{"gene":"ECM1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2003,"finding":"ECM1 physically interacts with perlecan domain V; specifically, the C-terminus of ECM1 binds the EGF-like modules flanking the LG2 subdomain of perlecan domain V. This was identified by yeast two-hybrid screening of a human keratinocyte cDNA library and validated by co-immunoprecipitation in cell-free systems and mammalian cells using deletion mutants to map the binding sites.","method":"Yeast two-hybrid, co-immunoprecipitation (cell-free and mammalian cells), deletion mutant mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid discovery validated by reciprocal Co-IP in two systems; binding domain mapped by deletion mutants","pmids":["12604605"],"is_preprint":false},{"year":2001,"finding":"Recombinant ECM1 protein stimulates proliferation of cultured endothelial cells and promotes blood vessel formation in the chick chorioallantoic membrane assay, establishing direct pro-angiogenic activity.","method":"Endothelial cell proliferation assay with purified recombinant ECM1; chorioallantoic membrane (CAM) angiogenesis assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional assay with purified recombinant protein, two orthogonal methods, single lab","pmids":["11292659"],"is_preprint":false},{"year":2008,"finding":"ECM1a binds multiple extracellular matrix components including laminin 332, collagen type IV, fibronectin, hyaluronan, heparin, and chondroitin sulfate A via distinct regions of the protein, as shown by solid-phase binding assays. ECM1a enhances collagen IV binding to laminin 332 in a dose-dependent manner. Ultrastructural analysis placed ECM1 at the skin basement membrane within a network containing perlecan, collagen IV, and laminin 332.","method":"Solid-phase binding assay, immunoelectron microscopy, immunohistochemistry","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding assay with multiple substrates plus ultrastructural localization, single lab but multiple orthogonal methods","pmids":["18200062"],"is_preprint":false},{"year":2009,"finding":"ECM1a binds fibulin-3 and the beta-3 chain of laminin 332 through its serum albumin subdomain-like 2 (SASDL2) domain, as established by yeast two-hybrid screening and confirmed by in vitro and in vivo co-immunoprecipitation. Both partners co-localize with ECM1 in human skin by immunohistochemistry.","method":"Yeast two-hybrid, in vitro co-immunoprecipitation, in vivo co-immunoprecipitation, immunohistochemistry","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid discovery validated by reciprocal Co-IP in vitro and in vivo plus domain mapping; multiple orthogonal methods, single lab","pmids":["19275936"],"is_preprint":false},{"year":2011,"finding":"ECM1 is selectively expressed in TH2 cells and controls their egress from lymph nodes by directly binding the IL-2 receptor to inhibit IL-2 signaling, which in turn promotes re-expression of KLF2 and S1P1. ECM1-deficient T cells showed impaired migration and retention in lymphoid organs despite normal TH2 polarization.","method":"ECM1-knockout mouse model; in vivo TH2 response assays; direct IL-2 receptor binding experiment; flow cytometry; gene expression analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular phenotype, direct receptor-binding assay, multiple orthogonal readouts, published in high-tier journal","pmids":["21217760"],"is_preprint":false},{"year":2019,"finding":"ECM1 (produced mainly by hepatocytes) stabilizes extracellular matrix-deposited TGF-β1 in its inactive (latent) form by interacting with αv integrins, thereby preventing hepatic stellate cell (HSC) activation and fibrogenesis. ECM1-knockout mice spontaneously develop fatal liver fibrosis without significant hepatocyte damage. Ectopic expression of ECM1 or soluble TGFBR2 prevented fibrogenesis in ECM1-KO mice.","method":"ECM1-KO and hepatocyte-specific KO mice; AAV-mediated ECM1 overexpression; co-culture assays; immunohistochemistry; CCl4 fibrosis model; reporter gene assays","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple KO models, rescue by ectopic expression, mechanistic pathway identified (αv integrin interaction), replicated across multiple experimental conditions","pmids":["31362006"],"is_preprint":false},{"year":2020,"finding":"ECM1 in macrophages promotes M1 polarization in response to LPS through the GM-CSF/STAT5 signaling pathway. Macrophage-specific ECM1 knockout increased ARG1 expression and impaired M1 polarization, and alleviated DSS-induced IBD pathology in mice.","method":"Macrophage-specific ECM1 knockout mice; LPS stimulation; STAT5 pathway analysis; DSS-induced colitis model; cytokine measurement","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with defined molecular pathway (GM-CSF/STAT5), in vivo disease model rescue, multiple orthogonal methods","pmids":["31980528"],"is_preprint":false},{"year":2015,"finding":"ECM1 stabilizes β-catenin expression at the post-translational level through induction of MUC1, which physically associates with β-catenin. This β-catenin stabilization drives EMT progression and cancer stem cell maintenance, promoting breast cancer metastasis.","method":"ECM1 knockdown/overexpression; co-immunoprecipitation of MUC1–β-catenin complex; Western blot; sphere-forming assay; migration/invasion assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP establishing physical association, KD/OE with phenotypic readouts, mechanistic pathway placed, single lab","pmids":["25746001"],"is_preprint":false},{"year":2014,"finding":"ECM1 promotes the Warburg effect in cancer cells by inducing EGF-dependent ERK activation, which phosphorylates PKM2 at Ser37, leading to upregulation of GLUT1, LDHA, and HIF-1α gene expression.","method":"2D-LC-MS/MS proteomics; Western blot for PKM2 phosphorylation; gene expression analysis; ECM1 overexpression/knockdown","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — phosphorylation of PKM2 shown by WB with ECM1 modulation, pathway placed via EGF/ERK axis; single lab, limited reconstitution","pmids":["25446258"],"is_preprint":false},{"year":2013,"finding":"In kidney development, ECM1 is secreted from cortical stromal cells and acts on the ureteric bud to restrict Ret expression to the tips; inhibition of Ecm1 results in an expanded domain of Ret expression and reduced ureteric bud branching. Ecm1 was identified as a retinoic acid-regulated target in stromal cells.","method":"In vivo kidney development studies; Ecm1 inhibition; immunofluorescence; Ret expression analysis; retinoic acid signaling studies","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vivo with specific molecular readout (Ret domain expansion), pathway placement (RA→Ecm1→Ret), single lab","pmids":["24391906"],"is_preprint":false},{"year":2014,"finding":"N-glycosylation of ECM1 at Asn354 negatively regulates its secretion; this site (and Asn444) were identified as actual N-glycosylation sites by mass spectrometry. LP-associated ECM1 mutations suppress ECM1 secretion, but this suppression is not caused by loss of N-glycosylation at these sites.","method":"Mass spectrometry identification of glycosylation sites; mutagenesis of N-glycosylation sites; secretion assay","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — MS-based site identification plus functional mutagenesis assay for secretion; single lab","pmids":["25379385"],"is_preprint":false},{"year":1999,"finding":"The Ecm1 promoter requires AP1, Sp1, and Ets binding sites for expression in osteogenic cells; a 110-bp fragment containing these sites is sufficient for promoter activity. Point mutation analysis showed that all three sites are absolutely necessary. A repressive region was identified between −110 and −317.","method":"Reporter gene (CAT) assays; progressive promoter deletion; point mutagenesis; transient transfection in MN7 cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional readout (CAT reporter), single lab, well-controlled deletion series","pmids":["9931498"],"is_preprint":false},{"year":2016,"finding":"ECM1 regulates the actin cytoskeletal architecture of breast cancer cells partly via S100A4 and RhoA GTPase. ECM1 silencing decreased S100A4 and TGFβR2 expression, increased F/G actin ratio, induced stress fiber formation, reduced RhoA activation, and impaired cell migration and invasion. Re-expression of S100A4 rescued the phenotype in Hs578T cells.","method":"siRNA knockdown; activated Rho GTPase pull-down assay; F/G actin ratio measurement; fluorescent actin staining; migration/invasion assays; rescue experiment","journal":"Clinical & experimental metastasis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RhoA activity pulldown, rescue experiment linking ECM1→S100A4→RhoA axis; single lab, multiple methods","pmids":["27770373"],"is_preprint":false},{"year":2013,"finding":"TFAP2C directly binds the ECM1 promoter at an AP2 regulatory region and transcriptionally activates ECM1 expression in melanoma cells. TFAP2C knockdown reduced ECM1 expression; TFAP2C overexpression increased it. The minimal promoter (∼100 bp) containing AP1, SP1, Ets, and TATA box binding sites was sufficient for promoter activity.","method":"siRNA knockdown; adenoviral overexpression; luciferase reporter assays; 5' RACE; ChIP-seq for TFAP2C; gel shift assay (EMSA)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (ChIP-seq, EMSA, reporter assays, KD/OE) in single study establishing TFAP2C as ECM1 transcriptional activator","pmids":["24023917"],"is_preprint":false},{"year":2020,"finding":"ECM1 secreted by HER2-overexpressing breast cancer cells induces NOTCH1 and NOTCH3 upregulation in endothelial cells, promoting endothelial network formation and an endothelial feedback that enhances cancer cell migration and invasion. ECM1 knockdown by CRISPRi abolished these effects; recombinant ECM1 recapitulated them.","method":"Secretome MS; CRISPRi/CRISPRa knockdown/overexpression; conditioned medium experiments; recombinant ECM1 treatment; NOTCH inhibitor studies; 2D/3D co-culture","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPRi KD and recombinant protein rescue establishing causality; pathway to NOTCH identified; single lab","pmids":["32203150"],"is_preprint":false},{"year":2024,"finding":"ECM1 inhibits latent TGF-β1 activation by directly interacting with TSP-1 and ADAMTS1 via their KRFK or KTFR amino acid sequences, and by suppressing MMP-2/9 proteolytic activity. In vitro interaction assays confirmed these direct protein-protein interactions; ECM1 overexpression in mice attenuated KRFK-induced LTGF-β1 activation.","method":"In vitro interaction assays; HSC overexpression; Ecm1-KO and Fxr-KO mice; RNAseq; KTFR peptide treatment; computer modeling","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro binding assays mapping interaction sequences, multiple KO models, in vivo rescue with specific peptides, complementary computational model","pmids":["39448254"],"is_preprint":false},{"year":2024,"finding":"ECM1 interacts with the K-homology 3 (KH3) domain of PCBP1 to suppress intracellular iron overload, thereby limiting lipid peroxidation and MASH progression. ECM1 overexpression blocked hepatic steatosis and inflammation; ECM1 ablation exacerbated MASH. Re-expression of both ECM1 and PCBP1 ameliorated liver disease.","method":"Co-immunoprecipitation (ECM1–PCBP1 interaction); hepatocyte-specific ECM1 KO; AAV-mediated ECM1 overexpression; multiple MASH mouse models; iron and lipid peroxidation assays","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP mapping binding domain, multiple KO/OE models, specific molecular mechanism (iron homeostasis via PCBP1), multiple orthogonal methods","pmids":["40372944"],"is_preprint":false},{"year":2024,"finding":"ECM1 interacts with the cell-surface receptor enolase 1 (ENO1) on prostate cancer cells, leading to ENO1 phosphorylation at Y189, which recruits GRB2 and SOS1 adapter proteins and activates the MAPK signaling pathway, thereby promoting anti-androgen resistance in bone metastatic prostate cancer.","method":"Co-immunoprecipitation; phosphorylation assays; ENO1 inhibitor (PhAH); ENO1/ECM1 knockdown; MAPK pathway analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP establishing ECM1–ENO1 interaction, phosphorylation site identified, pathway activation shown; single lab","pmids":["39563492"],"is_preprint":false},{"year":2025,"finding":"ECM1 directly binds the cell-surface receptor LRP1α (low-density lipoprotein receptor-related protein 1α) as confirmed by Co-IP, Duolink Proximity Ligation Assay, and pull-down assays. The ECM1–LRP1 axis attenuates liver fibrosis by suppressing AKT/mTOR while activating the FoxO1 signaling pathway. LRP1-deficient mice lost the antifibrotic effect of ECM1-modified MenSCs.","method":"Co-immunoprecipitation, proximity ligation assay, pull-down; LRP1-deficient mice (AAV8-mediated); non-target metabolomics; RNA-seq","journal":"Stem cell research & therapy","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — three independent binding assays (Co-IP, PLA, pull-down) plus in vivo loss-of-function (LRP1 KO) showing pathway dependency; single lab","pmids":["40336034"],"is_preprint":false},{"year":2025,"finding":"In healthy hepatocytes, EGF/EGFR signaling sustains ECM1 expression by phosphorylating STAT1 at Ser727, enhancing its binding to the ECM1 promoter. During liver inflammation, IFNγ inhibits this mechanism by phosphorylating STAT1 at Tyr701 (impairing pSTAT1-S727 promoter binding) and induces NRF2 nuclear translocation, which repressively binds the ECM1 promoter, together reducing ECM1 transcription.","method":"Promoter analysis; STAT1 phospho-mutant assays; ChIP; functional assays in AML12 cells and primary hepatocytes; multiple CLD mouse models; scRNA-seq; AAV8-ECM1 rescue","journal":"JHEP reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — promoter analysis combined with ChIP, phospho-specific mutants, multiple mouse models, and patient correlation; multiple orthogonal methods","pmids":["40671832"],"is_preprint":false},{"year":2022,"finding":"ECM1 gene transcription is regulated by NF-κB through EP881C/T-EP266C binding sites in its promoter. Cisplatin activates NF-κB phosphorylation to enhance ECM1 expression, and the IKK/IκB/NF-κB pathway governs ECM1 levels. Secreted ECM1 can activate normal fibroblasts to acquire cancer-associated fibroblast characteristics.","method":"Promoter analysis; NF-κB inhibition (WA compound targeting IKK/IκB); Western blot for phospho-NF-κB; ECM1 overexpression; fibroblast co-culture","journal":"Nutrients","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — promoter binding sites identified with pharmacological NF-κB inhibition and ECM1 expression readout; mechanistic but limited to single lab with indirect methods","pmids":["36145166"],"is_preprint":false},{"year":2024,"finding":"ECM1 interacts with the cystine/glutamate transporter xCT (SLC7A11) to regulate hepatocyte ferroptosis. ECM1 deletion in hepatocytes abolished the antifibrotic effect of Sal B and exacerbated ferroptosis. Sal B upregulates ECM1 expression and directly binds ECM1 (binding kinetics determined).","method":"Co-interaction assay (ECM1–xCT); Ecm1 hepatocyte-specific KO mice; in vitro ferroptosis models; binding kinetics assay","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct interaction assay between ECM1 and xCT, hepatocyte-specific KO with specific phenotype; single lab","pmids":["38184998"],"is_preprint":false},{"year":2024,"finding":"TET2-mediated demethylation of the ECM1 promoter upregulates ECM1 expression in high-glucose-treated retinal microvascular endothelial cells. TET2 knockdown decreased both ECM1 expression and promoter methylation reversion, reducing tube formation and migration, implicating ECM1 as a downstream effector of TET2-driven neovascularization in diabetic retinopathy.","method":"TET2 knockdown; ECM1 promoter methylation analysis; tube formation and migration assays in HRMECs; gene expression datasets","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD with specific methylation and functional readouts establishing TET2→ECM1 axis; single lab","pmids":["38172938"],"is_preprint":false},{"year":2024,"finding":"Celastrol directly binds ECM1 and promotes its ubiquitination and proteasomal degradation, thereby inhibiting M1-like macrophage polarization and the ECM1/STAT5 pathway in IgA nephropathy. Confirmed by molecular docking, cellular thermal shift assay (CESTA), and co-immunoprecipitation.","method":"Molecular docking; CESTA (cellular thermal shift assay); co-immunoprecipitation; ubiquitination assay; macrophage polarization assay; IgAN mouse model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three independent binding verification methods (docking, CESTA, Co-IP), ubiquitination shown, functional readout; single lab","pmids":["39494325"],"is_preprint":false},{"year":2019,"finding":"ECM1 stimulation of cardiac fibroblasts induces ERK1/2 and AKT activation and upregulates collagen-I expression in vitro, suggesting a pro-fibrotic signaling role. ECM1 is expressed by bone marrow-derived granulocytes rather than resident cardiac cells, and is expressed at the infarct zone at day 3 post-MI.","method":"Recombinant ECM1 treatment of cardiac fibroblasts; Western blot for pERK1/2, pAKT; collagen-I qPCR; mRNA-FISH; flow cytometry of bone marrow","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct recombinant protein treatment with defined signaling readouts; cell source identified by mRNA-FISH and flow cytometry; single lab","pmids":["30789914"],"is_preprint":false},{"year":2026,"finding":"In the MASH disease context, ECM1 produced by hepatic stellate cells enforces HSC quiescence. HSC-specific ECM1 overexpression suppressed CCl4-induced fibrosis. ECM1 expression in quiescent HSCs inversely correlated with fibrosis stage in human biopsies across multiple CLD etiologies.","method":"HSC-specific ablation (Lrat-iDTR mice); HSC-specific ECM1 overexpression; RNA-seq; multi-parametric analysis; human biopsy correlation","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific overexpression with fibrosis readout, human validation; single recent report","pmids":["41854361"],"is_preprint":false}],"current_model":"ECM1 is a secreted glycoprotein that acts as a multivalent extracellular scaffold and signaling modulator: it maintains latent TGF-β1 in its inactive form by binding and blocking activators (αv integrins, TSP-1, ADAMTS1, MMP-2/9), directly interacts with perlecan domain V, laminin 332, fibulin-3, collagen IV, xCT, PCBP1, and LRP1α to regulate basement membrane integrity and cellular iron/lipid homeostasis, binds the IL-2 receptor on TH2 cells to suppress IL-2 signaling and enable lymph node egress via KLF2/S1P1, drives M1 macrophage polarization through GM-CSF/STAT5 signaling, and promotes cancer cell invasion/EMT through pathways involving β-catenin/MUC1 stabilization, EGF/ERK/PKM2-driven Warburg metabolism, and ENO1/MAPK signaling; its transcription is activated by EGF/EGFR/STAT1(S727) and TFAP2C, and repressed by IFNγ-induced STAT1(Y701) and NRF2 nuclear translocation, while loss-of-function mutations cause lipoid proteinosis through failure of basement membrane scaffolding in skin."},"narrative":{"mechanistic_narrative":"ECM1 is a secreted glycoprotein that functions as a multivalent extracellular scaffold and signaling modulator, organizing basement membrane architecture while restraining latent TGF-β1 activation across multiple tissues [PMID:31362006, PMID:39448254]. As a structural organizer it binds perlecan domain V through its C-terminus [PMID:12604605] and engages laminin 332, collagen IV, fibronectin, fibulin-3, and glycosaminoglycans through distinct domains, enhancing collagen IV–laminin 332 association within the skin basement membrane [PMID:18200062, PMID:19275936]. In the liver, hepatocyte- and hepatic stellate cell–derived ECM1 maintains TGF-β1 in its inactive latent state by binding αv integrins and by directly interacting with the TGF-β1 activators TSP-1 and ADAMTS1 (via their KRFK/KTFR sequences) while suppressing MMP-2/9 activity, thereby enforcing stellate cell quiescence; its loss precipitates spontaneous, fatal liver fibrosis [PMID:31362006, PMID:39448254, PMID:41854361]. ECM1 further protects hepatocytes by engaging the iron chaperone PCBP1 to limit iron overload and lipid peroxidation [PMID:40372944] and the cystine/glutamate transporter xCT (SLC7A11) to restrain ferroptosis [PMID:38184998], and signals through the surface receptor LRP1α to suppress AKT/mTOR and activate FoxO1 [PMID:40336034]. In immunity, ECM1 binds the IL-2 receptor on TH2 cells to inhibit IL-2 signaling and restore KLF2/S1P1-driven lymph node egress [PMID:21217760], and drives LPS-induced M1 macrophage polarization via GM-CSF/STAT5 signaling [PMID:31980528]. In cancer, ECM1 promotes invasion and EMT through MUC1-dependent β-catenin stabilization [PMID:25746001], EGF/ERK-driven PKM2(Ser37) phosphorylation and Warburg metabolism [PMID:25446258], and ENO1(Y189)/GRB2/SOS1/MAPK signaling [PMID:39563492]. ECM1 transcription is activated by TFAP2C [PMID:24023917] and by EGF/EGFR–STAT1(S727) signaling, and repressed during inflammation by IFNγ-induced STAT1(Y701) and NRF2 [PMID:40671832]. Loss-of-function affecting ECM1 secretion underlies lipoid proteinosis, reflecting failure of basement membrane scaffolding [PMID:25379385].","teleology":[{"year":2001,"claim":"Established that ECM1 is not merely a structural component but has direct biological activity, showing it stimulates endothelial proliferation and angiogenesis.","evidence":"Recombinant ECM1 in endothelial proliferation and chick chorioallantoic membrane assays","pmids":["11292659"],"confidence":"Medium","gaps":["No receptor or signaling pathway for the angiogenic effect identified","Single lab, in vitro/CAM only"]},{"year":2003,"claim":"Identified the first physical partner of ECM1, defining a molecular basis for its incorporation into the basement membrane network.","evidence":"Yeast two-hybrid plus reciprocal Co-IP and deletion mapping of ECM1 C-terminus–perlecan domain V interaction","pmids":["12604605"],"confidence":"High","gaps":["Functional consequence of perlecan binding in vivo not established","No structural model of the interface"]},{"year":2008,"claim":"Demonstrated ECM1 acts as a multivalent matrix cross-linker, mapping its binding to several ECM components and placing it ultrastructurally in the skin basement membrane.","evidence":"Solid-phase binding assays, immunoelectron microscopy, immunohistochemistry","pmids":["18200062"],"confidence":"Medium","gaps":["Binding affinities not quantified","Causal role of cross-linking in basement membrane integrity not tested by mutation"]},{"year":2009,"claim":"Mapped a specific ECM1 domain (SASDL2) to fibulin-3 and laminin 332 β3 binding, refining the structural logic of its scaffolding function.","evidence":"Yeast two-hybrid, in vitro/in vivo Co-IP, domain mapping, immunohistochemistry","pmids":["19275936"],"confidence":"High","gaps":["Effect of disrupting SASDL2 binding on tissue phenotype not shown"]},{"year":2011,"claim":"Revealed an unexpected immunological role, showing ECM1 controls TH2 cell lymph node egress by binding the IL-2 receptor and modulating KLF2/S1P1.","evidence":"ECM1-knockout mice, in vivo TH2 assays, direct IL-2 receptor binding, flow cytometry","pmids":["21217760"],"confidence":"High","gaps":["Stoichiometry and structural basis of IL-2 receptor binding undefined","Whether secreted vs cell-associated ECM1 mediates this is unclear"]},{"year":2014,"claim":"Connected ECM1 to cancer metabolism and post-translational regulation, linking it to PKM2(Ser37) phosphorylation/Warburg effect and identifying N-glycosylation sites that govern its secretion.","evidence":"Proteomics and Western blot for PKM2 phosphorylation; mass spectrometry glycosite mapping and secretion mutagenesis","pmids":["25446258","25379385"],"confidence":"Medium","gaps":["Direct ECM1–EGF/EGFR engagement not reconstituted","Glycosylation findings do not explain LP-mutation secretion defects"]},{"year":2015,"claim":"Defined a mechanism for ECM1-driven metastasis through MUC1-dependent post-translational β-catenin stabilization and EMT.","evidence":"ECM1 KD/OE, MUC1–β-catenin Co-IP, sphere-forming and invasion assays in breast cancer","pmids":["25746001"],"confidence":"Medium","gaps":["How extracellular ECM1 signals to intracellular MUC1/β-catenin not established","Single lab"]},{"year":2013,"claim":"Established the transcriptional control of ECM1, defining its minimal promoter elements and identifying TFAP2C as a direct activator in melanoma.","evidence":"Promoter deletion/point mutagenesis CAT and luciferase reporters; ChIP-seq, EMSA, KD/OE for TFAP2C","pmids":["9931498","24023917"],"confidence":"High","gaps":["Upstream signals converging on AP1/Sp1/Ets in non-cancer tissues not mapped"]},{"year":2013,"claim":"Showed a developmental patterning role, with stromal ECM1 restricting Ret expression and ureteric bud branching during kidney development downstream of retinoic acid.","evidence":"In vivo Ecm1 inhibition, immunofluorescence, Ret expression analysis","pmids":["24391906"],"confidence":"Medium","gaps":["Receptor mediating ECM1 action on ureteric bud unknown","Single model system"]},{"year":2016,"claim":"Linked ECM1 to cytoskeletal regulation in cancer cells via an S100A4/RhoA axis controlling actin dynamics and migration.","evidence":"siRNA KD, RhoA pull-down, F/G actin ratio, S100A4 rescue in breast cancer cells","pmids":["27770373"],"confidence":"Medium","gaps":["Mechanism connecting secreted ECM1 to intracellular S100A4/RhoA not defined"]},{"year":2019,"claim":"Identified the central antifibrotic mechanism of ECM1 in liver: maintaining latent TGF-β1 inactive via αv integrin interaction to keep hepatic stellate cells quiescent.","evidence":"Global and hepatocyte-specific ECM1-KO mice, AAV rescue, soluble TGFBR2 rescue, CCl4 model","pmids":["31362006"],"confidence":"High","gaps":["Structural basis of ECM1–αv integrin binding not resolved","Cross-tissue generality of TGF-β1 control not addressed here"]},{"year":2020,"claim":"Extended ECM1's immune role to innate immunity, showing it drives M1 macrophage polarization through GM-CSF/STAT5 with relevance to IBD; in parallel established its role in tumor angiogenic crosstalk via NOTCH.","evidence":"Macrophage-specific KO, DSS colitis model, STAT5 analysis; secretome MS, CRISPRi/CRISPRa, recombinant ECM1 in endothelial co-culture","pmids":["31980528","32203150"],"confidence":"High","gaps":["Receptor coupling ECM1 to GM-CSF/STAT5 in macrophages not identified","NOTCH induction mechanism by ECM1 indirect"]},{"year":2024,"claim":"Resolved the mechanistic detail of TGF-β1 restraint and uncovered new hepatocyte-protective interactions, showing ECM1 binds TSP-1/ADAMTS1 (KRFK/KTFR) and MMP-2/9 to block activation, binds PCBP1 to limit iron-driven lipid peroxidation, and binds xCT to restrain ferroptosis.","evidence":"In vitro interaction/peptide assays and KO mice (TGF-β1); Co-IP and KO/OE MASH models (PCBP1); ECM1–xCT interaction and hepatocyte KO (ferroptosis)","pmids":["39448254","40372944","38184998"],"confidence":"High","gaps":["Whether one ECM1 molecule coordinates multiple partners simultaneously unknown","Stoichiometry of xCT and PCBP1 binding undefined"]},{"year":2024,"claim":"Identified additional surface-receptor signaling axes for ECM1 in cancer (ENO1/MAPK driving anti-androgen resistance) and a transcriptional/degradation control layer (NF-κB induction, TET2 demethylation, celastrol-induced ubiquitination).","evidence":"Co-IP and phospho-ENO1(Y189) assays in prostate cancer; promoter/NF-κB and TET2 methylation analyses; docking/CESTA/ubiquitination assays","pmids":["39563492","36145166","38172938","39494325"],"confidence":"Medium","gaps":["Direct ECM1–ENO1 binding interface not structurally defined","Generality of NF-κB and TET2 regulation across tissues untested"]},{"year":2025,"claim":"Completed the liver regulatory circuit by defining how ECM1 transcription is sustained and suppressed (EGF/EGFR–STAT1-S727 activating; IFNγ–STAT1-Y701/NRF2 repressing) and identified LRP1α as a receptor mediating antifibrotic AKT/mTOR-FoxO1 signaling.","evidence":"Phospho-specific STAT1 mutants, ChIP, multiple CLD mouse models; Co-IP/PLA/pull-down and LRP1-deficient mice","pmids":["40671832","40336034"],"confidence":"High","gaps":["How ECM1 selects among LRP1, αv integrin, and other receptors in a given context unclear","Interplay between transcriptional repression and protein-level regulation not integrated"]},{"year":null,"claim":"It remains unresolved how a single secreted ECM1 protein selects among its many partners and surface receptors (integrins, IL-2R, LRP1, ENO1, xCT, PCBP1) to produce context-specific outcomes, and whether a common structural/biochemical logic governs these engagements.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of ECM1's multivalent binding","Receptor selection rules across cell types unknown","Quantitative affinities and competition among partners undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,15,4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,5,14]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,2,3]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[13,19,20]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,15,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,16,10]}],"complexes":[],"partners":["HSPG2","LAMB3","FBLN3","ITGAV","THBS1","PCBP1","SLC7A11","LRP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16610","full_name":"Extracellular matrix protein 1","aliases":["Secretory component p85"],"length_aa":540,"mass_kda":60.7,"function":"Involved in endochondral bone formation as negative regulator of bone mineralization. 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/38842389","citation_count":5,"is_preprint":false},{"pmid":"9549064","id":"PMC_9549064","title":"Identification, characterization, and mapping of Ecm1, a locus affecting extracellular matrix production and lesion size in Cochliobolus heterostrophus.","date":"1998","source":"Genome","url":"https://pubmed.ncbi.nlm.nih.gov/9549064","citation_count":5,"is_preprint":false},{"pmid":"38968654","id":"PMC_38968654","title":"Au-decorated Ti3C2Tx/porous carbon immunoplatform for ECM1 breast cancer biomarker detection with machine learning computation for predictive accuracy.","date":"2024","source":"Talanta","url":"https://pubmed.ncbi.nlm.nih.gov/38968654","citation_count":5,"is_preprint":false},{"pmid":"26778481","id":"PMC_26778481","title":"Treatment of lipoid proteinosis with acitretin in two patients from two unrelated Chinese families with novel nonsense mutations of the ECM1 gene.","date":"2016","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/26778481","citation_count":5,"is_preprint":false},{"pmid":"40336034","id":"PMC_40336034","title":"Human menstrual blood-derived stem cells secreted ECM1 directly interacts with LRP1α to ameliorate hepatic fibrosis through FoxO1 and mTOR signaling pathway.","date":"2025","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40336034","citation_count":4,"is_preprint":false},{"pmid":"39612152","id":"PMC_39612152","title":"TRPV4 drives the progression of leiomyosarcoma by promoting ECM1 generation and co-activating the FAK/PI3K/AKT/GSK3β pathway.","date":"2024","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/39612152","citation_count":4,"is_preprint":false},{"pmid":"25812648","id":"PMC_25812648","title":"Expression of ECM1 and MMP-2 in follicular thyroid lesions among Egyptians.","date":"2015","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/25812648","citation_count":4,"is_preprint":false},{"pmid":"21886756","id":"PMC_21886756","title":"Homozygous frame shift mutation in ECM1 gene in two siblings with lipoid proteinosis.","date":"2010","source":"Journal of dermatological case reports","url":"https://pubmed.ncbi.nlm.nih.gov/21886756","citation_count":4,"is_preprint":false},{"pmid":"38266317","id":"PMC_38266317","title":"ECM1-associated miR-1260b promotes osteogenic differentiation by targeting GDI1.","date":"2024","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/38266317","citation_count":3,"is_preprint":false},{"pmid":"16646403","id":"PMC_16646403","title":"[The relationship between ECM1 and the angiogenesis and metastasis of laryngeal carcinoma].","date":"2006","source":"Lin chuang er bi yan hou ke za zhi = Journal of clinical otorhinolaryngology","url":"https://pubmed.ncbi.nlm.nih.gov/16646403","citation_count":3,"is_preprint":false},{"pmid":"23212332","id":"PMC_23212332","title":"A novel missense mutation in exon 7 of the ECM1 gene in an Iranian lipoid proteinosis patient.","date":"2012","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/23212332","citation_count":3,"is_preprint":false},{"pmid":"40671832","id":"PMC_40671832","title":"ECM1 expression in chronic liver disease: Regulation by EGF/STAT1 and IFNγ/NRF2 signalling.","date":"2025","source":"JHEP reports : innovation in hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/40671832","citation_count":2,"is_preprint":false},{"pmid":"38546916","id":"PMC_38546916","title":"Extracellular matrix protein 1 (ECM1) is a potential biomarker in B cell acute lymphoblastic leukemia.","date":"2024","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38546916","citation_count":2,"is_preprint":false},{"pmid":"39348048","id":"PMC_39348048","title":"Serum ECM1 is a promising biomarker for staging and monitoring fibrosis in patients with chronic hepatitis B.","date":"2024","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39348048","citation_count":2,"is_preprint":false},{"pmid":"39639242","id":"PMC_39639242","title":"NTRK fusion promotes tumor migration and invasion through epithelial-mesenchymal transition and closely interacts with ECM1 and NOVA1.","date":"2024","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39639242","citation_count":2,"is_preprint":false},{"pmid":"36670503","id":"PMC_36670503","title":"Lipoid proteinosis: Novel ECM1 pathogenic variants and intrafamilial variability in four unrelated Arab families.","date":"2022","source":"Pediatric dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/36670503","citation_count":2,"is_preprint":false},{"pmid":"24413997","id":"PMC_24413997","title":"Identification of recurrent c.742G>T nonsense mutation in ECM1 in Pakistani families suffering from lipoid proteinosis.","date":"2014","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24413997","citation_count":2,"is_preprint":false},{"pmid":"30914052","id":"PMC_30914052","title":"Correction to: ECM1 regulates cell proliferation and trastuzumab resistance through activation of EGF-signaling.","date":"2019","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/30914052","citation_count":2,"is_preprint":false},{"pmid":"38651074","id":"PMC_38651074","title":"A Sporadic Family of Lipoid Proteinosis with Novel ECM1 Gene Mutations.","date":"2024","source":"Clinical, cosmetic and investigational dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/38651074","citation_count":2,"is_preprint":false},{"pmid":"41149731","id":"PMC_41149731","title":"Opportunities and Risks of Promoting Skin and Bone Healing via Implant Biofunctionalization of Extracellular Matrix Protein ECM1.","date":"2025","source":"Journal of functional biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/41149731","citation_count":1,"is_preprint":false},{"pmid":"39799499","id":"PMC_39799499","title":"Association between extracellular matrix protein 1 (ECM1) gene polymorphisms (rs3834087 and rs3754217) and Hepatitis B Virus evolution in an African cohort.","date":"2025","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/39799499","citation_count":1,"is_preprint":false},{"pmid":"41854361","id":"PMC_41854361","title":"ECM1 produced by hepatic stellate cells serves as a gatekeeper of liver homeostasis in hepatic fibrosis.","date":"2026","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/41854361","citation_count":0,"is_preprint":false},{"pmid":"40859530","id":"PMC_40859530","title":"Identification and validation of ECM1 as a causal plasma biomarker in knee osteoarthritis through proteome-wide association study and bioinformatics.","date":"2025","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40859530","citation_count":0,"is_preprint":false},{"pmid":"41361743","id":"PMC_41361743","title":"The correlation between serum ECM1 and cardiac fibrosis in heart failure patients.","date":"2025","source":"BMC cardiovascular disorders","url":"https://pubmed.ncbi.nlm.nih.gov/41361743","citation_count":0,"is_preprint":false},{"pmid":"37492299","id":"PMC_37492299","title":"Lipoid Proteinosis: Identification of a Novel Nonsense Mutation c.1246C>T:p.R416X in ECM1 gene from Bangladesh.","date":"2023","source":"Pakistan journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37492299","citation_count":0,"is_preprint":false},{"pmid":"41927423","id":"PMC_41927423","title":"Oral and maxillofacial manifestations of lipoid proteinosis with a novel ECM1 mutation: case report and literature review.","date":"2026","source":"Oral surgery, oral medicine, oral pathology and oral radiology","url":"https://pubmed.ncbi.nlm.nih.gov/41927423","citation_count":0,"is_preprint":false},{"pmid":"33159951","id":"PMC_33159951","title":"Identification of a novel three-nucleotide duplication in ECM1 in Chinese siblings affected with lipoid proteinosis.","date":"2020","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33159951","citation_count":0,"is_preprint":false},{"pmid":"41651902","id":"PMC_41651902","title":"H19 enhances pancreatic cancer proliferation and invasion by reducing miR-29c-5p's inhibitory effects on ATF2/ECM1.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41651902","citation_count":0,"is_preprint":false},{"pmid":"41986409","id":"PMC_41986409","title":"Extracellular vesicle delivery of Myricetin suppresses ovarian cancer through mitochondrial dynamics by downregulating the ECM1/NF-κB/TGFβ signaling pathway.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41986409","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51617,"output_tokens":6874,"usd":0.12898,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15974,"output_tokens":5180,"usd":0.104685,"stage2_stop_reason":"end_turn"},"total_usd":0.233665,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"ECM1 physically interacts with perlecan domain V; specifically, the C-terminus of ECM1 binds the EGF-like modules flanking the LG2 subdomain of perlecan domain V. This was identified by yeast two-hybrid screening of a human keratinocyte cDNA library and validated by co-immunoprecipitation in cell-free systems and mammalian cells using deletion mutants to map the binding sites.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation (cell-free and mammalian cells), deletion mutant mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid discovery validated by reciprocal Co-IP in two systems; binding domain mapped by deletion mutants\",\n      \"pmids\": [\"12604605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Recombinant ECM1 protein stimulates proliferation of cultured endothelial cells and promotes blood vessel formation in the chick chorioallantoic membrane assay, establishing direct pro-angiogenic activity.\",\n      \"method\": \"Endothelial cell proliferation assay with purified recombinant ECM1; chorioallantoic membrane (CAM) angiogenesis assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional assay with purified recombinant protein, two orthogonal methods, single lab\",\n      \"pmids\": [\"11292659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ECM1a binds multiple extracellular matrix components including laminin 332, collagen type IV, fibronectin, hyaluronan, heparin, and chondroitin sulfate A via distinct regions of the protein, as shown by solid-phase binding assays. ECM1a enhances collagen IV binding to laminin 332 in a dose-dependent manner. Ultrastructural analysis placed ECM1 at the skin basement membrane within a network containing perlecan, collagen IV, and laminin 332.\",\n      \"method\": \"Solid-phase binding assay, immunoelectron microscopy, immunohistochemistry\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding assay with multiple substrates plus ultrastructural localization, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18200062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ECM1a binds fibulin-3 and the beta-3 chain of laminin 332 through its serum albumin subdomain-like 2 (SASDL2) domain, as established by yeast two-hybrid screening and confirmed by in vitro and in vivo co-immunoprecipitation. Both partners co-localize with ECM1 in human skin by immunohistochemistry.\",\n      \"method\": \"Yeast two-hybrid, in vitro co-immunoprecipitation, in vivo co-immunoprecipitation, immunohistochemistry\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid discovery validated by reciprocal Co-IP in vitro and in vivo plus domain mapping; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"19275936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ECM1 is selectively expressed in TH2 cells and controls their egress from lymph nodes by directly binding the IL-2 receptor to inhibit IL-2 signaling, which in turn promotes re-expression of KLF2 and S1P1. ECM1-deficient T cells showed impaired migration and retention in lymphoid organs despite normal TH2 polarization.\",\n      \"method\": \"ECM1-knockout mouse model; in vivo TH2 response assays; direct IL-2 receptor binding experiment; flow cytometry; gene expression analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined cellular phenotype, direct receptor-binding assay, multiple orthogonal readouts, published in high-tier journal\",\n      \"pmids\": [\"21217760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ECM1 (produced mainly by hepatocytes) stabilizes extracellular matrix-deposited TGF-β1 in its inactive (latent) form by interacting with αv integrins, thereby preventing hepatic stellate cell (HSC) activation and fibrogenesis. ECM1-knockout mice spontaneously develop fatal liver fibrosis without significant hepatocyte damage. Ectopic expression of ECM1 or soluble TGFBR2 prevented fibrogenesis in ECM1-KO mice.\",\n      \"method\": \"ECM1-KO and hepatocyte-specific KO mice; AAV-mediated ECM1 overexpression; co-culture assays; immunohistochemistry; CCl4 fibrosis model; reporter gene assays\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple KO models, rescue by ectopic expression, mechanistic pathway identified (αv integrin interaction), replicated across multiple experimental conditions\",\n      \"pmids\": [\"31362006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ECM1 in macrophages promotes M1 polarization in response to LPS through the GM-CSF/STAT5 signaling pathway. Macrophage-specific ECM1 knockout increased ARG1 expression and impaired M1 polarization, and alleviated DSS-induced IBD pathology in mice.\",\n      \"method\": \"Macrophage-specific ECM1 knockout mice; LPS stimulation; STAT5 pathway analysis; DSS-induced colitis model; cytokine measurement\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with defined molecular pathway (GM-CSF/STAT5), in vivo disease model rescue, multiple orthogonal methods\",\n      \"pmids\": [\"31980528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ECM1 stabilizes β-catenin expression at the post-translational level through induction of MUC1, which physically associates with β-catenin. This β-catenin stabilization drives EMT progression and cancer stem cell maintenance, promoting breast cancer metastasis.\",\n      \"method\": \"ECM1 knockdown/overexpression; co-immunoprecipitation of MUC1–β-catenin complex; Western blot; sphere-forming assay; migration/invasion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP establishing physical association, KD/OE with phenotypic readouts, mechanistic pathway placed, single lab\",\n      \"pmids\": [\"25746001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ECM1 promotes the Warburg effect in cancer cells by inducing EGF-dependent ERK activation, which phosphorylates PKM2 at Ser37, leading to upregulation of GLUT1, LDHA, and HIF-1α gene expression.\",\n      \"method\": \"2D-LC-MS/MS proteomics; Western blot for PKM2 phosphorylation; gene expression analysis; ECM1 overexpression/knockdown\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — phosphorylation of PKM2 shown by WB with ECM1 modulation, pathway placed via EGF/ERK axis; single lab, limited reconstitution\",\n      \"pmids\": [\"25446258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In kidney development, ECM1 is secreted from cortical stromal cells and acts on the ureteric bud to restrict Ret expression to the tips; inhibition of Ecm1 results in an expanded domain of Ret expression and reduced ureteric bud branching. Ecm1 was identified as a retinoic acid-regulated target in stromal cells.\",\n      \"method\": \"In vivo kidney development studies; Ecm1 inhibition; immunofluorescence; Ret expression analysis; retinoic acid signaling studies\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vivo with specific molecular readout (Ret domain expansion), pathway placement (RA→Ecm1→Ret), single lab\",\n      \"pmids\": [\"24391906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"N-glycosylation of ECM1 at Asn354 negatively regulates its secretion; this site (and Asn444) were identified as actual N-glycosylation sites by mass spectrometry. LP-associated ECM1 mutations suppress ECM1 secretion, but this suppression is not caused by loss of N-glycosylation at these sites.\",\n      \"method\": \"Mass spectrometry identification of glycosylation sites; mutagenesis of N-glycosylation sites; secretion assay\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS-based site identification plus functional mutagenesis assay for secretion; single lab\",\n      \"pmids\": [\"25379385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The Ecm1 promoter requires AP1, Sp1, and Ets binding sites for expression in osteogenic cells; a 110-bp fragment containing these sites is sufficient for promoter activity. Point mutation analysis showed that all three sites are absolutely necessary. A repressive region was identified between −110 and −317.\",\n      \"method\": \"Reporter gene (CAT) assays; progressive promoter deletion; point mutagenesis; transient transfection in MN7 cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional readout (CAT reporter), single lab, well-controlled deletion series\",\n      \"pmids\": [\"9931498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ECM1 regulates the actin cytoskeletal architecture of breast cancer cells partly via S100A4 and RhoA GTPase. ECM1 silencing decreased S100A4 and TGFβR2 expression, increased F/G actin ratio, induced stress fiber formation, reduced RhoA activation, and impaired cell migration and invasion. Re-expression of S100A4 rescued the phenotype in Hs578T cells.\",\n      \"method\": \"siRNA knockdown; activated Rho GTPase pull-down assay; F/G actin ratio measurement; fluorescent actin staining; migration/invasion assays; rescue experiment\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RhoA activity pulldown, rescue experiment linking ECM1→S100A4→RhoA axis; single lab, multiple methods\",\n      \"pmids\": [\"27770373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TFAP2C directly binds the ECM1 promoter at an AP2 regulatory region and transcriptionally activates ECM1 expression in melanoma cells. TFAP2C knockdown reduced ECM1 expression; TFAP2C overexpression increased it. The minimal promoter (∼100 bp) containing AP1, SP1, Ets, and TATA box binding sites was sufficient for promoter activity.\",\n      \"method\": \"siRNA knockdown; adenoviral overexpression; luciferase reporter assays; 5' RACE; ChIP-seq for TFAP2C; gel shift assay (EMSA)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (ChIP-seq, EMSA, reporter assays, KD/OE) in single study establishing TFAP2C as ECM1 transcriptional activator\",\n      \"pmids\": [\"24023917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ECM1 secreted by HER2-overexpressing breast cancer cells induces NOTCH1 and NOTCH3 upregulation in endothelial cells, promoting endothelial network formation and an endothelial feedback that enhances cancer cell migration and invasion. ECM1 knockdown by CRISPRi abolished these effects; recombinant ECM1 recapitulated them.\",\n      \"method\": \"Secretome MS; CRISPRi/CRISPRa knockdown/overexpression; conditioned medium experiments; recombinant ECM1 treatment; NOTCH inhibitor studies; 2D/3D co-culture\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPRi KD and recombinant protein rescue establishing causality; pathway to NOTCH identified; single lab\",\n      \"pmids\": [\"32203150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ECM1 inhibits latent TGF-β1 activation by directly interacting with TSP-1 and ADAMTS1 via their KRFK or KTFR amino acid sequences, and by suppressing MMP-2/9 proteolytic activity. In vitro interaction assays confirmed these direct protein-protein interactions; ECM1 overexpression in mice attenuated KRFK-induced LTGF-β1 activation.\",\n      \"method\": \"In vitro interaction assays; HSC overexpression; Ecm1-KO and Fxr-KO mice; RNAseq; KTFR peptide treatment; computer modeling\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro binding assays mapping interaction sequences, multiple KO models, in vivo rescue with specific peptides, complementary computational model\",\n      \"pmids\": [\"39448254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ECM1 interacts with the K-homology 3 (KH3) domain of PCBP1 to suppress intracellular iron overload, thereby limiting lipid peroxidation and MASH progression. ECM1 overexpression blocked hepatic steatosis and inflammation; ECM1 ablation exacerbated MASH. Re-expression of both ECM1 and PCBP1 ameliorated liver disease.\",\n      \"method\": \"Co-immunoprecipitation (ECM1–PCBP1 interaction); hepatocyte-specific ECM1 KO; AAV-mediated ECM1 overexpression; multiple MASH mouse models; iron and lipid peroxidation assays\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP mapping binding domain, multiple KO/OE models, specific molecular mechanism (iron homeostasis via PCBP1), multiple orthogonal methods\",\n      \"pmids\": [\"40372944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ECM1 interacts with the cell-surface receptor enolase 1 (ENO1) on prostate cancer cells, leading to ENO1 phosphorylation at Y189, which recruits GRB2 and SOS1 adapter proteins and activates the MAPK signaling pathway, thereby promoting anti-androgen resistance in bone metastatic prostate cancer.\",\n      \"method\": \"Co-immunoprecipitation; phosphorylation assays; ENO1 inhibitor (PhAH); ENO1/ECM1 knockdown; MAPK pathway analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP establishing ECM1–ENO1 interaction, phosphorylation site identified, pathway activation shown; single lab\",\n      \"pmids\": [\"39563492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ECM1 directly binds the cell-surface receptor LRP1α (low-density lipoprotein receptor-related protein 1α) as confirmed by Co-IP, Duolink Proximity Ligation Assay, and pull-down assays. The ECM1–LRP1 axis attenuates liver fibrosis by suppressing AKT/mTOR while activating the FoxO1 signaling pathway. LRP1-deficient mice lost the antifibrotic effect of ECM1-modified MenSCs.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, pull-down; LRP1-deficient mice (AAV8-mediated); non-target metabolomics; RNA-seq\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — three independent binding assays (Co-IP, PLA, pull-down) plus in vivo loss-of-function (LRP1 KO) showing pathway dependency; single lab\",\n      \"pmids\": [\"40336034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In healthy hepatocytes, EGF/EGFR signaling sustains ECM1 expression by phosphorylating STAT1 at Ser727, enhancing its binding to the ECM1 promoter. During liver inflammation, IFNγ inhibits this mechanism by phosphorylating STAT1 at Tyr701 (impairing pSTAT1-S727 promoter binding) and induces NRF2 nuclear translocation, which repressively binds the ECM1 promoter, together reducing ECM1 transcription.\",\n      \"method\": \"Promoter analysis; STAT1 phospho-mutant assays; ChIP; functional assays in AML12 cells and primary hepatocytes; multiple CLD mouse models; scRNA-seq; AAV8-ECM1 rescue\",\n      \"journal\": \"JHEP reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — promoter analysis combined with ChIP, phospho-specific mutants, multiple mouse models, and patient correlation; multiple orthogonal methods\",\n      \"pmids\": [\"40671832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ECM1 gene transcription is regulated by NF-κB through EP881C/T-EP266C binding sites in its promoter. Cisplatin activates NF-κB phosphorylation to enhance ECM1 expression, and the IKK/IκB/NF-κB pathway governs ECM1 levels. Secreted ECM1 can activate normal fibroblasts to acquire cancer-associated fibroblast characteristics.\",\n      \"method\": \"Promoter analysis; NF-κB inhibition (WA compound targeting IKK/IκB); Western blot for phospho-NF-κB; ECM1 overexpression; fibroblast co-culture\",\n      \"journal\": \"Nutrients\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — promoter binding sites identified with pharmacological NF-κB inhibition and ECM1 expression readout; mechanistic but limited to single lab with indirect methods\",\n      \"pmids\": [\"36145166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ECM1 interacts with the cystine/glutamate transporter xCT (SLC7A11) to regulate hepatocyte ferroptosis. ECM1 deletion in hepatocytes abolished the antifibrotic effect of Sal B and exacerbated ferroptosis. Sal B upregulates ECM1 expression and directly binds ECM1 (binding kinetics determined).\",\n      \"method\": \"Co-interaction assay (ECM1–xCT); Ecm1 hepatocyte-specific KO mice; in vitro ferroptosis models; binding kinetics assay\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct interaction assay between ECM1 and xCT, hepatocyte-specific KO with specific phenotype; single lab\",\n      \"pmids\": [\"38184998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TET2-mediated demethylation of the ECM1 promoter upregulates ECM1 expression in high-glucose-treated retinal microvascular endothelial cells. TET2 knockdown decreased both ECM1 expression and promoter methylation reversion, reducing tube formation and migration, implicating ECM1 as a downstream effector of TET2-driven neovascularization in diabetic retinopathy.\",\n      \"method\": \"TET2 knockdown; ECM1 promoter methylation analysis; tube formation and migration assays in HRMECs; gene expression datasets\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD with specific methylation and functional readouts establishing TET2→ECM1 axis; single lab\",\n      \"pmids\": [\"38172938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Celastrol directly binds ECM1 and promotes its ubiquitination and proteasomal degradation, thereby inhibiting M1-like macrophage polarization and the ECM1/STAT5 pathway in IgA nephropathy. Confirmed by molecular docking, cellular thermal shift assay (CESTA), and co-immunoprecipitation.\",\n      \"method\": \"Molecular docking; CESTA (cellular thermal shift assay); co-immunoprecipitation; ubiquitination assay; macrophage polarization assay; IgAN mouse model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three independent binding verification methods (docking, CESTA, Co-IP), ubiquitination shown, functional readout; single lab\",\n      \"pmids\": [\"39494325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ECM1 stimulation of cardiac fibroblasts induces ERK1/2 and AKT activation and upregulates collagen-I expression in vitro, suggesting a pro-fibrotic signaling role. ECM1 is expressed by bone marrow-derived granulocytes rather than resident cardiac cells, and is expressed at the infarct zone at day 3 post-MI.\",\n      \"method\": \"Recombinant ECM1 treatment of cardiac fibroblasts; Western blot for pERK1/2, pAKT; collagen-I qPCR; mRNA-FISH; flow cytometry of bone marrow\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct recombinant protein treatment with defined signaling readouts; cell source identified by mRNA-FISH and flow cytometry; single lab\",\n      \"pmids\": [\"30789914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In the MASH disease context, ECM1 produced by hepatic stellate cells enforces HSC quiescence. HSC-specific ECM1 overexpression suppressed CCl4-induced fibrosis. ECM1 expression in quiescent HSCs inversely correlated with fibrosis stage in human biopsies across multiple CLD etiologies.\",\n      \"method\": \"HSC-specific ablation (Lrat-iDTR mice); HSC-specific ECM1 overexpression; RNA-seq; multi-parametric analysis; human biopsy correlation\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific overexpression with fibrosis readout, human validation; single recent report\",\n      \"pmids\": [\"41854361\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ECM1 is a secreted glycoprotein that acts as a multivalent extracellular scaffold and signaling modulator: it maintains latent TGF-β1 in its inactive form by binding and blocking activators (αv integrins, TSP-1, ADAMTS1, MMP-2/9), directly interacts with perlecan domain V, laminin 332, fibulin-3, collagen IV, xCT, PCBP1, and LRP1α to regulate basement membrane integrity and cellular iron/lipid homeostasis, binds the IL-2 receptor on TH2 cells to suppress IL-2 signaling and enable lymph node egress via KLF2/S1P1, drives M1 macrophage polarization through GM-CSF/STAT5 signaling, and promotes cancer cell invasion/EMT through pathways involving β-catenin/MUC1 stabilization, EGF/ERK/PKM2-driven Warburg metabolism, and ENO1/MAPK signaling; its transcription is activated by EGF/EGFR/STAT1(S727) and TFAP2C, and repressed by IFNγ-induced STAT1(Y701) and NRF2 nuclear translocation, while loss-of-function mutations cause lipoid proteinosis through failure of basement membrane scaffolding in skin.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ECM1 is a secreted glycoprotein that functions as a multivalent extracellular scaffold and signaling modulator, organizing basement membrane architecture while restraining latent TGF-\\u03b21 activation across multiple tissues [#5, #15]. As a structural organizer it binds perlecan domain V through its C-terminus [#0] and engages laminin 332, collagen IV, fibronectin, fibulin-3, and glycosaminoglycans through distinct domains, enhancing collagen IV\\u2013laminin 332 association within the skin basement membrane [#2, #3]. In the liver, hepatocyte- and hepatic stellate cell\\u2013derived ECM1 maintains TGF-\\u03b21 in its inactive latent state by binding \\u03b1v integrins and by directly interacting with the TGF-\\u03b21 activators TSP-1 and ADAMTS1 (via their KRFK/KTFR sequences) while suppressing MMP-2/9 activity, thereby enforcing stellate cell quiescence; its loss precipitates spontaneous, fatal liver fibrosis [#5, #15, #25]. ECM1 further protects hepatocytes by engaging the iron chaperone PCBP1 to limit iron overload and lipid peroxidation [#16] and the cystine/glutamate transporter xCT (SLC7A11) to restrain ferroptosis [#21], and signals through the surface receptor LRP1\\u03b1 to suppress AKT/mTOR and activate FoxO1 [#18]. In immunity, ECM1 binds the IL-2 receptor on TH2 cells to inhibit IL-2 signaling and restore KLF2/S1P1-driven lymph node egress [#4], and drives LPS-induced M1 macrophage polarization via GM-CSF/STAT5 signaling [#6]. In cancer, ECM1 promotes invasion and EMT through MUC1-dependent \\u03b2-catenin stabilization [#7], EGF/ERK-driven PKM2(Ser37) phosphorylation and Warburg metabolism [#8], and ENO1(Y189)/GRB2/SOS1/MAPK signaling [#17]. ECM1 transcription is activated by TFAP2C [#13] and by EGF/EGFR\\u2013STAT1(S727) signaling, and repressed during inflammation by IFN\\u03b3-induced STAT1(Y701) and NRF2 [#19]. Loss-of-function affecting ECM1 secretion underlies lipoid proteinosis, reflecting failure of basement membrane scaffolding [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that ECM1 is not merely a structural component but has direct biological activity, showing it stimulates endothelial proliferation and angiogenesis.\",\n      \"evidence\": \"Recombinant ECM1 in endothelial proliferation and chick chorioallantoic membrane assays\",\n      \"pmids\": [\"11292659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor or signaling pathway for the angiogenic effect identified\", \"Single lab, in vitro/CAM only\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified the first physical partner of ECM1, defining a molecular basis for its incorporation into the basement membrane network.\",\n      \"evidence\": \"Yeast two-hybrid plus reciprocal Co-IP and deletion mapping of ECM1 C-terminus\\u2013perlecan domain V interaction\",\n      \"pmids\": [\"12604605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of perlecan binding in vivo not established\", \"No structural model of the interface\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated ECM1 acts as a multivalent matrix cross-linker, mapping its binding to several ECM components and placing it ultrastructurally in the skin basement membrane.\",\n      \"evidence\": \"Solid-phase binding assays, immunoelectron microscopy, immunohistochemistry\",\n      \"pmids\": [\"18200062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding affinities not quantified\", \"Causal role of cross-linking in basement membrane integrity not tested by mutation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped a specific ECM1 domain (SASDL2) to fibulin-3 and laminin 332 \\u03b23 binding, refining the structural logic of its scaffolding function.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro/in vivo Co-IP, domain mapping, immunohistochemistry\",\n      \"pmids\": [\"19275936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effect of disrupting SASDL2 binding on tissue phenotype not shown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed an unexpected immunological role, showing ECM1 controls TH2 cell lymph node egress by binding the IL-2 receptor and modulating KLF2/S1P1.\",\n      \"evidence\": \"ECM1-knockout mice, in vivo TH2 assays, direct IL-2 receptor binding, flow cytometry\",\n      \"pmids\": [\"21217760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of IL-2 receptor binding undefined\", \"Whether secreted vs cell-associated ECM1 mediates this is unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected ECM1 to cancer metabolism and post-translational regulation, linking it to PKM2(Ser37) phosphorylation/Warburg effect and identifying N-glycosylation sites that govern its secretion.\",\n      \"evidence\": \"Proteomics and Western blot for PKM2 phosphorylation; mass spectrometry glycosite mapping and secretion mutagenesis\",\n      \"pmids\": [\"25446258\", \"25379385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ECM1\\u2013EGF/EGFR engagement not reconstituted\", \"Glycosylation findings do not explain LP-mutation secretion defects\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a mechanism for ECM1-driven metastasis through MUC1-dependent post-translational \\u03b2-catenin stabilization and EMT.\",\n      \"evidence\": \"ECM1 KD/OE, MUC1\\u2013\\u03b2-catenin Co-IP, sphere-forming and invasion assays in breast cancer\",\n      \"pmids\": [\"25746001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How extracellular ECM1 signals to intracellular MUC1/\\u03b2-catenin not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the transcriptional control of ECM1, defining its minimal promoter elements and identifying TFAP2C as a direct activator in melanoma.\",\n      \"evidence\": \"Promoter deletion/point mutagenesis CAT and luciferase reporters; ChIP-seq, EMSA, KD/OE for TFAP2C\",\n      \"pmids\": [\"9931498\", \"24023917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals converging on AP1/Sp1/Ets in non-cancer tissues not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed a developmental patterning role, with stromal ECM1 restricting Ret expression and ureteric bud branching during kidney development downstream of retinoic acid.\",\n      \"evidence\": \"In vivo Ecm1 inhibition, immunofluorescence, Ret expression analysis\",\n      \"pmids\": [\"24391906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating ECM1 action on ureteric bud unknown\", \"Single model system\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked ECM1 to cytoskeletal regulation in cancer cells via an S100A4/RhoA axis controlling actin dynamics and migration.\",\n      \"evidence\": \"siRNA KD, RhoA pull-down, F/G actin ratio, S100A4 rescue in breast cancer cells\",\n      \"pmids\": [\"27770373\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting secreted ECM1 to intracellular S100A4/RhoA not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the central antifibrotic mechanism of ECM1 in liver: maintaining latent TGF-\\u03b21 inactive via \\u03b1v integrin interaction to keep hepatic stellate cells quiescent.\",\n      \"evidence\": \"Global and hepatocyte-specific ECM1-KO mice, AAV rescue, soluble TGFBR2 rescue, CCl4 model\",\n      \"pmids\": [\"31362006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ECM1\\u2013\\u03b1v integrin binding not resolved\", \"Cross-tissue generality of TGF-\\u03b21 control not addressed here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended ECM1's immune role to innate immunity, showing it drives M1 macrophage polarization through GM-CSF/STAT5 with relevance to IBD; in parallel established its role in tumor angiogenic crosstalk via NOTCH.\",\n      \"evidence\": \"Macrophage-specific KO, DSS colitis model, STAT5 analysis; secretome MS, CRISPRi/CRISPRa, recombinant ECM1 in endothelial co-culture\",\n      \"pmids\": [\"31980528\", \"32203150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor coupling ECM1 to GM-CSF/STAT5 in macrophages not identified\", \"NOTCH induction mechanism by ECM1 indirect\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the mechanistic detail of TGF-\\u03b21 restraint and uncovered new hepatocyte-protective interactions, showing ECM1 binds TSP-1/ADAMTS1 (KRFK/KTFR) and MMP-2/9 to block activation, binds PCBP1 to limit iron-driven lipid peroxidation, and binds xCT to restrain ferroptosis.\",\n      \"evidence\": \"In vitro interaction/peptide assays and KO mice (TGF-\\u03b21); Co-IP and KO/OE MASH models (PCBP1); ECM1\\u2013xCT interaction and hepatocyte KO (ferroptosis)\",\n      \"pmids\": [\"39448254\", \"40372944\", \"38184998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether one ECM1 molecule coordinates multiple partners simultaneously unknown\", \"Stoichiometry of xCT and PCBP1 binding undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified additional surface-receptor signaling axes for ECM1 in cancer (ENO1/MAPK driving anti-androgen resistance) and a transcriptional/degradation control layer (NF-\\u03baB induction, TET2 demethylation, celastrol-induced ubiquitination).\",\n      \"evidence\": \"Co-IP and phospho-ENO1(Y189) assays in prostate cancer; promoter/NF-\\u03baB and TET2 methylation analyses; docking/CESTA/ubiquitination assays\",\n      \"pmids\": [\"39563492\", \"36145166\", \"38172938\", \"39494325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ECM1\\u2013ENO1 binding interface not structurally defined\", \"Generality of NF-\\u03baB and TET2 regulation across tissues untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Completed the liver regulatory circuit by defining how ECM1 transcription is sustained and suppressed (EGF/EGFR\\u2013STAT1-S727 activating; IFN\\u03b3\\u2013STAT1-Y701/NRF2 repressing) and identified LRP1\\u03b1 as a receptor mediating antifibrotic AKT/mTOR-FoxO1 signaling.\",\n      \"evidence\": \"Phospho-specific STAT1 mutants, ChIP, multiple CLD mouse models; Co-IP/PLA/pull-down and LRP1-deficient mice\",\n      \"pmids\": [\"40671832\", \"40336034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ECM1 selects among LRP1, \\u03b1v integrin, and other receptors in a given context unclear\", \"Interplay between transcriptional repression and protein-level regulation not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single secreted ECM1 protein selects among its many partners and surface receptors (integrins, IL-2R, LRP1, ENO1, xCT, PCBP1) to produce context-specific outcomes, and whether a common structural/biochemical logic governs these engagements.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of ECM1's multivalent binding\", \"Receptor selection rules across cell types unknown\", \"Quantitative affinities and competition among partners undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 15, 4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 5, 14]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [13, 19, 20]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 15, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 16, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HSPG2\", \"LAMB3\", \"FBLN3\", \"ITGAV\", \"THBS1\", \"PCBP1\", \"SLC7A11\", \"LRP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}