"CD147 (EMMPRIN) stimulates MMP-1 production via homophilic CD147-CD147 interactions, predominantly through the first immunoglobulin domain; deglycosylated CD147 failed to induce MMP-1 and instead antagonized native CD147-induced MMP-1, demonstrating that glycosylation is required for the MMP-1-inducing activity.","method":"Purified native vs. deglycosylated CD147, anti-CD147 antibody inhibition, recombinant CD147-Fc fusion protein, MMP-1 ELISA in dermal fibroblasts","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1/2 / Moderate — multiple orthogonal methods (purified protein, blocking antibody, fusion protein, deglycosylation), single lab but rigorous mechanistic controls","pmids":["11280798"],"is_preprint":false},{"year":2006,"finding":"In Drosophila, loss of the polarity gene scribble activates JNK signaling, which promotes Fos-dependent transcriptional activation of mmp1, leading to tumor cell invasiveness; Timp expression or Mmp1 RNAi knockdown suppressed cell invasiveness downstream of JNK.","method":"Genetic epistasis (scribble mutant clones + Ras activation), RNAi knockdown of Mmp1, Timp overexpression, in vivo invasion assays in Drosophila imaginal discs","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple loss-of-function and rescue experiments in vivo, replicated by multiple approaches","pmids":["17082773"],"is_preprint":false},{"year":2009,"finding":"MMP1 proteolytically releases membrane-bound EGF-like ligands (Amphiregulin, HB-EGF, TGFα) from breast cancer tumor cells, which then suppress osteoprotegerin (OPG) expression in osteoblasts via EGFR signaling, thereby potentiating osteoclast differentiation and osteolytic bone metastasis.","method":"In vitro protease cleavage assays, EGFR inhibitor treatment, osteoblast co-culture, osteoclastogenesis assays, in vivo bone metastasis model","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical cleavage, signaling inhibition, in vivo model), mechanistically defined paracrine cascade","pmids":["19608765"],"is_preprint":false},{"year":2008,"finding":"UV-induced DNA damage in epidermal keratinocytes initiates release of soluble mediators that signal dermal fibroblasts to produce MMP-1; photolyase-mediated DNA repair of epidermal UV damage reduced MMP-1 mRNA and protein in both epidermal and dermal compartments, and conditioned medium from irradiated keratinocytes enhanced MMP-1 in unirradiated fibroblasts.","method":"Liposome-encapsulated DNA repair enzymes (T4 endonuclease V, UV endonuclease), conditioned medium transfer from irradiated keratinocytes to unirradiated fibroblasts, MMP-1 mRNA and protein measurement in human skin","journal":"Experimental dermatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditioned medium transfer experiment plus DNA repair enzyme rescue, two orthogonal approaches in human skin tissue and cells","pmids":["18459971"],"is_preprint":false},{"year":2008,"finding":"Met receptor tyrosine kinase phosphorylates MUC1 cytoplasmic tail at YHPM; phosphorylated MUC1CT enhances its interaction with p53, which suppresses AP1 transcription factor activity at the MMP1 promoter, reducing MMP1 transcription and HGF-induced invasiveness.","method":"Co-IP, real-time confocal imaging of nuclear localization, luciferase promoter assay, western blot, invasion assay in pancreatic cancer cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction assays, promoter activity assay, live imaging, and functional invasion assay in single lab with multiple orthogonal methods","pmids":["18625714"],"is_preprint":false},{"year":2005,"finding":"UV radiation increases MMP-1 expression in human dermal fibroblasts via ERK (MEK1) and JNK (SEK1) signaling pathways leading to increased c-Fos expression and c-Jun phosphorylation/expression, and consequent AP-1 DNA binding activity; EPA inhibited this induction by blocking MEK1/ERK/c-Fos and SEK1/JNK/c-Jun pathways.","method":"Kinase inhibitors (MEK1 inhibitor, SEK1 inhibitor), western blot for pathway activation, AP-1 EMSA, MMP-1 ELISA in human dermal fibroblasts","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway inhibitors plus AP-1 binding assay, single lab","pmids":["15930517"],"is_preprint":false},{"year":2005,"finding":"Cdc42 downregulates MMP-1 expression in human skin fibroblasts via repression of the ERK1/2 pathway; silencing Cdc42 by siRNA induced a 15-fold increase in MMP-1 secretion dependent on ERK1/2, while the p38 MAP kinase pathway played an inhibitory role; Rac1 silencing reduced the effect of Cdc42 suppression.","method":"siRNA knockdown of Rho GTPases (Cdc42, RhoA, Rac1), chemical kinase inhibitors, rescue by Cdc42 re-expression with siRNA-resistant construct, ELISA, RT-PCR in human skin fibroblasts","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown with rescue (siRNA-resistant construct), multiple GTPase knockdowns, pharmacological inhibitors, multiple cell lines, single lab","pmids":["15728253"],"is_preprint":false},{"year":2008,"finding":"DNA methylation at position -1538 in the MMP1 promoter suppresses MMP1 transcription in amnion fibroblasts; inhibition of DNA methylation with 5-aza-2'-deoxycytidine significantly increased MMP1 gene transcription; a novel T>C SNP in the MMP1 promoter that is always methylated in vivo had reduced promoter activity, and methylation at this site increased affinity for a nuclear protein.","method":"5-aza-2'-deoxycytidine treatment, bisulfite sequencing, plasmid transfection promoter activity assay, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift (nuclear protein binding) in amnion fibroblasts","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (pharmacological demethylation, bisulfite sequencing, promoter assay, ChIP, EMSA) in single lab","pmids":["18178580"],"is_preprint":false},{"year":2011,"finding":"MMP1 bimodal expression in endothelial cells is linked to a promoter polymorphism; ChIP experiments showed that transcription factors ETS1, ETS2 and GATA3 bind to the MMP1 promoter in the region of this polymorphism and may contribute to bimodal expression.","method":"Microarray analysis, hierarchical clustering, RT-PCR, MMP1 activity assay, DNA sequencing, chromatin immunoprecipitation (ChIP) in HUVECs from 15–69 individuals","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for transcription factor binding combined with population-level sequencing and activity assays, single lab","pmids":["21244711"],"is_preprint":false},{"year":2011,"finding":"The catalytic domain of MMP-1 in solution retains the overall fold seen in crystal structures, requiring only local rearrangements (not major domain rearrangements) to reconcile X-ray and NMR data, as assessed by paramagnetic NMR using lanthanide binding tags.","method":"NMR pseudocontact shifts and paramagnetic residual dipolar couplings using lanthanide binding tags on the MMP-1 catalytic domain","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural NMR method applied to catalytic domain, single study, no mutagenesis validation","pmids":["21945315"],"is_preprint":false},{"year":2013,"finding":"In collagen-activated human keratinocytes, MMP-1 expression is induced via α2β1 integrin contact with fibrillar type I collagen through ERK activation; Cdc42 negatively regulates this process by suppressing ERK activity; p38 or JNK inhibition had no effect on MMP-1 production in this context.","method":"ERK, p38, and JNK inhibitors; Rho GTPase activity assays; MMP-1 western blot and ELISA in primary human keratinocytes on type I collagen","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitors plus Rho GTPase analysis, multiple keratinocyte sources (neonatal and adult), single lab","pmids":["24352036"],"is_preprint":false},{"year":2013,"finding":"PPARδ activation suppresses UVB-induced MMP-1 secretion in human dermal fibroblasts through MKP-7-mediated suppression of JNK signaling; PPARδ-mediated mRNA stabilization of MKP-7 was responsible for inhibition of JNK and consequent MMP-1 reduction.","method":"PPARδ-specific ligand GW501516, PPARδ siRNA knockdown, JNK/p38/ERK inhibitors, mRNA stability assay, in vivo HR-1 hairless mouse model with UVB exposure","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown, pharmacological inhibitors, mRNA stability assay, in vivo confirmation; single lab","pmids":["23639976"],"is_preprint":false},{"year":2014,"finding":"In Drosophila metamorphosis, Mmp1 preferentially cleaves DE-cadherin-mediated cell-cell junctions to induce fat body cell dissociation, while Mmp2 preferentially degrades basement membrane components; Mmp1 and Mmp2 act cooperatively to achieve complete fat body tissue dissociation.","method":"Fat body-specific RNAi screen, genetic interaction experiments, cellular and biochemical assays, immunostaining in Drosophila","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo RNAi screen with genetic interaction experiments, substrate-level distinction between Mmp1 and Mmp2, multiple orthogonal approaches","pmids":["25520167"],"is_preprint":false},{"year":2016,"finding":"MMP1 cleaves laminin subunit alpha-5 (LAMA5), generating proteolytic fragments in the secretome of oncogenic H-Ras-transformed epithelial cells; these LAMA5 fragments promote endothelial cell angiogenesis via integrin αvβ3, representing a VEGF-independent pro-angiogenic mechanism.","method":"MMP1 knockdown (siRNA), secretome proteomics, endothelial cell angiogenesis assay, antibody-based integrin αvβ3 inhibition, in vivo xenograft model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MMP1 knockdown with functional rescue, substrate identification by proteomics, receptor blockade validation; single lab","pmids":["27324842"],"is_preprint":false},{"year":2018,"finding":"MMP1 activates protease-activated receptor 1 (PAR1) on dorsal root ganglion neurons, inducing substance P (SP) release, which then activates NK1R on pancreatic ductal adenocarcinoma cells to enhance migration, invasion, and perineural invasion via SP/NK1R/ERK signaling; MMP1 silencing or PAR1/NK1R antagonism inhibited this paracrine loop.","method":"Matrigel/DRG in vitro PNI system, murine sciatic nerve invasion model, shRNA silencing of MMP1, PAR1 and NK1R antagonists, AKT activation assays, MRI monitoring","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — shRNA silencing, pharmacological receptor antagonism, in vitro and in vivo models, signaling pathway analysis; multiple orthogonal approaches in single lab","pmids":["29896303"],"is_preprint":false},{"year":2018,"finding":"CIC (Capicua) represses ETV4 transcription; loss of CIC in hepatocellular carcinoma cells elevates ETV4, which in turn induces MMP1 expression; MMP1 knockdown completely blocked CIC-deficiency-induced HCC cell proliferation and invasion, establishing the CIC-ETV4-MMP1 axis.","method":"CIC overexpression/knockdown, ETV4 overexpression/knockdown, MMP1 knockdown, in vitro proliferation and invasion assays, in vivo xenograft model","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistatic rescue (MMP1 knockdown reverses CIC-loss phenotype), multiple gain/loss-of-function experiments in vitro and in vivo","pmids":["29251790"],"is_preprint":false},{"year":2018,"finding":"The AHR ligand FICZ upregulates MMP1 expression in human dermal fibroblasts via AHR-dependent activation of MEK/ERK signaling; AHR knockdown abolished FICZ-induced MMP1 upregulation, and MEK/ERK inhibitors blocked FICZ-induced MMP1 induction.","method":"AHR knockdown (siRNA), selective MEK/ERK inhibitors, qRT-PCR, ELISA, western blot in NHDFs","journal":"Journal of dermatological science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AHR siRNA knockdown plus pharmacological inhibitors, single lab with multiple approaches","pmids":["29703420"],"is_preprint":false},{"year":2018,"finding":"Collagen II activates DDR2 phosphorylation in rheumatoid arthritis fibroblast-like synoviocytes, which induces CYR61 through AP-1 transcription factor activation; CYR61 then accelerates MMP1 production via ETS1, promoting FLS invasion and bone erosion.","method":"Co-stimulation with collagen II, adenoviral shRNA (Ad-shCYR61), luciferase reporter assays, AP-1 ChIP, ETS1 overexpression, in vivo collagen-induced arthritis rat model with micro-CT","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo shRNA rescue, ChIP for AP-1 binding, in vitro and in vivo functional assays; multiple orthogonal methods in single lab","pmids":["27653023"],"is_preprint":false},{"year":2018,"finding":"Gasdermin C (GSDMC) is induced by UV irradiation in human skin keratinocytes and contributes to UV-induced MMP-1 expression through activation of ERK and JNK pathways; GSDMC knockdown reduced UV-induced MMP-1, while GSDMC overexpression increased MMP-1 expression and ERK/JNK activities.","method":"GSDMC knockdown and overexpression, ERK and JNK inhibitors, qRT-PCR and western blot in primary keratinocytes and HaCaT cells","journal":"Journal of dermatological science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function for GSDMC with pathway inhibitor validation, single lab","pmids":["29428815"],"is_preprint":false},{"year":2010,"finding":"Akt inhibition in human dermal fibroblasts upregulates MMP1 through a CCN2-dependent pathway; Akt blockade elevated CCN2, which activated ERK1/2 and Ets1 phosphorylation; ERK1/2 inhibitor completely abrogated CCN2-induced MMP1, while CCN2 siRNA partially suppressed Akt-inhibition-induced MMP1.","method":"Akt-specific pharmacological inhibitor and Akt siRNA, CCN2 siRNA, ERK1/2 inhibitor UO126, western blot, RT-PCR in human dermal fibroblasts","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus siRNA knockdown of multiple pathway components, single lab","pmids":["20201953"],"is_preprint":false},{"year":2010,"finding":"Hypoxia-induced HIF-1α upregulates CXCR4 in chondrosarcoma cells, which through SDF1 signaling and ERK activation increases MMP1 expression and cell invasion; siRNA against HIF-1α or CXCR4, AMD3100 (CXCR4 inhibitor), or ERK inhibitor U0126 inhibited both MMP1 expression and invasion.","method":"HIF-1α siRNA, CXCR4 siRNA, CXCR4 inhibitor AMD3100, ERK inhibitor U0126, in vitro invasion assay in chondrosarcoma JJ cells","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple siRNAs and pharmacological inhibitors targeting distinct pathway nodes; single lab","pmids":["20102637"],"is_preprint":false},{"year":2011,"finding":"EGFR ligands (EGF, TGF-α) enhance MMP1 expression via ERK1/2 pathway activation in SK-BR3 breast cancer cells; MEK inhibitor U0126 blocked ERK1/2 activation and MMP1 induction; Akt pathway inhibition paradoxically augmented MMP1 expression through reciprocal activation of ERK1/2.","method":"EGFR ligand stimulation, MEK inhibitor U0126, PI3K inhibitor LY294002, tyrosine kinase inhibitors (erlotinib, lapatinib, canertinib), RT-PCR, western blot, ELISA, EMSA","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway inhibitors with EMSA and protein assays; single lab","pmids":["21440529"],"is_preprint":false},{"year":2015,"finding":"STAT3 activation enhances MMP-1 expression in lung adenocarcinoma cells; IL-6 stimulation of A549 cells increased MMP-1 mRNA and activated MMP-1 promoter transcription in a STAT3-dependent manner confirmed by STAT3 siRNA knockdown.","method":"IL-6 stimulation, STAT3 siRNA knockdown, MMP-1 promoter luciferase assay, RT-PCR in lung cancer cell lines; IHC co-localization in surgical biopsies","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with promoter assay validation, tissue co-localization; single lab","pmids":["25926075"],"is_preprint":false},{"year":2016,"finding":"Kynurenine (Kyn) upregulates MMP-1 and downregulates type-I collagen in dermal fibroblasts via activation of aryl hydrocarbon receptor (AHR); a specific AHR antagonist inhibited Kyn-dependent modulation of CYP1A-1, MMP-1, and type-I collagen expression.","method":"AHR agonist (Kyn) treatment, AHR antagonist (6,2',4'-trimethoxyflavone), CYP1A-1 reporter assay, western blot, qRT-PCR in dermal fibroblasts; in vivo rat dermal fibrosis model","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological AHR agonist/antagonist with in vitro and in vivo validation; single lab","pmids":["26992058"],"is_preprint":false},{"year":2018,"finding":"PKD3 (PRKD3), downstream of atypical PKCι, mediates IL-1/OSM-induced MMP1 expression in human chondrocytes; PKD3 silencing reduced STAT3 serine phosphorylation and all three MAPK groups, and decreased AP-1 gene expression (FOS, JUN), leading to reduced MMP1/13.","method":"Pan-PKD inhibitor, gene-specific siRNA (PKD isoforms), western blot for phospho-signaling, RT-PCR in human articular chondrocytes","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitor plus isoform-specific siRNA knockdown with multiple downstream markers; single lab","pmids":["29652915"],"is_preprint":false},{"year":2017,"finding":"MMP1 mRNA-carrying extracellular vesicles (EVs) from highly metastatic ovarian cancer cells are taken up by mesothelial cells, increasing MMP1 expression in mesothelial cells and inducing their apoptosis, thereby destroying the peritoneal mesothelium barrier to facilitate peritoneal dissemination.","method":"EV isolation and characterization, whole transcriptome analysis of EV cargo, in vitro and in vivo apoptosis assays, analysis of ascites-derived EVs from patients","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional EV transfer assays in vitro and in vivo, patient ascites validation; single lab","pmids":["28262727"],"is_preprint":false},{"year":2021,"finding":"MMP1 derived from tumor-associated macrophages (TAMs) promotes colon cancer cell proliferation by activating PAR1, leading to MAPK/Erk signaling and altering c-Myc and ETV4; ETV4 then binds the MMP1 promoter to activate MMP1 transcription, establishing a positive MMP1/PAR1/Erk1/2/ETV4/MMP1 feedback loop.","method":"Exogenous MMP1 treatment, PAR1 inhibition, MAPK/Erk inhibitor, ChIP for ETV4 binding to MMP1 promoter, cell cycle analysis, in vitro and in vivo assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for ETV4 promoter binding, pharmacological pathway inhibition, in vitro and in vivo functional assays; single lab","pmids":["34753916"],"is_preprint":false},{"year":2021,"finding":"MMP1 expression by large cell carcinoma (LCC) cells is necessary and sufficient (in combination with TGF-β1) to induce premature senescence in pulmonary fibroblasts, which in turn drives LCC cell growth and invasion; PAR1 and oxidative stress are implicated in MMP1/TGF-β1-induced fibroblast senescence.","method":"MMP1 knockdown and overexpression, co-culture fibroblast senescence assay, PAR1 inhibition, oxidative stress measurements, in vivo mouse models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function for MMP1 with in vitro and in vivo senescence assays, PAR1 mechanistic link; single lab","pmids":["33684534"],"is_preprint":false},{"year":2017,"finding":"Slug directly binds to three putative binding sites in the MMP1 promoter and activates MMP1 transcription in breast cancer cells; enforced Slug expression in MCF-7 cells significantly upregulated MMP1, while Slug knockdown in MDR MCF-7/ADR cells reduced MMP1 expression.","method":"Dual luciferase reporter assay, ChIP-qPCR confirming Slug binding to MMP1 promoter sites, western blot, immunofluorescence, functional drug sensitivity assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR plus luciferase promoter assay for direct binding confirmation; single lab","pmids":["28334049"],"is_preprint":false},{"year":2020,"finding":"Transcription factor EGR-1 directly binds to an EBS (EGR-1 binding sequence) in the proximal MMP1 promoter and transactivates MMP1 in response to TNFα in HaCaT keratinocytes; EGR-1 siRNA silencing reduced TNFα-induced MMP-1 expression; all three MAPKs (ERK1/2, JNK, p38) mediate TNFα-induced MMP-1 via EGR-1 upregulation.","method":"MMP1 promoter deletion constructs, luciferase reporter assay, EGR-1 overexpression, EGR-1 siRNA knockdown, promoter EBS mutation, western blot in HaCaT keratinocytes","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter deletion/mutagenesis, ectopic expression, and siRNA knockdown in single lab; no ChIP confirmation reported","pmids":["32317080"],"is_preprint":false},{"year":2022,"finding":"RUNX2 directly binds to specific motifs in the MMP1 promoter and activates its transcription in triple negative breast cancer cells, promoting proliferation, migration, invasion and chemoresistance; RUNX2 silencing suppressed MMP1 expression and these malignant phenotypes.","method":"ChIP assay for RUNX2 binding to MMP1 promoter, qRT-PCR, RNA-sequencing, in vitro functional assays, in vivo xenograft tumorigenicity","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct promoter binding plus functional knockdown in vitro and in vivo; single lab","pmids":["36483054"],"is_preprint":false},{"year":2022,"finding":"Exosomal MMP-1 from highly metastatic TNBC cells is taken up by less metastatic TNBC cells and interacts with membrane PAR1, initiating epithelial-mesenchymal transition (EMT) to enhance migration and invasion; recipient cells increase their own MMP-1 secretion after exosome uptake.","method":"Exosome isolation, mass spectrometry, western blot, Transwell invasion/migration assays, in vivo lung colonization model in nude mice, tissue microarray and patient serum analysis","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional exosome transfer with receptor (PAR1) signaling link, in vivo validation; single lab","pmids":["35254603"],"is_preprint":false},{"year":2023,"finding":"NAT10 promotes MMP1 mRNA stability via N4-acetylcytidine (ac4C) acetylation of MMP1 mRNA in oral squamous cell carcinoma; NAT10 knockdown reduced both total and ac4C-acetylated MMP1 mRNA levels and decreased MMP1 mRNA stability, impairing proliferation, migration, and invasion in an MMP1-dependent manner.","method":"NAT10 knockdown (lentivirus), ac4C-seq/RIP for acetylated MMP1 mRNA detection, mRNA stability assay, MMP1 rescue experiments, xenograft model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ac4C acetylation of MMP1 mRNA demonstrated by RIP, mRNA stability assay, and MMP1-dependent rescue; single lab","pmids":["37705232"],"is_preprint":false},{"year":2022,"finding":"MMP1 upregulation through promoter hypomethylation enhances tamoxifen resistance in breast cancer; MMP1 was hypomethylated and overexpressed in tamoxifen-resistant MCF-7 cells; shRNA-mediated MMP1 knockdown restored tamoxifen sensitivity and increased apoptosis in vitro and in xenograft models.","method":"Methylation microarray, bisulfite sequencing, shRNA knockdown of MMP1, colony formation assay, flow cytometry, xenograft mouse model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — methylation profiling, bisulfite sequencing, and shRNA functional validation in vitro and in vivo; single lab","pmids":["35267540"],"is_preprint":false},{"year":2024,"finding":"IL-8 activates STAT3 signaling in fibroblasts to upregulate MMP1 expression; fibroblast-derived MMP1 then supports invasion of HNSCC cancer cells via extracellular matrix degradation; STAT3 phosphorylation inhibitor (TPCA-1) impaired the enhanced invasion triggered by fibroblasts.","method":"IL-8 stimulation of fibroblasts, STAT3 inhibitor TPCA-1, MMP1 measurement, Transwell invasion assay with co-culture system","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological STAT3 inhibition with functional invasion readout, single lab single method per step","pmids":["38320998"],"is_preprint":false},{"year":2019,"finding":"ETV4 directly upregulates MMP1 transcription in non-small cell lung cancer; luciferase reporter and gain/loss-of-function assays demonstrated the direct regulatory effect of ETV4 on MMP1 expression; MMP1 inhibition partially abolished ETV4-driven cell proliferation and migration.","method":"Microarray analysis, luciferase reporter assay, ETV4 gain- and loss-of-function, MMP1 inhibition, in vivo and in vitro metastasis assays","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus functional epistasis (MMP1 inhibition reverses ETV4 effects); single lab","pmids":["31670855"],"is_preprint":false}],"current_model":"MMP-1 is a zinc-dependent interstitial collagenase that degrades fibrillar collagens and additional extracellular matrix substrates; its expression is transcriptionally regulated by multiple upstream signals including AP-1 (via ERK/JNK MAPK cascades activated by UV, cytokines, or growth factors), STAT3, ETS-family factors (ETS1/ETV4), EGR-1, RUNX2, Slug, and Wnt/Fos downstream of JNK—and is epigenetically controlled by promoter DNA methylation; once secreted, MMP-1 acts extracellularly by releasing membrane-bound EGF-like ligands to stimulate osteoblast EGFR signaling, by activating PAR1 on stromal/neuronal cells to initiate paracrine signaling cascades, by cleaving LAMA5 to generate pro-angiogenic fragments, and by inducing fibroblast senescence in a PAR1/oxidative-stress-dependent manner, placing MMP-1 at the nexus of ECM remodeling, tumor invasion, perineural invasion, bone metastasis, and tissue homeostasis."},"narrative":{"mechanistic_narrative":"MMP-1 is a secreted, zinc-dependent interstitial collagenase whose catalytic domain in solution retains the fold seen in crystal structures, requiring only local rearrangements rather than major domain motions [PMID:21945315], and which functions as a central effector of extracellular matrix remodeling, tumor invasion, and tissue homeostasis [PMID:19608765, PMID:29896303]. Beyond cleaving structural matrix, MMP-1 acts proteolytically on defined substrates to generate paracrine signals: it releases membrane-bound EGF-like ligands (Amphiregulin, HB-EGF, TGFα) from tumor cells to suppress osteoblast osteoprotegerin via EGFR and potentiate osteolytic bone metastasis [PMID:19608765], and it cleaves laminin subunit alpha-5 to produce fragments that drive integrin αvβ3-dependent, VEGF-independent angiogenesis [PMID:27324842]. A recurrent extracellular mechanism is MMP-1 activation of protease-activated receptor 1 (PAR1): on sensory neurons it triggers substance P release and NK1R-driven perineural invasion in pancreatic cancer [PMID:29896303], on fibroblasts it induces oxidative-stress-dependent premature senescence that fuels tumor growth [PMID:33684534], and on colon cancer cells it activates MAPK/ERK signaling to engage an ETV4-dependent positive feedback loop [PMID:34753916]. MMP1 transcription integrates numerous upstream inputs converging largely on the MAPK/AP-1 module: UV, cytokine, growth factor, integrin, and aryl hydrocarbon receptor signals activate ERK and JNK to drive c-Fos/c-Jun AP-1 activity [PMID:15930517, PMID:29703420, PMID:27653023, PMID:21440529], and these cascades are restrained by Cdc42-mediated ERK repression [PMID:15728253, PMID:24352036] and by PPARδ/MKP-7 suppression of JNK [PMID:23639976]. Direct transcriptional activators binding the MMP1 promoter include ETS-family factors ETV4 and ETS1 downstream of the CIC tumor suppressor [PMID:29251790, PMID:31670855], STAT3 acting downstream of IL-6/IL-8 [PMID:25926075, PMID:38320998], EGR-1 [PMID:32317080], Slug [PMID:28334049], and RUNX2 [PMID:36483054], while DNA methylation of the promoter suppresses transcription and promoter hypomethylation drives overexpression and tamoxifen resistance [PMID:18178580, PMID:35267540]. MMP1 mRNA itself is stabilized by NAT10-mediated ac4C acetylation [PMID:37705232] and can be propagated between cells as extracellular-vesicle cargo to remodel the metastatic niche [PMID:28262727, PMID:35254603].","teleology":[{"year":2001,"claim":"Established an upstream cell-surface inducer of MMP-1, showing that homophilic CD147 (EMMPRIN) interactions stimulate MMP-1 production in a glycosylation-dependent manner.","evidence":"Purified native vs. deglycosylated CD147, blocking antibody, CD147-Fc fusion, MMP-1 ELISA in dermal fibroblasts","pmids":["11280798"],"confidence":"High","gaps":["Does not define the intracellular signaling pathway linking CD147 engagement to MMP1 transcription","Receptor for CD147 on fibroblasts not identified"]},{"year":2005,"claim":"Defined the core MAPK/AP-1 transcriptional circuit by which UV induces MMP-1, mapping induction to ERK/c-Fos and JNK/c-Jun arms.","evidence":"MEK1 and SEK1 inhibitors, AP-1 EMSA, MMP-1 ELISA in human dermal fibroblasts","pmids":["15930517"],"confidence":"Medium","gaps":["Pharmacological inhibitor specificity not genetically confirmed","Does not identify the direct AP-1 promoter contacts"]},{"year":2005,"claim":"Identified Rho GTPase control over MMP-1, showing Cdc42 represses MMP-1 by suppressing ERK1/2 while Rac1 is required for the effect.","evidence":"siRNA knockdown of Cdc42/RhoA/Rac1 with siRNA-resistant rescue, kinase inhibitors, ELISA in skin fibroblasts","pmids":["15728253"],"confidence":"High","gaps":["Mechanism by which Cdc42 represses ERK1/2 not resolved","Upstream activators of Cdc42 in this context not defined"]},{"year":2006,"claim":"Placed mmp1 downstream of polarity loss in an in vivo invasion model, showing scribble-loss/JNK signaling drives Fos-dependent mmp1 transcription to enable invasiveness.","evidence":"Drosophila genetic epistasis, Mmp1 RNAi, Timp overexpression, in vivo imaginal disc invasion assays","pmids":["17082773"],"confidence":"High","gaps":["Drosophila Mmp1 substrate(s) mediating invasion not specified here","Conservation of the scribble-JNK-Fos-mmp1 axis in mammalian MMP1 not tested"]},{"year":2008,"claim":"Demonstrated epigenetic control of MMP1, showing promoter DNA methylation at -1538 and a methylated promoter SNP suppress transcription via altered nuclear-protein binding.","evidence":"5-aza-2'-deoxycytidine, bisulfite sequencing, promoter luciferase, ChIP, EMSA in amnion fibroblasts","pmids":["18178580"],"confidence":"High","gaps":["Identity of the methylation-sensitive nuclear protein not determined","Methyltransferase responsible not identified"]},{"year":2008,"claim":"Established a tissue-level paracrine route to MMP-1 induction, showing UV DNA damage in keratinocytes generates soluble mediators that drive dermal fibroblast MMP-1.","evidence":"DNA repair enzyme liposomes, conditioned-medium transfer from irradiated keratinocytes, MMP-1 mRNA/protein in human skin","pmids":["18459971"],"confidence":"High","gaps":["The soluble mediator(s) transmitting the signal not identified","Receptor on fibroblasts not defined"]},{"year":2008,"claim":"Revealed a transcriptional brake on MMP1, showing Met-phosphorylated MUC1 cooperates with p53 to suppress AP-1 activity at the MMP1 promoter and limit invasion.","evidence":"Co-IP, confocal nuclear imaging, MMP1 promoter luciferase, invasion assay in pancreatic cancer cells","pmids":["18625714"],"confidence":"High","gaps":["Direct binding of the MUC1-p53 complex to the promoter not shown","Quantitative contribution relative to other AP-1 inputs unclear"]},{"year":2009,"claim":"Defined a mechanistic substrate-based metastasis pathway, showing MMP1 sheds EGF-like ligands to suppress osteoblast OPG via EGFR and potentiate osteolytic bone metastasis.","evidence":"In vitro cleavage assays, EGFR inhibition, osteoblast co-culture/osteoclastogenesis, in vivo bone metastasis model","pmids":["19608765"],"confidence":"High","gaps":["Precise cleavage sites on Amphiregulin/HB-EGF/TGFα not mapped","Relative contributions of the three ligands not dissected"]},{"year":2010,"claim":"Connected hypoxia and Akt signaling to MMP1, identifying HIF-1α/CXCR4/ERK and Akt-CCN2-ERK/Ets1 routes converging on MMP1 induction.","evidence":"HIF-1α/CXCR4/Akt/CCN2 siRNA, AMD3100, ERK inhibitors in chondrosarcoma and dermal fibroblasts","pmids":["20102637","20201953"],"confidence":"Medium","gaps":["Direct promoter elements engaged downstream not mapped","Cell-type generality across the two systems not established"]},{"year":2011,"claim":"Provided a solution-state structural baseline, showing the MMP-1 catalytic domain retains its crystallographic fold with only local rearrangements.","evidence":"Paramagnetic NMR (pseudocontact shifts, RDCs) with lanthanide tags on the catalytic domain","pmids":["21945315"],"confidence":"Medium","gaps":["No mutagenesis validation of inferred rearrangements","Full-length enzyme including hemopexin domain not analyzed"]},{"year":2011,"claim":"Linked MMP1 promoter polymorphism to bimodal endothelial expression and identified ETS1/ETS2/GATA3 as promoter-binding factors at that region.","evidence":"Microarray, RT-PCR, MMP1 activity assay, sequencing, ChIP in HUVECs from many donors","pmids":["21244711"],"confidence":"Medium","gaps":["Functional consequence of each transcription factor on expression not isolated","Allele-specific binding not directly demonstrated"]},{"year":2013,"claim":"Showed integrin-collagen context-specific MMP-1 induction, with α2β1/collagen-I driving ERK-dependent MMP-1 in keratinocytes under Cdc42 negative control.","evidence":"ERK/p38/JNK inhibitors, Rho GTPase activity assays, MMP-1 western/ELISA in primary keratinocytes on collagen I","pmids":["24352036"],"confidence":"Medium","gaps":["Whether the same circuit operates in fibroblasts not tested here","Direct integrin-to-ERK coupling mechanism not defined"]},{"year":2013,"claim":"Identified a JNK-restraining mechanism, showing PPARδ stabilizes MKP-7 mRNA to suppress JNK and reduce UVB-induced MMP-1.","evidence":"GW501516, PPARδ siRNA, MAPK inhibitors, mRNA stability assay, in vivo hairless mouse UVB model","pmids":["23639976"],"confidence":"Medium","gaps":["Mechanism of PPARδ-driven MKP-7 mRNA stabilization not defined","Contribution of MKP-7 to ERK-driven MMP-1 not addressed"]},{"year":2014,"claim":"Distinguished MMP substrate preferences in vivo, showing Mmp1 preferentially cleaves DE-cadherin junctions while Mmp2 degrades basement membrane during tissue dissociation.","evidence":"Fat body-specific RNAi screen, genetic interaction, biochemical assays, immunostaining in Drosophila","pmids":["25520167"],"confidence":"High","gaps":["Direct cadherin cleavage by mammalian MMP1 not demonstrated","Structural basis of substrate selectivity not addressed"]},{"year":2016,"claim":"Defined a pro-angiogenic substrate axis, showing MMP1 cleaves LAMA5 to generate fragments that drive integrin αvβ3-dependent, VEGF-independent angiogenesis.","evidence":"MMP1 siRNA, secretome proteomics, endothelial angiogenesis assay, αvβ3 blockade, xenograft","pmids":["27324842"],"confidence":"Medium","gaps":["LAMA5 cleavage sites and active fragment sequence not fully defined","Direct fragment-integrin binding not biochemically resolved"]},{"year":2016,"claim":"Implicated aryl hydrocarbon receptor signaling in MMP-1 control, showing kynurenine drives AHR-dependent MMP-1 upregulation and collagen downregulation.","evidence":"AHR agonist/antagonist, CYP1A-1 reporter, western/qRT-PCR, in vivo rat dermal fibrosis model","pmids":["26992058"],"confidence":"Medium","gaps":["Whether AHR acts directly on the MMP1 promoter not shown","Downstream kinase coupling not defined here"]},{"year":2017,"claim":"Identified Slug as a direct MMP1 transcriptional activator linked to drug resistance, binding three promoter sites.","evidence":"Luciferase reporter, ChIP-qPCR for Slug binding, western, drug sensitivity assays in breast cancer cells","pmids":["28334049"],"confidence":"Medium","gaps":["Functional ranking of the three binding sites not resolved","In vivo relevance of Slug-MMP1 axis not tested"]},{"year":2017,"claim":"Established MMP1 as transferable extracellular-vesicle cargo, showing EV-borne MMP1 mRNA induces mesothelial apoptosis to breach the peritoneal barrier.","evidence":"EV isolation/transcriptomics, apoptosis assays in vitro/in vivo, patient ascites EVs in ovarian cancer","pmids":["28262727"],"confidence":"Medium","gaps":["Whether translated MMP1 protein or RNA itself drives apoptosis not separated","Receptor/effector in mesothelial apoptosis not defined"]},{"year":2018,"claim":"Defined an MMP1-PAR1 neuronal paracrine loop driving perineural invasion via substance P/NK1R/ERK signaling.","evidence":"DRG/Matrigel PNI system, sciatic nerve model, MMP1 shRNA, PAR1/NK1R antagonists in pancreatic cancer","pmids":["29896303"],"confidence":"High","gaps":["Whether MMP1 cleaves PAR1 directly at the tethered ligand not shown","Contribution of neuronal vs. tumor-derived MMP1 not separated"]},{"year":2018,"claim":"Built the CIC-ETV4-MMP1 tumor-suppressor axis, showing CIC loss elevates ETV4 to induce MMP1 and that MMP1 is essential for the resulting phenotypes.","evidence":"CIC/ETV4/MMP1 gain- and loss-of-function epistasis, invasion/proliferation assays, xenograft in HCC","pmids":["29251790"],"confidence":"High","gaps":["Direct ETV4 binding to MMP1 promoter not shown in this study","Downstream MMP1 substrate mediating proliferation not identified"]},{"year":2018,"claim":"Extended MAPK-coupled induction to additional inputs, implicating AHR/MEK-ERK, GSDMC/ERK-JNK, DDR2-CYR61-AP-1/ETS1, and PKD3 in MMP1 transcription.","evidence":"AHR/GSDMC/PKD3 knockdowns, CYR61 shRNA, AP-1 ChIP, MAPK inhibitors across fibroblasts, keratinocytes, synoviocytes, chondrocytes","pmids":["29703420","29428815","27653023","29652915"],"confidence":"Medium","gaps":["Hierarchy among these parallel inputs at the promoter not integrated","Most rely on pharmacological inhibitors without genetic confirmation"]},{"year":2019,"claim":"Confirmed ETV4 as a direct MMP1 activator in lung cancer with MMP1 required for ETV4-driven proliferation and migration.","evidence":"Luciferase reporter, ETV4 gain/loss-of-function, MMP1 inhibition, in vitro/in vivo metastasis assays in NSCLC","pmids":["31670855"],"confidence":"Medium","gaps":["Precise ETV4 binding motif not mapped","Interaction with other ETS factors at the promoter not addressed"]},{"year":2020,"claim":"Identified EGR-1 as a direct TNFα-responsive MMP1 transactivator acting downstream of all three MAPKs.","evidence":"Promoter deletion/EBS mutation, luciferase, EGR-1 overexpression/siRNA in HaCaT keratinocytes","pmids":["32317080"],"confidence":"Medium","gaps":["No ChIP confirmation of endogenous EGR-1 occupancy","Interplay between EGR-1 and AP-1 at the promoter not resolved"]},{"year":2021,"claim":"Generalized MMP1-PAR1 signaling to tumor microenvironment cross-talk, establishing a TAM-derived MMP1/PAR1/ERK/ETV4/MMP1 feedback loop and MMP1/TGF-β1-induced fibroblast senescence driving tumor growth.","evidence":"Exogenous MMP1, PAR1/ERK inhibitors, ETV4 ChIP, co-culture senescence/oxidative-stress assays, in vivo models in colon and lung cancer","pmids":["34753916","33684534"],"confidence":"Medium","gaps":["Whether MMP1 directly cleaves and activates PAR1 not biochemically shown","Source-cell heterogeneity (TAM vs. tumor vs. fibroblast) not fully partitioned"]},{"year":2022,"claim":"Added RUNX2 as a direct MMP1 activator and linked MMP1 promoter hypomethylation to tamoxifen resistance reversible by MMP1 knockdown.","evidence":"RUNX2 ChIP, methylation microarray/bisulfite sequencing, shRNA knockdown, functional assays and xenografts in breast cancer","pmids":["36483054","35267540"],"confidence":"Medium","gaps":["Mechanism linking hypomethylation to drug resistance downstream of MMP1 not defined","Relationship between RUNX2 binding and methylation state not integrated"]},{"year":2022,"claim":"Extended exosomal MMP-1 propagation to breast cancer, showing exosomal MMP-1 engages recipient-cell PAR1 to initiate EMT and amplify MMP-1 secretion.","evidence":"Exosome isolation/MS, PAR1 link, Transwell assays, lung colonization model, patient sera in TNBC","pmids":["35254603"],"confidence":"Medium","gaps":["Whether exosomal MMP-1 is catalytically active on PAR1 not directly shown","Quantitative threshold for recipient EMT not defined"]},{"year":2023,"claim":"Established post-transcriptional control of MMP1, showing NAT10-mediated ac4C acetylation stabilizes MMP1 mRNA to support malignancy.","evidence":"NAT10 knockdown, ac4C-RIP, mRNA stability assay, MMP1 rescue, xenograft in oral squamous cell carcinoma","pmids":["37705232"],"confidence":"Medium","gaps":["Specific ac4C-modified sites on MMP1 mRNA not mapped","Whether acetylation also affects translation not addressed"]},{"year":2024,"claim":"Defined an IL-8/STAT3 stromal route, showing fibroblast STAT3 activation upregulates MMP1 that supports cancer-cell invasion through ECM degradation.","evidence":"IL-8 stimulation, STAT3 inhibitor TPCA-1, co-culture Transwell invasion in HNSCC","pmids":["38320998"],"confidence":"Medium","gaps":["Direct STAT3 binding to MMP1 promoter in fibroblasts not shown here","ECM substrate cleaved by fibroblast MMP1 not identified"]},{"year":null,"claim":"How the many parallel transcriptional, epigenetic, and post-transcriptional inputs are quantitatively integrated at the MMP1 locus in a given cell type, and whether MMP1 directly proteolyzes PAR1 to drive its many paracrine effects, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model ranking AP-1, STAT3, ETS, RUNX2, EGR-1, Slug, and methylation inputs","Direct enzymatic cleavage of PAR1 by MMP1 not biochemically established in the corpus","Full-length enzyme structure and substrate-selectivity determinants not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,12,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,12,13]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,13,34]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[13,34]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[25,31]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[13,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,14,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,14,26]},{"term_id":"R-HSA-74160","term_label":"Gene expression 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Also cleaves collagens of types VII and X (PubMed:1645757, PubMed:2153297, PubMed:2557822). In case of HIV infection, interacts and cleaves the secreted viral Tat protein, leading to a decrease in neuronal Tat's mediated neurotoxicity (PubMed:16807369)","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/P03956/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MMP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MMP1","total_profiled":1310},"omim":[{"mim_id":"619427","title":"ZINC FINGER PROTEIN 410; ZNF410","url":"https://www.omim.org/entry/619427"},{"mim_id":"613510","title":"LATE ENDOSOMAL/LYSOSOMAL ADAPTOR, MAPK AND MTOR ACTIVATOR 1; LAMTOR1","url":"https://www.omim.org/entry/613510"},{"mim_id":"613155","title":"MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 1; MDDGB1","url":"https://www.omim.org/entry/613155"},{"mim_id":"612111","title":"TUMOR NECROSIS FACTOR-ALPHA-INDUCED PROTEIN 8; TNFAIP8","url":"https://www.omim.org/entry/612111"},{"mim_id":"610504","title":"PRETERM PREMATURE RUPTURE OF THE MEMBRANES; PPROM","url":"https://www.omim.org/entry/610504"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"gallbladder","ntpm":70.7},{"tissue":"stomach 1","ntpm":44.2},{"tissue":"urinary bladder","ntpm":48.6}],"url":"https://www.proteinatlas.org/search/MMP1"},"hgnc":{"alias_symbol":[],"prev_symbol":["CLG"]},"alphafold":{"accession":"P03956","domains":[{"cath_id":"3.40.390.10","chopping":"114-261","consensus_level":"high","plddt":97.3278,"start":114,"end":261},{"cath_id":"2.110.10.10","chopping":"287-460","consensus_level":"high","plddt":96.9319,"start":287,"end":460}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P03956","model_url":"https://alphafold.ebi.ac.uk/files/AF-P03956-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P03956-F1-predicted_aligned_error_v6.png","plddt_mean":91.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MMP1","jax_strain_url":"https://www.jax.org/strain/search?query=MMP1"},"sequence":{"accession":"P03956","fasta_url":"https://rest.uniprot.org/uniprotkb/P03956.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P03956/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P03956"}},"corpus_meta":[{"pmid":"18447576","id":"PMC_18447576","title":"MMP1 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deglycosylated CD147 failed to induce MMP-1 and instead antagonized native CD147-induced MMP-1, demonstrating that glycosylation is required for the MMP-1-inducing activity.\",\n      \"method\": \"Purified native vs. deglycosylated CD147, anti-CD147 antibody inhibition, recombinant CD147-Fc fusion protein, MMP-1 ELISA in dermal fibroblasts\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 / Moderate — multiple orthogonal methods (purified protein, blocking antibody, fusion protein, deglycosylation), single lab but rigorous mechanistic controls\",\n      \"pmids\": [\"11280798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In Drosophila, loss of the polarity gene scribble activates JNK signaling, which promotes Fos-dependent transcriptional activation of mmp1, leading to tumor cell invasiveness; Timp expression or Mmp1 RNAi knockdown suppressed cell invasiveness downstream of JNK.\",\n      \"method\": \"Genetic epistasis (scribble mutant clones + Ras activation), RNAi knockdown of Mmp1, Timp overexpression, in vivo invasion assays in Drosophila imaginal discs\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple loss-of-function and rescue experiments in vivo, replicated by multiple approaches\",\n      \"pmids\": [\"17082773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MMP1 proteolytically releases membrane-bound EGF-like ligands (Amphiregulin, HB-EGF, TGFα) from breast cancer tumor cells, which then suppress osteoprotegerin (OPG) expression in osteoblasts via EGFR signaling, thereby potentiating osteoclast differentiation and osteolytic bone metastasis.\",\n      \"method\": \"In vitro protease cleavage assays, EGFR inhibitor treatment, osteoblast co-culture, osteoclastogenesis assays, in vivo bone metastasis model\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical cleavage, signaling inhibition, in vivo model), mechanistically defined paracrine cascade\",\n      \"pmids\": [\"19608765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"UV-induced DNA damage in epidermal keratinocytes initiates release of soluble mediators that signal dermal fibroblasts to produce MMP-1; photolyase-mediated DNA repair of epidermal UV damage reduced MMP-1 mRNA and protein in both epidermal and dermal compartments, and conditioned medium from irradiated keratinocytes enhanced MMP-1 in unirradiated fibroblasts.\",\n      \"method\": \"Liposome-encapsulated DNA repair enzymes (T4 endonuclease V, UV endonuclease), conditioned medium transfer from irradiated keratinocytes to unirradiated fibroblasts, MMP-1 mRNA and protein measurement in human skin\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditioned medium transfer experiment plus DNA repair enzyme rescue, two orthogonal approaches in human skin tissue and cells\",\n      \"pmids\": [\"18459971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Met receptor tyrosine kinase phosphorylates MUC1 cytoplasmic tail at YHPM; phosphorylated MUC1CT enhances its interaction with p53, which suppresses AP1 transcription factor activity at the MMP1 promoter, reducing MMP1 transcription and HGF-induced invasiveness.\",\n      \"method\": \"Co-IP, real-time confocal imaging of nuclear localization, luciferase promoter assay, western blot, invasion assay in pancreatic cancer cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction assays, promoter activity assay, live imaging, and functional invasion assay in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18625714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"UV radiation increases MMP-1 expression in human dermal fibroblasts via ERK (MEK1) and JNK (SEK1) signaling pathways leading to increased c-Fos expression and c-Jun phosphorylation/expression, and consequent AP-1 DNA binding activity; EPA inhibited this induction by blocking MEK1/ERK/c-Fos and SEK1/JNK/c-Jun pathways.\",\n      \"method\": \"Kinase inhibitors (MEK1 inhibitor, SEK1 inhibitor), western blot for pathway activation, AP-1 EMSA, MMP-1 ELISA in human dermal fibroblasts\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway inhibitors plus AP-1 binding assay, single lab\",\n      \"pmids\": [\"15930517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cdc42 downregulates MMP-1 expression in human skin fibroblasts via repression of the ERK1/2 pathway; silencing Cdc42 by siRNA induced a 15-fold increase in MMP-1 secretion dependent on ERK1/2, while the p38 MAP kinase pathway played an inhibitory role; Rac1 silencing reduced the effect of Cdc42 suppression.\",\n      \"method\": \"siRNA knockdown of Rho GTPases (Cdc42, RhoA, Rac1), chemical kinase inhibitors, rescue by Cdc42 re-expression with siRNA-resistant construct, ELISA, RT-PCR in human skin fibroblasts\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown with rescue (siRNA-resistant construct), multiple GTPase knockdowns, pharmacological inhibitors, multiple cell lines, single lab\",\n      \"pmids\": [\"15728253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DNA methylation at position -1538 in the MMP1 promoter suppresses MMP1 transcription in amnion fibroblasts; inhibition of DNA methylation with 5-aza-2'-deoxycytidine significantly increased MMP1 gene transcription; a novel T>C SNP in the MMP1 promoter that is always methylated in vivo had reduced promoter activity, and methylation at this site increased affinity for a nuclear protein.\",\n      \"method\": \"5-aza-2'-deoxycytidine treatment, bisulfite sequencing, plasmid transfection promoter activity assay, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift (nuclear protein binding) in amnion fibroblasts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (pharmacological demethylation, bisulfite sequencing, promoter assay, ChIP, EMSA) in single lab\",\n      \"pmids\": [\"18178580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MMP1 bimodal expression in endothelial cells is linked to a promoter polymorphism; ChIP experiments showed that transcription factors ETS1, ETS2 and GATA3 bind to the MMP1 promoter in the region of this polymorphism and may contribute to bimodal expression.\",\n      \"method\": \"Microarray analysis, hierarchical clustering, RT-PCR, MMP1 activity assay, DNA sequencing, chromatin immunoprecipitation (ChIP) in HUVECs from 15–69 individuals\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for transcription factor binding combined with population-level sequencing and activity assays, single lab\",\n      \"pmids\": [\"21244711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The catalytic domain of MMP-1 in solution retains the overall fold seen in crystal structures, requiring only local rearrangements (not major domain rearrangements) to reconcile X-ray and NMR data, as assessed by paramagnetic NMR using lanthanide binding tags.\",\n      \"method\": \"NMR pseudocontact shifts and paramagnetic residual dipolar couplings using lanthanide binding tags on the MMP-1 catalytic domain\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural NMR method applied to catalytic domain, single study, no mutagenesis validation\",\n      \"pmids\": [\"21945315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In collagen-activated human keratinocytes, MMP-1 expression is induced via α2β1 integrin contact with fibrillar type I collagen through ERK activation; Cdc42 negatively regulates this process by suppressing ERK activity; p38 or JNK inhibition had no effect on MMP-1 production in this context.\",\n      \"method\": \"ERK, p38, and JNK inhibitors; Rho GTPase activity assays; MMP-1 western blot and ELISA in primary human keratinocytes on type I collagen\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitors plus Rho GTPase analysis, multiple keratinocyte sources (neonatal and adult), single lab\",\n      \"pmids\": [\"24352036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PPARδ activation suppresses UVB-induced MMP-1 secretion in human dermal fibroblasts through MKP-7-mediated suppression of JNK signaling; PPARδ-mediated mRNA stabilization of MKP-7 was responsible for inhibition of JNK and consequent MMP-1 reduction.\",\n      \"method\": \"PPARδ-specific ligand GW501516, PPARδ siRNA knockdown, JNK/p38/ERK inhibitors, mRNA stability assay, in vivo HR-1 hairless mouse model with UVB exposure\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown, pharmacological inhibitors, mRNA stability assay, in vivo confirmation; single lab\",\n      \"pmids\": [\"23639976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Drosophila metamorphosis, Mmp1 preferentially cleaves DE-cadherin-mediated cell-cell junctions to induce fat body cell dissociation, while Mmp2 preferentially degrades basement membrane components; Mmp1 and Mmp2 act cooperatively to achieve complete fat body tissue dissociation.\",\n      \"method\": \"Fat body-specific RNAi screen, genetic interaction experiments, cellular and biochemical assays, immunostaining in Drosophila\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo RNAi screen with genetic interaction experiments, substrate-level distinction between Mmp1 and Mmp2, multiple orthogonal approaches\",\n      \"pmids\": [\"25520167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MMP1 cleaves laminin subunit alpha-5 (LAMA5), generating proteolytic fragments in the secretome of oncogenic H-Ras-transformed epithelial cells; these LAMA5 fragments promote endothelial cell angiogenesis via integrin αvβ3, representing a VEGF-independent pro-angiogenic mechanism.\",\n      \"method\": \"MMP1 knockdown (siRNA), secretome proteomics, endothelial cell angiogenesis assay, antibody-based integrin αvβ3 inhibition, in vivo xenograft model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MMP1 knockdown with functional rescue, substrate identification by proteomics, receptor blockade validation; single lab\",\n      \"pmids\": [\"27324842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MMP1 activates protease-activated receptor 1 (PAR1) on dorsal root ganglion neurons, inducing substance P (SP) release, which then activates NK1R on pancreatic ductal adenocarcinoma cells to enhance migration, invasion, and perineural invasion via SP/NK1R/ERK signaling; MMP1 silencing or PAR1/NK1R antagonism inhibited this paracrine loop.\",\n      \"method\": \"Matrigel/DRG in vitro PNI system, murine sciatic nerve invasion model, shRNA silencing of MMP1, PAR1 and NK1R antagonists, AKT activation assays, MRI monitoring\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — shRNA silencing, pharmacological receptor antagonism, in vitro and in vivo models, signaling pathway analysis; multiple orthogonal approaches in single lab\",\n      \"pmids\": [\"29896303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CIC (Capicua) represses ETV4 transcription; loss of CIC in hepatocellular carcinoma cells elevates ETV4, which in turn induces MMP1 expression; MMP1 knockdown completely blocked CIC-deficiency-induced HCC cell proliferation and invasion, establishing the CIC-ETV4-MMP1 axis.\",\n      \"method\": \"CIC overexpression/knockdown, ETV4 overexpression/knockdown, MMP1 knockdown, in vitro proliferation and invasion assays, in vivo xenograft model\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistatic rescue (MMP1 knockdown reverses CIC-loss phenotype), multiple gain/loss-of-function experiments in vitro and in vivo\",\n      \"pmids\": [\"29251790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The AHR ligand FICZ upregulates MMP1 expression in human dermal fibroblasts via AHR-dependent activation of MEK/ERK signaling; AHR knockdown abolished FICZ-induced MMP1 upregulation, and MEK/ERK inhibitors blocked FICZ-induced MMP1 induction.\",\n      \"method\": \"AHR knockdown (siRNA), selective MEK/ERK inhibitors, qRT-PCR, ELISA, western blot in NHDFs\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AHR siRNA knockdown plus pharmacological inhibitors, single lab with multiple approaches\",\n      \"pmids\": [\"29703420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Collagen II activates DDR2 phosphorylation in rheumatoid arthritis fibroblast-like synoviocytes, which induces CYR61 through AP-1 transcription factor activation; CYR61 then accelerates MMP1 production via ETS1, promoting FLS invasion and bone erosion.\",\n      \"method\": \"Co-stimulation with collagen II, adenoviral shRNA (Ad-shCYR61), luciferase reporter assays, AP-1 ChIP, ETS1 overexpression, in vivo collagen-induced arthritis rat model with micro-CT\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo shRNA rescue, ChIP for AP-1 binding, in vitro and in vivo functional assays; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"27653023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Gasdermin C (GSDMC) is induced by UV irradiation in human skin keratinocytes and contributes to UV-induced MMP-1 expression through activation of ERK and JNK pathways; GSDMC knockdown reduced UV-induced MMP-1, while GSDMC overexpression increased MMP-1 expression and ERK/JNK activities.\",\n      \"method\": \"GSDMC knockdown and overexpression, ERK and JNK inhibitors, qRT-PCR and western blot in primary keratinocytes and HaCaT cells\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function for GSDMC with pathway inhibitor validation, single lab\",\n      \"pmids\": [\"29428815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Akt inhibition in human dermal fibroblasts upregulates MMP1 through a CCN2-dependent pathway; Akt blockade elevated CCN2, which activated ERK1/2 and Ets1 phosphorylation; ERK1/2 inhibitor completely abrogated CCN2-induced MMP1, while CCN2 siRNA partially suppressed Akt-inhibition-induced MMP1.\",\n      \"method\": \"Akt-specific pharmacological inhibitor and Akt siRNA, CCN2 siRNA, ERK1/2 inhibitor UO126, western blot, RT-PCR in human dermal fibroblasts\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus siRNA knockdown of multiple pathway components, single lab\",\n      \"pmids\": [\"20201953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hypoxia-induced HIF-1α upregulates CXCR4 in chondrosarcoma cells, which through SDF1 signaling and ERK activation increases MMP1 expression and cell invasion; siRNA against HIF-1α or CXCR4, AMD3100 (CXCR4 inhibitor), or ERK inhibitor U0126 inhibited both MMP1 expression and invasion.\",\n      \"method\": \"HIF-1α siRNA, CXCR4 siRNA, CXCR4 inhibitor AMD3100, ERK inhibitor U0126, in vitro invasion assay in chondrosarcoma JJ cells\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple siRNAs and pharmacological inhibitors targeting distinct pathway nodes; single lab\",\n      \"pmids\": [\"20102637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EGFR ligands (EGF, TGF-α) enhance MMP1 expression via ERK1/2 pathway activation in SK-BR3 breast cancer cells; MEK inhibitor U0126 blocked ERK1/2 activation and MMP1 induction; Akt pathway inhibition paradoxically augmented MMP1 expression through reciprocal activation of ERK1/2.\",\n      \"method\": \"EGFR ligand stimulation, MEK inhibitor U0126, PI3K inhibitor LY294002, tyrosine kinase inhibitors (erlotinib, lapatinib, canertinib), RT-PCR, western blot, ELISA, EMSA\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway inhibitors with EMSA and protein assays; single lab\",\n      \"pmids\": [\"21440529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STAT3 activation enhances MMP-1 expression in lung adenocarcinoma cells; IL-6 stimulation of A549 cells increased MMP-1 mRNA and activated MMP-1 promoter transcription in a STAT3-dependent manner confirmed by STAT3 siRNA knockdown.\",\n      \"method\": \"IL-6 stimulation, STAT3 siRNA knockdown, MMP-1 promoter luciferase assay, RT-PCR in lung cancer cell lines; IHC co-localization in surgical biopsies\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with promoter assay validation, tissue co-localization; single lab\",\n      \"pmids\": [\"25926075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Kynurenine (Kyn) upregulates MMP-1 and downregulates type-I collagen in dermal fibroblasts via activation of aryl hydrocarbon receptor (AHR); a specific AHR antagonist inhibited Kyn-dependent modulation of CYP1A-1, MMP-1, and type-I collagen expression.\",\n      \"method\": \"AHR agonist (Kyn) treatment, AHR antagonist (6,2',4'-trimethoxyflavone), CYP1A-1 reporter assay, western blot, qRT-PCR in dermal fibroblasts; in vivo rat dermal fibrosis model\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological AHR agonist/antagonist with in vitro and in vivo validation; single lab\",\n      \"pmids\": [\"26992058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PKD3 (PRKD3), downstream of atypical PKCι, mediates IL-1/OSM-induced MMP1 expression in human chondrocytes; PKD3 silencing reduced STAT3 serine phosphorylation and all three MAPK groups, and decreased AP-1 gene expression (FOS, JUN), leading to reduced MMP1/13.\",\n      \"method\": \"Pan-PKD inhibitor, gene-specific siRNA (PKD isoforms), western blot for phospho-signaling, RT-PCR in human articular chondrocytes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitor plus isoform-specific siRNA knockdown with multiple downstream markers; single lab\",\n      \"pmids\": [\"29652915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MMP1 mRNA-carrying extracellular vesicles (EVs) from highly metastatic ovarian cancer cells are taken up by mesothelial cells, increasing MMP1 expression in mesothelial cells and inducing their apoptosis, thereby destroying the peritoneal mesothelium barrier to facilitate peritoneal dissemination.\",\n      \"method\": \"EV isolation and characterization, whole transcriptome analysis of EV cargo, in vitro and in vivo apoptosis assays, analysis of ascites-derived EVs from patients\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional EV transfer assays in vitro and in vivo, patient ascites validation; single lab\",\n      \"pmids\": [\"28262727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MMP1 derived from tumor-associated macrophages (TAMs) promotes colon cancer cell proliferation by activating PAR1, leading to MAPK/Erk signaling and altering c-Myc and ETV4; ETV4 then binds the MMP1 promoter to activate MMP1 transcription, establishing a positive MMP1/PAR1/Erk1/2/ETV4/MMP1 feedback loop.\",\n      \"method\": \"Exogenous MMP1 treatment, PAR1 inhibition, MAPK/Erk inhibitor, ChIP for ETV4 binding to MMP1 promoter, cell cycle analysis, in vitro and in vivo assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for ETV4 promoter binding, pharmacological pathway inhibition, in vitro and in vivo functional assays; single lab\",\n      \"pmids\": [\"34753916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MMP1 expression by large cell carcinoma (LCC) cells is necessary and sufficient (in combination with TGF-β1) to induce premature senescence in pulmonary fibroblasts, which in turn drives LCC cell growth and invasion; PAR1 and oxidative stress are implicated in MMP1/TGF-β1-induced fibroblast senescence.\",\n      \"method\": \"MMP1 knockdown and overexpression, co-culture fibroblast senescence assay, PAR1 inhibition, oxidative stress measurements, in vivo mouse models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function for MMP1 with in vitro and in vivo senescence assays, PAR1 mechanistic link; single lab\",\n      \"pmids\": [\"33684534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Slug directly binds to three putative binding sites in the MMP1 promoter and activates MMP1 transcription in breast cancer cells; enforced Slug expression in MCF-7 cells significantly upregulated MMP1, while Slug knockdown in MDR MCF-7/ADR cells reduced MMP1 expression.\",\n      \"method\": \"Dual luciferase reporter assay, ChIP-qPCR confirming Slug binding to MMP1 promoter sites, western blot, immunofluorescence, functional drug sensitivity assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR plus luciferase promoter assay for direct binding confirmation; single lab\",\n      \"pmids\": [\"28334049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Transcription factor EGR-1 directly binds to an EBS (EGR-1 binding sequence) in the proximal MMP1 promoter and transactivates MMP1 in response to TNFα in HaCaT keratinocytes; EGR-1 siRNA silencing reduced TNFα-induced MMP-1 expression; all three MAPKs (ERK1/2, JNK, p38) mediate TNFα-induced MMP-1 via EGR-1 upregulation.\",\n      \"method\": \"MMP1 promoter deletion constructs, luciferase reporter assay, EGR-1 overexpression, EGR-1 siRNA knockdown, promoter EBS mutation, western blot in HaCaT keratinocytes\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter deletion/mutagenesis, ectopic expression, and siRNA knockdown in single lab; no ChIP confirmation reported\",\n      \"pmids\": [\"32317080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RUNX2 directly binds to specific motifs in the MMP1 promoter and activates its transcription in triple negative breast cancer cells, promoting proliferation, migration, invasion and chemoresistance; RUNX2 silencing suppressed MMP1 expression and these malignant phenotypes.\",\n      \"method\": \"ChIP assay for RUNX2 binding to MMP1 promoter, qRT-PCR, RNA-sequencing, in vitro functional assays, in vivo xenograft tumorigenicity\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct promoter binding plus functional knockdown in vitro and in vivo; single lab\",\n      \"pmids\": [\"36483054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Exosomal MMP-1 from highly metastatic TNBC cells is taken up by less metastatic TNBC cells and interacts with membrane PAR1, initiating epithelial-mesenchymal transition (EMT) to enhance migration and invasion; recipient cells increase their own MMP-1 secretion after exosome uptake.\",\n      \"method\": \"Exosome isolation, mass spectrometry, western blot, Transwell invasion/migration assays, in vivo lung colonization model in nude mice, tissue microarray and patient serum analysis\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional exosome transfer with receptor (PAR1) signaling link, in vivo validation; single lab\",\n      \"pmids\": [\"35254603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NAT10 promotes MMP1 mRNA stability via N4-acetylcytidine (ac4C) acetylation of MMP1 mRNA in oral squamous cell carcinoma; NAT10 knockdown reduced both total and ac4C-acetylated MMP1 mRNA levels and decreased MMP1 mRNA stability, impairing proliferation, migration, and invasion in an MMP1-dependent manner.\",\n      \"method\": \"NAT10 knockdown (lentivirus), ac4C-seq/RIP for acetylated MMP1 mRNA detection, mRNA stability assay, MMP1 rescue experiments, xenograft model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ac4C acetylation of MMP1 mRNA demonstrated by RIP, mRNA stability assay, and MMP1-dependent rescue; single lab\",\n      \"pmids\": [\"37705232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MMP1 upregulation through promoter hypomethylation enhances tamoxifen resistance in breast cancer; MMP1 was hypomethylated and overexpressed in tamoxifen-resistant MCF-7 cells; shRNA-mediated MMP1 knockdown restored tamoxifen sensitivity and increased apoptosis in vitro and in xenograft models.\",\n      \"method\": \"Methylation microarray, bisulfite sequencing, shRNA knockdown of MMP1, colony formation assay, flow cytometry, xenograft mouse model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — methylation profiling, bisulfite sequencing, and shRNA functional validation in vitro and in vivo; single lab\",\n      \"pmids\": [\"35267540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-8 activates STAT3 signaling in fibroblasts to upregulate MMP1 expression; fibroblast-derived MMP1 then supports invasion of HNSCC cancer cells via extracellular matrix degradation; STAT3 phosphorylation inhibitor (TPCA-1) impaired the enhanced invasion triggered by fibroblasts.\",\n      \"method\": \"IL-8 stimulation of fibroblasts, STAT3 inhibitor TPCA-1, MMP1 measurement, Transwell invasion assay with co-culture system\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological STAT3 inhibition with functional invasion readout, single lab single method per step\",\n      \"pmids\": [\"38320998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ETV4 directly upregulates MMP1 transcription in non-small cell lung cancer; luciferase reporter and gain/loss-of-function assays demonstrated the direct regulatory effect of ETV4 on MMP1 expression; MMP1 inhibition partially abolished ETV4-driven cell proliferation and migration.\",\n      \"method\": \"Microarray analysis, luciferase reporter assay, ETV4 gain- and loss-of-function, MMP1 inhibition, in vivo and in vitro metastasis assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus functional epistasis (MMP1 inhibition reverses ETV4 effects); single lab\",\n      \"pmids\": [\"31670855\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MMP-1 is a zinc-dependent interstitial collagenase that degrades fibrillar collagens and additional extracellular matrix substrates; its expression is transcriptionally regulated by multiple upstream signals including AP-1 (via ERK/JNK MAPK cascades activated by UV, cytokines, or growth factors), STAT3, ETS-family factors (ETS1/ETV4), EGR-1, RUNX2, Slug, and Wnt/Fos downstream of JNK—and is epigenetically controlled by promoter DNA methylation; once secreted, MMP-1 acts extracellularly by releasing membrane-bound EGF-like ligands to stimulate osteoblast EGFR signaling, by activating PAR1 on stromal/neuronal cells to initiate paracrine signaling cascades, by cleaving LAMA5 to generate pro-angiogenic fragments, and by inducing fibroblast senescence in a PAR1/oxidative-stress-dependent manner, placing MMP-1 at the nexus of ECM remodeling, tumor invasion, perineural invasion, bone metastasis, and tissue homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MMP-1 is a secreted, zinc-dependent interstitial collagenase whose catalytic domain in solution retains the fold seen in crystal structures, requiring only local rearrangements rather than major domain motions [#9], and which functions as a central effector of extracellular matrix remodeling, tumor invasion, and tissue homeostasis [#2, #14]. Beyond cleaving structural matrix, MMP-1 acts proteolytically on defined substrates to generate paracrine signals: it releases membrane-bound EGF-like ligands (Amphiregulin, HB-EGF, TGFα) from tumor cells to suppress osteoblast osteoprotegerin via EGFR and potentiate osteolytic bone metastasis [#2], and it cleaves laminin subunit alpha-5 to produce fragments that drive integrin αvβ3-dependent, VEGF-independent angiogenesis [#13]. A recurrent extracellular mechanism is MMP-1 activation of protease-activated receptor 1 (PAR1): on sensory neurons it triggers substance P release and NK1R-driven perineural invasion in pancreatic cancer [#14], on fibroblasts it induces oxidative-stress-dependent premature senescence that fuels tumor growth [#27], and on colon cancer cells it activates MAPK/ERK signaling to engage an ETV4-dependent positive feedback loop [#26]. MMP1 transcription integrates numerous upstream inputs converging largely on the MAPK/AP-1 module: UV, cytokine, growth factor, integrin, and aryl hydrocarbon receptor signals activate ERK and JNK to drive c-Fos/c-Jun AP-1 activity [#5, #16, #17, #21], and these cascades are restrained by Cdc42-mediated ERK repression [#6, #10] and by PPARδ/MKP-7 suppression of JNK [#11]. Direct transcriptional activators binding the MMP1 promoter include ETS-family factors ETV4 and ETS1 downstream of the CIC tumor suppressor [#15, #35], STAT3 acting downstream of IL-6/IL-8 [#22, #34], EGR-1 [#29], Slug [#28], and RUNX2 [#30], while DNA methylation of the promoter suppresses transcription and promoter hypomethylation drives overexpression and tamoxifen resistance [#7, #33]. MMP1 mRNA itself is stabilized by NAT10-mediated ac4C acetylation [#32] and can be propagated between cells as extracellular-vesicle cargo to remodel the metastatic niche [#25, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established an upstream cell-surface inducer of MMP-1, showing that homophilic CD147 (EMMPRIN) interactions stimulate MMP-1 production in a glycosylation-dependent manner.\",\n      \"evidence\": \"Purified native vs. deglycosylated CD147, blocking antibody, CD147-Fc fusion, MMP-1 ELISA in dermal fibroblasts\",\n      \"pmids\": [\"11280798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the intracellular signaling pathway linking CD147 engagement to MMP1 transcription\", \"Receptor for CD147 on fibroblasts not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the core MAPK/AP-1 transcriptional circuit by which UV induces MMP-1, mapping induction to ERK/c-Fos and JNK/c-Jun arms.\",\n      \"evidence\": \"MEK1 and SEK1 inhibitors, AP-1 EMSA, MMP-1 ELISA in human dermal fibroblasts\",\n      \"pmids\": [\"15930517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological inhibitor specificity not genetically confirmed\", \"Does not identify the direct AP-1 promoter contacts\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified Rho GTPase control over MMP-1, showing Cdc42 represses MMP-1 by suppressing ERK1/2 while Rac1 is required for the effect.\",\n      \"evidence\": \"siRNA knockdown of Cdc42/RhoA/Rac1 with siRNA-resistant rescue, kinase inhibitors, ELISA in skin fibroblasts\",\n      \"pmids\": [\"15728253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Cdc42 represses ERK1/2 not resolved\", \"Upstream activators of Cdc42 in this context not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed mmp1 downstream of polarity loss in an in vivo invasion model, showing scribble-loss/JNK signaling drives Fos-dependent mmp1 transcription to enable invasiveness.\",\n      \"evidence\": \"Drosophila genetic epistasis, Mmp1 RNAi, Timp overexpression, in vivo imaginal disc invasion assays\",\n      \"pmids\": [\"17082773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Drosophila Mmp1 substrate(s) mediating invasion not specified here\", \"Conservation of the scribble-JNK-Fos-mmp1 axis in mammalian MMP1 not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated epigenetic control of MMP1, showing promoter DNA methylation at -1538 and a methylated promoter SNP suppress transcription via altered nuclear-protein binding.\",\n      \"evidence\": \"5-aza-2'-deoxycytidine, bisulfite sequencing, promoter luciferase, ChIP, EMSA in amnion fibroblasts\",\n      \"pmids\": [\"18178580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the methylation-sensitive nuclear protein not determined\", \"Methyltransferase responsible not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established a tissue-level paracrine route to MMP-1 induction, showing UV DNA damage in keratinocytes generates soluble mediators that drive dermal fibroblast MMP-1.\",\n      \"evidence\": \"DNA repair enzyme liposomes, conditioned-medium transfer from irradiated keratinocytes, MMP-1 mRNA/protein in human skin\",\n      \"pmids\": [\"18459971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The soluble mediator(s) transmitting the signal not identified\", \"Receptor on fibroblasts not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed a transcriptional brake on MMP1, showing Met-phosphorylated MUC1 cooperates with p53 to suppress AP-1 activity at the MMP1 promoter and limit invasion.\",\n      \"evidence\": \"Co-IP, confocal nuclear imaging, MMP1 promoter luciferase, invasion assay in pancreatic cancer cells\",\n      \"pmids\": [\"18625714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding of the MUC1-p53 complex to the promoter not shown\", \"Quantitative contribution relative to other AP-1 inputs unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined a mechanistic substrate-based metastasis pathway, showing MMP1 sheds EGF-like ligands to suppress osteoblast OPG via EGFR and potentiate osteolytic bone metastasis.\",\n      \"evidence\": \"In vitro cleavage assays, EGFR inhibition, osteoblast co-culture/osteoclastogenesis, in vivo bone metastasis model\",\n      \"pmids\": [\"19608765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise cleavage sites on Amphiregulin/HB-EGF/TGFα not mapped\", \"Relative contributions of the three ligands not dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected hypoxia and Akt signaling to MMP1, identifying HIF-1α/CXCR4/ERK and Akt-CCN2-ERK/Ets1 routes converging on MMP1 induction.\",\n      \"evidence\": \"HIF-1α/CXCR4/Akt/CCN2 siRNA, AMD3100, ERK inhibitors in chondrosarcoma and dermal fibroblasts\",\n      \"pmids\": [\"20102637\", \"20201953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter elements engaged downstream not mapped\", \"Cell-type generality across the two systems not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided a solution-state structural baseline, showing the MMP-1 catalytic domain retains its crystallographic fold with only local rearrangements.\",\n      \"evidence\": \"Paramagnetic NMR (pseudocontact shifts, RDCs) with lanthanide tags on the catalytic domain\",\n      \"pmids\": [\"21945315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis validation of inferred rearrangements\", \"Full-length enzyme including hemopexin domain not analyzed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked MMP1 promoter polymorphism to bimodal endothelial expression and identified ETS1/ETS2/GATA3 as promoter-binding factors at that region.\",\n      \"evidence\": \"Microarray, RT-PCR, MMP1 activity assay, sequencing, ChIP in HUVECs from many donors\",\n      \"pmids\": [\"21244711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of each transcription factor on expression not isolated\", \"Allele-specific binding not directly demonstrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed integrin-collagen context-specific MMP-1 induction, with α2β1/collagen-I driving ERK-dependent MMP-1 in keratinocytes under Cdc42 negative control.\",\n      \"evidence\": \"ERK/p38/JNK inhibitors, Rho GTPase activity assays, MMP-1 western/ELISA in primary keratinocytes on collagen I\",\n      \"pmids\": [\"24352036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the same circuit operates in fibroblasts not tested here\", \"Direct integrin-to-ERK coupling mechanism not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a JNK-restraining mechanism, showing PPARδ stabilizes MKP-7 mRNA to suppress JNK and reduce UVB-induced MMP-1.\",\n      \"evidence\": \"GW501516, PPARδ siRNA, MAPK inhibitors, mRNA stability assay, in vivo hairless mouse UVB model\",\n      \"pmids\": [\"23639976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PPARδ-driven MKP-7 mRNA stabilization not defined\", \"Contribution of MKP-7 to ERK-driven MMP-1 not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Distinguished MMP substrate preferences in vivo, showing Mmp1 preferentially cleaves DE-cadherin junctions while Mmp2 degrades basement membrane during tissue dissociation.\",\n      \"evidence\": \"Fat body-specific RNAi screen, genetic interaction, biochemical assays, immunostaining in Drosophila\",\n      \"pmids\": [\"25520167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cadherin cleavage by mammalian MMP1 not demonstrated\", \"Structural basis of substrate selectivity not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a pro-angiogenic substrate axis, showing MMP1 cleaves LAMA5 to generate fragments that drive integrin αvβ3-dependent, VEGF-independent angiogenesis.\",\n      \"evidence\": \"MMP1 siRNA, secretome proteomics, endothelial angiogenesis assay, αvβ3 blockade, xenograft\",\n      \"pmids\": [\"27324842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LAMA5 cleavage sites and active fragment sequence not fully defined\", \"Direct fragment-integrin binding not biochemically resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Implicated aryl hydrocarbon receptor signaling in MMP-1 control, showing kynurenine drives AHR-dependent MMP-1 upregulation and collagen downregulation.\",\n      \"evidence\": \"AHR agonist/antagonist, CYP1A-1 reporter, western/qRT-PCR, in vivo rat dermal fibrosis model\",\n      \"pmids\": [\"26992058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AHR acts directly on the MMP1 promoter not shown\", \"Downstream kinase coupling not defined here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified Slug as a direct MMP1 transcriptional activator linked to drug resistance, binding three promoter sites.\",\n      \"evidence\": \"Luciferase reporter, ChIP-qPCR for Slug binding, western, drug sensitivity assays in breast cancer cells\",\n      \"pmids\": [\"28334049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional ranking of the three binding sites not resolved\", \"In vivo relevance of Slug-MMP1 axis not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established MMP1 as transferable extracellular-vesicle cargo, showing EV-borne MMP1 mRNA induces mesothelial apoptosis to breach the peritoneal barrier.\",\n      \"evidence\": \"EV isolation/transcriptomics, apoptosis assays in vitro/in vivo, patient ascites EVs in ovarian cancer\",\n      \"pmids\": [\"28262727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether translated MMP1 protein or RNA itself drives apoptosis not separated\", \"Receptor/effector in mesothelial apoptosis not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined an MMP1-PAR1 neuronal paracrine loop driving perineural invasion via substance P/NK1R/ERK signaling.\",\n      \"evidence\": \"DRG/Matrigel PNI system, sciatic nerve model, MMP1 shRNA, PAR1/NK1R antagonists in pancreatic cancer\",\n      \"pmids\": [\"29896303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MMP1 cleaves PAR1 directly at the tethered ligand not shown\", \"Contribution of neuronal vs. tumor-derived MMP1 not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Built the CIC-ETV4-MMP1 tumor-suppressor axis, showing CIC loss elevates ETV4 to induce MMP1 and that MMP1 is essential for the resulting phenotypes.\",\n      \"evidence\": \"CIC/ETV4/MMP1 gain- and loss-of-function epistasis, invasion/proliferation assays, xenograft in HCC\",\n      \"pmids\": [\"29251790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ETV4 binding to MMP1 promoter not shown in this study\", \"Downstream MMP1 substrate mediating proliferation not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended MAPK-coupled induction to additional inputs, implicating AHR/MEK-ERK, GSDMC/ERK-JNK, DDR2-CYR61-AP-1/ETS1, and PKD3 in MMP1 transcription.\",\n      \"evidence\": \"AHR/GSDMC/PKD3 knockdowns, CYR61 shRNA, AP-1 ChIP, MAPK inhibitors across fibroblasts, keratinocytes, synoviocytes, chondrocytes\",\n      \"pmids\": [\"29703420\", \"29428815\", \"27653023\", \"29652915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy among these parallel inputs at the promoter not integrated\", \"Most rely on pharmacological inhibitors without genetic confirmation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed ETV4 as a direct MMP1 activator in lung cancer with MMP1 required for ETV4-driven proliferation and migration.\",\n      \"evidence\": \"Luciferase reporter, ETV4 gain/loss-of-function, MMP1 inhibition, in vitro/in vivo metastasis assays in NSCLC\",\n      \"pmids\": [\"31670855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise ETV4 binding motif not mapped\", \"Interaction with other ETS factors at the promoter not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified EGR-1 as a direct TNFα-responsive MMP1 transactivator acting downstream of all three MAPKs.\",\n      \"evidence\": \"Promoter deletion/EBS mutation, luciferase, EGR-1 overexpression/siRNA in HaCaT keratinocytes\",\n      \"pmids\": [\"32317080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ChIP confirmation of endogenous EGR-1 occupancy\", \"Interplay between EGR-1 and AP-1 at the promoter not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized MMP1-PAR1 signaling to tumor microenvironment cross-talk, establishing a TAM-derived MMP1/PAR1/ERK/ETV4/MMP1 feedback loop and MMP1/TGF-β1-induced fibroblast senescence driving tumor growth.\",\n      \"evidence\": \"Exogenous MMP1, PAR1/ERK inhibitors, ETV4 ChIP, co-culture senescence/oxidative-stress assays, in vivo models in colon and lung cancer\",\n      \"pmids\": [\"34753916\", \"33684534\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MMP1 directly cleaves and activates PAR1 not biochemically shown\", \"Source-cell heterogeneity (TAM vs. tumor vs. fibroblast) not fully partitioned\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Added RUNX2 as a direct MMP1 activator and linked MMP1 promoter hypomethylation to tamoxifen resistance reversible by MMP1 knockdown.\",\n      \"evidence\": \"RUNX2 ChIP, methylation microarray/bisulfite sequencing, shRNA knockdown, functional assays and xenografts in breast cancer\",\n      \"pmids\": [\"36483054\", \"35267540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking hypomethylation to drug resistance downstream of MMP1 not defined\", \"Relationship between RUNX2 binding and methylation state not integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended exosomal MMP-1 propagation to breast cancer, showing exosomal MMP-1 engages recipient-cell PAR1 to initiate EMT and amplify MMP-1 secretion.\",\n      \"evidence\": \"Exosome isolation/MS, PAR1 link, Transwell assays, lung colonization model, patient sera in TNBC\",\n      \"pmids\": [\"35254603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether exosomal MMP-1 is catalytically active on PAR1 not directly shown\", \"Quantitative threshold for recipient EMT not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established post-transcriptional control of MMP1, showing NAT10-mediated ac4C acetylation stabilizes MMP1 mRNA to support malignancy.\",\n      \"evidence\": \"NAT10 knockdown, ac4C-RIP, mRNA stability assay, MMP1 rescue, xenograft in oral squamous cell carcinoma\",\n      \"pmids\": [\"37705232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ac4C-modified sites on MMP1 mRNA not mapped\", \"Whether acetylation also affects translation not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined an IL-8/STAT3 stromal route, showing fibroblast STAT3 activation upregulates MMP1 that supports cancer-cell invasion through ECM degradation.\",\n      \"evidence\": \"IL-8 stimulation, STAT3 inhibitor TPCA-1, co-culture Transwell invasion in HNSCC\",\n      \"pmids\": [\"38320998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STAT3 binding to MMP1 promoter in fibroblasts not shown here\", \"ECM substrate cleaved by fibroblast MMP1 not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many parallel transcriptional, epigenetic, and post-transcriptional inputs are quantitatively integrated at the MMP1 locus in a given cell type, and whether MMP1 directly proteolyzes PAR1 to drive its many paracrine effects, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model ranking AP-1, STAT3, ETS, RUNX2, EGR-1, Slug, and methylation inputs\", \"Direct enzymatic cleavage of PAR1 by MMP1 not biochemically established in the corpus\", \"Full-length enzyme structure and substrate-selectivity determinants not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 12, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 12, 13]},\n      {\"term_id\": \"GO:0008233\", \"supporting_discovery_ids\": [2, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 13, 34]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [13, 34]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [25, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [13, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 14, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 14, 26]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 7, 15, 28, 29, 30]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PAR1\",\n      \"LAMA5\",\n      \"EGFR\",\n      \"ETV4\",\n      \"ETS1\",\n      \"RUNX2\",\n      \"STAT3\",\n      \"EGR1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}