{"gene":"LOXL2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1999,"finding":"LOXL2 encodes a new lysyl oxidase-like amine oxidase with conserved copper-binding and catalytic domains; unlike LOX and LOXL, exon 1 of LOXL2 does not encode a signal sequence, suggesting different processing and intracellular localization. The protein has four divergent N-terminal exons and five conserved C-terminal exons encoding the catalytic domain.","method":"cDNA cloning, gene structure analysis, in situ hybridization, sequence homology analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — primary molecular characterization with multiple orthogonal methods (sequencing, gene structure, expression), foundational paper replicated by subsequent work","pmids":["10212285"],"is_preprint":false},{"year":2005,"finding":"LOXL2 physically interacts with and functionally stabilizes the EMT transcription factor Snail1 by attenuating GSK3β-dependent phosphorylation and subsequent ubiquitination/degradation of Snail1, thereby promoting E-cadherin repression and EMT.","method":"Co-immunoprecipitation, functional interaction assays, discussion of epistasis between LOXL2 and GSK3β in Snail regulation","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — physical interaction reported, mechanistic model described; single lab, limited orthogonal methods in this paper specifically","pmids":["16294032"],"is_preprint":false},{"year":2009,"finding":"Secreted extracellular LOXL2 promotes gastric cancer invasion and metastasis via the Src/FAK signaling pathway, whereas intracellular LOXL2 also activates the Snail/E-cadherin pathway; antibody blockade of secreted LOXL2 inhibits tumor growth and metastasis.","method":"RNA interference knockdown, ectopic overexpression, Src/FAK western blot, in vivo xenograft, anti-LOXL2 antibody treatment","journal":"Carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function, in vivo validation, pathway analysis by western blot, single lab with multiple orthogonal methods","pmids":["19625348"],"is_preprint":false},{"year":2009,"finding":"LOX and LOXL2 are direct transcriptional targets of HIF-1 under hypoxia; their activation is necessary and sufficient for hypoxic repression of E-cadherin, mediating epithelial-to-mesenchymal transition and cellular invasion.","method":"HIF-1 transcription factor binding analysis, gene expression assays, cellular invasion assays, gain/loss-of-function experiments under hypoxic conditions","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct transcriptional target identification, necessity and sufficiency demonstrated via gain/loss-of-function, functional invasion readout","pmids":["20026874"],"is_preprint":false},{"year":2010,"finding":"LOXL2 is the major lysyl oxidase isoform expressed in chondrocytes during fracture healing; LOXL2 knockdown in ATDC5 chondrogenic cells impairs differentiation by altering expression of SNAIL and SOX9, demonstrating LOXL2 is required for chondrocyte differentiation.","method":"Expression profiling of LOX isoforms in fracture healing, in vitro LOXL2 knockdown in chondrogenic cell line, gene expression analysis of SNAIL and SOX9","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and downstream transcription factor readout, single lab","pmids":["21071451"],"is_preprint":false},{"year":2011,"finding":"LOXL2 promotes breast cancer invasion by regulating expression and activity of TIMP-1 and MMP9 in the extracellular environment; genetic, chemical, or antibody-mediated inhibition of LOXL2 reduces metastasis in orthotopic and transgenic models.","method":"Genetic knockdown, chemical inhibition, antibody inhibition, in vivo orthotopic and transgenic breast cancer models, protein expression analysis of TIMP1/MMP9","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal inhibition strategies (genetic, chemical, antibody), in vivo validation, mechanistic effectors identified","pmids":["21233336"],"is_preprint":false},{"year":2011,"finding":"Cytoplasmic/perinuclear LOXL2 maintains mesenchymal phenotype in basal-like breast carcinoma cells through transcriptional downregulation of Lgl2 and claudin-1, causing disorganization of cell polarity and tight junction complexes; LOXL2 silencing induces mesenchymal-to-epithelial transition.","method":"LOXL2 silencing, gene expression analysis, immunofluorescence of polarity/tight junction markers, in vivo tumorigenicity assay","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotypic readout and downstream gene targets, single lab","pmids":["21732535"],"is_preprint":false},{"year":2011,"finding":"LOXL2 inhibition in enzymatic activity assays using catalytically inactive mutants (LOXL2 Y689F) and deletion of catalytic domain still inhibits keratinocyte differentiation, demonstrating the enzymatic activity of LOXL2 is not required for inhibition of keratinocyte differentiation; this activity requires the fourth SRCR domain.","method":"Catalytically inactive point mutant (Y689F), catalytic domain deletion mutant, β-aminopropionitrile enzymatic inhibitor, AB0023 function-blocking antibody, involucrin expression as differentiation readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis with multiple mutants, chemical inhibitor controls, domain deletion, clear catalytic vs. non-catalytic function separation","pmids":["22157764"],"is_preprint":false},{"year":2013,"finding":"Tumor-secreted LOXL2 activates stromal fibroblasts through integrin-mediated focal adhesion kinase (FAK) activation, inducing α-SMA expression, fibroblast branching on collagen matrices, collagen contraction, and fibroblast invasion.","method":"In vitro fibroblast activation assays on collagen matrices, recombinant LOXL2 treatment, FAK phosphorylation western blot, α-SMA immunostaining, in vivo orthotopic tumor models with LOXL2 manipulation","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 / Moderate — recombinant protein functional assay, in vitro and in vivo validation, defined signaling pathway (integrin/FAK), multiple readouts","pmids":["24008674"],"is_preprint":false},{"year":2013,"finding":"LOXL2 induces aberrant acinar morphogenesis in normal mammary epithelial cells through production of reactive oxygen species (ROS) that activates ErbB2; ErbB2 inhibition (Herceptin, lapatinib) abrogates LOXL2-induced abnormal proliferation, disrupted polarity and lumen formation.","method":"LOXL2 overexpression in MCF10A 3D acinar cultures, ROS measurement, ErbB2 phosphorylation analysis, pharmacological ErbB2 inhibition, invasion assays","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined mechanistic pathway (ROS→ErbB2), rescue experiments with inhibitors, single lab","pmids":["23971878"],"is_preprint":false},{"year":2014,"finding":"Catalytically inactive LOXL2 mutants collaborate with Snail1 in E-cadherin gene repression and promote FAK/Src pathway activation to trigger EMT, demonstrating a non-catalytic role of LOXL2 in regulating epithelial cell plasticity.","method":"Catalytically inactive LOXL2 mutant overexpression, E-cadherin promoter activity assays, FAK/Src phosphorylation western blot, EMT marker analysis","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis approach, defined pathway activation, single lab","pmids":["24414204"],"is_preprint":false},{"year":2014,"finding":"LOXL2 interacts with the bHLH transcription factor E47 and functionally collaborates in repression of the E-cadherin promoter; LOXL2 and E47 together regulate recruitment of bone marrow progenitor cells to lungs and directly transcriptionally regulate fibronectin and cytokines TNFα, ANG-1 and GM-CSF during metastatic colonization.","method":"Co-immunoprecipitation, E-cadherin promoter luciferase assay, loss/gain-of-function in syngeneic breast cancer models, in vivo lung metastasis assay, bone marrow progenitor cell recruitment assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, promoter functional assay, in vivo validation, multiple mechanistic readouts","pmids":["24632622"],"is_preprint":false},{"year":2014,"finding":"LOXL2 regulates integrin α5 and integrin β1 protein levels via protease- and proteasome-dependent degradation systems, promoting stress fiber and focal adhesion formation in renal clear cell carcinoma cells.","method":"RNAi knockdown, protease/proteasome inhibitor experiments, integrin α5/β1 western blot, stress fiber and focal adhesion imaging","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined downstream mechanism, pharmacological dissection of degradation pathway, single lab","pmids":["25092917"],"is_preprint":false},{"year":2014,"finding":"LOXL2 interacts with MARCKSL1 through its scavenger receptor domain (interacting with the N-terminal domain of MARCKSL1); LOXL2 activates FAK/Akt/mTOR signaling pathways and inhibits MARCKSL1-induced apoptosis, promoting cell proliferation.","method":"Co-immunoprecipitation, domain mapping, luciferase reporter assay, cell cycle and apoptosis analysis, FAK/Akt/mTOR phosphorylation western blot","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with domain mapping, defined signaling pathway, single lab","pmids":["24863880"],"is_preprint":false},{"year":2014,"finding":"LOXL2 alternative splicing isoform LOXL2 Δe13, lacking exon 13, shows impaired deamination enzymatic activity but promotes cell migration and invasion of esophageal squamous cell carcinoma cells to greater degrees than full-length LOXL2, operating through MAPK8 rather than FAK/AKT/ERK pathways.","method":"Isoform identification and cloning, enzymatic deamination assay, gene expression profiling, MAPK8 knockdown rescue experiment, migration/invasion assays","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity measurement, isoform-specific pathway dissection, functional rescue experiment, single lab","pmids":["25275797"],"is_preprint":false},{"year":2015,"finding":"LOXL2 oxidizes methylated TAF10 (a TFIID complex member), causing its release from promoters and blocking TFIID-dependent gene transcription; in embryonic stem cells this inactivates pluripotency genes, and in zebrafish loss of LOXL2 causes aberrant Sox2 overexpression and impaired neural differentiation.","method":"Unbiased proteomic substrate identification, in vitro oxidation assay, ChIP-seq, embryonic stem cell pluripotency gene analysis, zebrafish LOXL2 loss-of-function","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with substrate identification, ChIP-seq, in vivo vertebrate model validation, multiple orthogonal methods","pmids":["25959397"],"is_preprint":false},{"year":2016,"finding":"Recombinant LOXL2 specifically deaminates trimethylated lysine 4 on histone H3 (H3K4me3), as shown by infrared spectroscopy and mass spectrometry; this LOXL2-catalyzed H3K4 deamination is linked to transcriptional control of the CDH1 (E-cadherin) gene, representing a novel unconventional chemical mechanism for histone modification.","method":"In vitro deamination assay with recombinant LOXL2, infrared spectroscopy, mass spectrometry, CDH1 transcription analysis","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with recombinant protein, multiple biophysical methods (IR spectroscopy + MS), functional gene expression link","pmids":["27735137"],"is_preprint":false},{"year":2016,"finding":"LOXL2 expression in metastatic lung cancer cells is directly regulated by ZEB1 (transcriptional activator) and repressed by the miR-200 family; LOXL2, as opposed to LOX, is the principal isoform crosslinking and stabilizing insoluble collagen deposition in tumor tissues, which activates focal adhesion/FAK/SRC signaling in mesenchymal tumor cells.","method":"miR-200/ZEB1 gain/loss-of-function, collagen solubility assay, FAK/SRC phosphorylation western blot, in vivo metastasis models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct regulatory axis (miR-200/ZEB1/LOXL2) with functional validation, isoform specificity demonstrated, downstream signaling defined, in vivo","pmids":["27694892"],"is_preprint":false},{"year":2016,"finding":"In cardiac stress, LOXL2 secreted by activated fibroblasts into the interstitium promotes cardiac fibrosis by stimulating fibroblasts through PI3K/AKT signaling to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; LOXL2 also acts downstream of TGF-β2 to stimulate myofibroblast migration.","method":"Genetic Loxl2 disruption in mice, antibody-mediated inhibition, PI3K/AKT and TGF-β2 pathway analysis, cardiac function assessment, fibrosis quantification","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus antibody inhibition, defined signaling pathway (PI3K/AKT→TGF-β2), in vivo cardiac phenotype, replicated in human samples","pmids":["27966531"],"is_preprint":false},{"year":2016,"finding":"SMYD3 methyltransferase directly binds the promoter regions of EZR and LOXL2 and stimulates their transcription in esophageal squamous cell carcinoma, as demonstrated by chromatin immunoprecipitation assay.","method":"Chromatin immunoprecipitation (ChIP) assay, RNAi knockdown, immunohistochemistry correlation analysis","journal":"Human pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-demonstrated direct promoter binding, single lab","pmids":["26980013"],"is_preprint":false},{"year":2017,"finding":"LOXL2 overexpression accumulates in the endoplasmic reticulum where it interacts with HSPA5 (GRP78), leading to activation of the IRE1-XBP1 arm of the ER stress response; XBP1 then directly transcriptionally activates EMT transcription factors SNAI1, SNAI2, ZEB2, and TCF3; IRE1 inhibition blocks LOXL2-dependent EMT.","method":"Co-immunoprecipitation, ER fractionation, IRE1/XBP1 pathway analysis, ChIP for XBP1 at EMT-TF promoters, IRE1 pharmacological inhibition rescue experiment","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, subcellular fractionation, defined pathway with rescue experiment, multiple downstream targets validated","pmids":["28332555"],"is_preprint":false},{"year":2017,"finding":"LOXL2 mediates collagen crosslinking in fibrotic liver septa and promotes hepatic progenitor cell (HPC) differentiation towards ductal/fibrogenic fate; anti-LOXL2 antibody reduces collagen crosslinking, suppresses bridging fibrosis progression, and promotes fibrosis reversal; LOXL2 blockade in vitro directly shifts primary EpCAM+ HPC differentiation towards hepatocytes away from ductal lineage.","method":"Anti-LOXL2 monoclonal antibody treatment in multiple mouse fibrosis models (TAA, Mdr2-/-, DDC), collagen crosslinking biochemical assay, morphometric collagen quantification, primary EpCAM+ cell in vitro differentiation assay","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — antibody inhibition across 3 independent mouse models, biochemical crosslinking assay, in vitro mechanistic cell differentiation assay","pmids":["28073888"],"is_preprint":false},{"year":2017,"finding":"LOXL2 ablation in conditional transgenic mouse models dramatically decreases lung metastasis without affecting primary tumor ECM stiffness or organization, indicating a function independent of conventional ECM crosslinking; LOXL2 action is associated with elevated Snail1 levels and expression of cytokines promoting premetastatic niche formation.","method":"Conditional transgenic PyMT mouse models with LOXL2 ablation or overexpression, ECM stiffness measurement, Snail1 and cytokine expression analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic models (ablation and overexpression), ECM-independent function rigorously established, in vivo metastasis readout","pmids":["28720577"],"is_preprint":false},{"year":2018,"finding":"Higher matrix stiffness upregulates LOXL2 expression in HCC cells through the integrin β1/α5 → JNK/c-JUN signaling pathway; secreted LOXL2 promotes pre-metastatic niche formation by upregulating MMP9 and fibronectin production in lung fibroblasts via Akt pathway activation, and increasing CXCL12 expression and BMDC recruitment.","method":"Gel-based stiffness substrate system, integrin shRNA knockdown, JNK inhibitor treatment, shRNA-c-JUN knockdown, conditioned medium experiments, MMP9/fibronectin/CXCL12 western blot/ELISA","journal":"Journal of experimental & clinical cancer research : CR","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with genetic and pharmacological inhibitors, multiple downstream effectors validated, single lab","pmids":["29728125"],"is_preprint":false},{"year":2019,"finding":"Full-length LOXL2 has a rod-like structure with SRCR domains forming a stalk and the catalytic domain at the tip; LOXL2 directly binds tropoelastin and catalyzes its deamination to form crosslinked elastin-like material resistant to trypsin proteolysis with mechanical properties similar to mature elastin; specific allysine-containing cross-linked peptides were identified by proteomics.","method":"X-ray scattering, electron microscopy (low-resolution structure), surface plasmon resonance or equivalent binding assay, in vitro deamination assay, proteomics identification of crosslinked peptides","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural characterization combined with in vitro enzymatic reconstitution, substrate binding detection, and proteomics identification of reaction products","pmids":["30676771"],"is_preprint":false},{"year":2019,"finding":"LOXL2 and its catalytically inactive isoform L2Δ13 interact physically with actin-binding proteins ezrin (EZR), fascin (FSCN1), HSPB1, and TMOD3 in the cytoplasm; LOXL2 promotes phosphorylation of ezrin at T567 (requiring PKCα co-activity), which is critical for cytoskeletal reorganization and tumor cell invasion in esophageal squamous cell carcinoma.","method":"Interactome analysis (mass spectrometry), Co-IP validation, ezrin T567 phosphorylation western blot after LOXL2 depletion/re-expression, PKCα inhibitor experiment, in vivo tumor progression assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proteomic interactome validated by Co-IP, phosphorylation site defined, pharmacological dissection with PKCα inhibitor, in vivo validation","pmids":["31409639"],"is_preprint":false},{"year":2019,"finding":"LOXL2 interacts physically with GATA6 via its scavenger receptor cysteine-rich domain; the LOXL2/GATA6 complex regulates VEGFA mRNA expression and protein secretion, promoting angiogenesis in cholangiocarcinoma.","method":"Co-immunoprecipitation, domain mapping (SRCR domain), qRT-PCR and ELISA for VEGFA, tube formation assay, in vivo tumor growth assay","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with domain mapping, functional downstream readout, single lab","pmids":["31322171"],"is_preprint":false},{"year":2019,"finding":"LOXL2-mediated H3K4ox (oxidation of H3K4me3) is elevated in triple-negative breast cancer and is located primarily in heterochromatin; LOXL2 knockdown reduces H3K4ox, causing chromatin decompaction and sustained DNA damage response activation, increasing susceptibility to anticancer agents.","method":"ChIP-seq for H3K4ox, LOXL2 knockdown, ATAC-seq or chromatin accessibility assay, DNA damage response markers, drug sensitivity assays, patient-derived xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq genome-wide mapping, loss-of-function with defined chromatin and DDR phenotype, PDX validation, single lab","pmids":["31462706"],"is_preprint":false},{"year":2020,"finding":"Wnt signaling (via Wnt7b and Wnt9a, regulated by c-Fos/AP-1) promotes Loxl2 expression through transcription factors Zeb1 and Zeb2 in osteosarcoma; Loxl2 inhibition reduces osteosarcoma cell proliferation and decreases tumor growth and lung colonization in murine and human orthotopic models.","method":"Genetically modified mouse models (GEMMs), c-Fos promoter binding (ChIP), Wls gene inactivation, BAPN and specific Loxl2 shRNA/antibody inhibition, in vitro and in vivo proliferation and tumor assays","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — GEMM epistasis, direct promoter binding (ChIP), multiple inhibition modalities (chemical, genetic, antibody), in vivo tumor models","pmids":["32686768"],"is_preprint":false},{"year":2019,"finding":"LOXL4 (not LOXL2) is the critical determinant of pathological collagen crosslinking and fibrosis in the lung; genetic ablation of LOXL2 alone leads to only modest reduction in pathological collagen crosslinking without reducing fibrosis, while LOXL4 deletion markedly disrupts both; double knockout offers no additive effect over LOXL4 deletion alone.","method":"Genetic knockout of Loxl2 and/or Loxl4 in mouse pulmonary fibrosis model, collagen crosslinking biochemical assay, fibrosis quantification","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic ablation with clean negative result for LOXL2, rigorous comparison with LOXL4, double-KO epistasis","pmids":["37235663"],"is_preprint":false},{"year":2020,"finding":"LOXL2 upregulates HIF-1α signaling through the Snail-FBP1 axis in hepatocellular carcinoma: intracellular LOXL2 (requiring enzymatic activity, as the Y689F mutant lacks this effect) upregulates Snail, which represses FBP1, thereby enhancing glycolysis and HIF-1α/VEGF signaling; extracellular LOXL2 blockade by antibody does not abrogate this intracellular pathway.","method":"LOXL2 overexpression/silencing, LOXL2 Y689F catalytic mutant, anti-LOXL2 antibody, FBP1 knockdown, Snail western blot, HIF-1α/VEGF expression, LOXL2-IN-1 small molecule inhibitor","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant distinguishes mechanism, rescue experiments, intracellular vs. extracellular compartment distinction, single lab","pmids":["32323822"],"is_preprint":false},{"year":2020,"finding":"Nuclear LOXL2 in lung fibroblasts is upregulated by TGF-β1 treatment and is required for TGF-β1-induced proto-myofibroblast appearance and myofibroblast differentiation; LOXL2 silencing abrogates TGF-β1-induced nuclear Snail upregulation and myofibroblast evolution.","method":"Nuclear LOXL2 fractionation/immunostaining in vivo (ARDS model), TGF-β1 treatment of lung fibroblasts, LOXL2 siRNA silencing, Snail and myofibroblast marker expression","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular localization with functional consequence, loss-of-function with defined phenotype, in vivo and in vitro correlation, single lab","pmids":["33248114"],"is_preprint":false},{"year":2021,"finding":"LOXL2 stabilizes HIF-1α from prolyl hydroxylase (PHD)-dependent hydroxylation via hydrogen peroxide generation, creating a positive feedback loop that facilitates transcription of glycolytic genes and the Warburg effect in pancreatic ductal adenocarcinoma.","method":"LOXL2 overexpression/knockdown, HIF-1α stability assay (PHD inhibitor comparison), H2O2 measurement, glycolytic gene expression, metabolic flux analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined biochemical mechanism (H2O2-mediated PHD inhibition), feedback loop characterization, single lab","pmids":["34836938"],"is_preprint":false},{"year":2021,"finding":"Tumor-associated macrophage-secreted oncostatin M (OSM) induces LOXL2 expression in pancreatic cancer cells; Loxl2 loss in PDAC mouse models significantly decreases metastasis through non-cell-autonomous ECM remodeling effects; targeting macrophages in vivo reduces Osm and Loxl2 expression and collagen fiber alignment.","method":"Conditional GEMM (KPC/KCL2KO and KCL2KI mice), OSM treatment and macrophage depletion in vivo, ECM collagen fiber alignment analysis, metastasis quantification, overall survival analysis","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — GEMM models with both KO and KI, identified upstream inducer (OSM from macrophages), defined non-cell-autonomous ECM mechanism, multiple in vivo models","pmids":["35428659"],"is_preprint":false},{"year":2021,"finding":"LOXL2 promotes SNAIL expression to enable vasculogenic mimicry formation in hepatocellular carcinoma; LOXL2 overexpression significantly promotes migration, invasion, and tube formation in HCC cells.","method":"LOXL2 gain/loss-of-function in HCC cell lines, tube formation assay, SNAIL western blot, in vivo xenograft, CD31/PAS double staining in patient samples","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional assay with defined downstream effector (Snail), in vivo correlation, single lab","pmids":["30506621"],"is_preprint":false},{"year":2022,"finding":"LOXL2 and its catalytically inactive L2Δ13 isoform function as novel deacetylases: they directly catalyze deacetylation of aldolase A at K13, stimulating aldolase mobilization from the actin cytoskeleton, enhancing glycolytic activity, and promoting metabolic reprogramming and tumor progression in esophageal cancer.","method":"SILAC proteomics, in vitro deacetylation assay, aldolase A K13 acetylation-specific antibody, aldolase activity assay, actin cytoskeleton fractionation, knock-in mouse model metabolomics/transcriptomics","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with substrate site identification, proteomic validation, knock-in mouse model with metabolomics, multiple orthogonal methods","pmids":["36209516"],"is_preprint":false},{"year":2022,"finding":"TRIM44 directly binds LOXL2 and regulates its protein stability via ubiquitination; TRIM44-mediated LOXL2 stabilization promotes ECM remodeling that modulates T-cell-mediated antitumor immunity in gastric cancer.","method":"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay, in vivo tumor immunity assay","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay demonstrate binding and PTM regulation, functional in vivo immune readout, single lab","pmids":["36512309"],"is_preprint":false},{"year":2022,"finding":"LOXL2 in rhabdomyosarcoma promotes cell migration, invasion, and lung metastasis independently of catalytic activity; vimentin was identified as a LOXL2-interacting cytoskeletal protein by pull-down/mass spectrometry, suggesting regulation of cytoskeleton dynamics as the mechanism.","method":"Stable LOXL2 knockdown, wild-type and catalytically inactive LOXL2 overexpression, in vivo metastasis assay, pull-down assay with mass spectrometry, vimentin validation","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant establishes independence from enzymatic activity, mass spectrometry interactor identification, in vivo metastasis, single lab","pmids":["31911079"],"is_preprint":false},{"year":2023,"finding":"LOXL2, MMP9, and LCN2 form a ternary protein complex; LCN2-LOXL2 and LCN2-MMP9 interactions occur both intracellularly and extracellularly, while LOXL2-MMP9 interactions only occur intracellularly; the complex promotes fibronectin and Matrigel degradation, filopodia formation, microfilament rearrangement via profilin 1 upregulation, and activates FAK/AKT/GSK3β signaling.","method":"Co-immunoprecipitation (intracellular and extracellular fractions), cell migration/invasion assays, filopodia imaging, signaling pathway western blot, in vivo tumor growth assay","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with compartment distinction, defined complex, multiple downstream pathway readouts, single lab","pmids":["37753805"],"is_preprint":false},{"year":2024,"finding":"RPS7 stabilizes LOXL2 mRNA by binding to AUUUA motifs in the 3155–3375 region of the LOXL2 3'UTR, increasing LOXL2 mRNA abundance; elevated LOXL2 then maintains ITGB1 protein stability and activates ITGB1-mediated FAK/SRC signaling, promoting HCC metastasis.","method":"RNA-binding protein immunoprecipitation (RIP), RNA-pulldown, dual luciferase reporter assay, LOXL2 mRNA decay assay, nascent RNA capture, ITGB1 protein stability assay, FAK/SRC phosphorylation western blot, in vivo lung metastasis model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal RNA binding assays (RIP, pulldown, luciferase, decay), defined mRNA stabilization mechanism, downstream signaling validated, in vivo","pmids":["38326908"],"is_preprint":false}],"current_model":"LOXL2 is a multifunctional copper-dependent lysine tyrosylquinone amine oxidase that operates both extracellularly and intracellularly: extracellularly it crosslinks collagen (via lysine oxidation/deamination) and tropoelastin to remodel the ECM and drive fibrosis and metastatic niche formation; intracellularly it deaminates H3K4me3 and TAF10 to regulate gene transcription (including E-cadherin repression), deacetylates glycolytic enzymes (aldolase A at K13) to reprogram tumor metabolism, accumulates in the ER to activate IRE1-XBP1 signaling and induce EMT transcription factors, stabilizes Snail1 from GSK3β-dependent degradation, interacts with E47 to repress E-cadherin, promotes cytoskeletal reorganization via ezrin phosphorylation and vimentin interaction, and activates integrin/FAK/Src and PI3K/AKT signaling; many of these intracellular functions do not require its catalytic amine oxidase activity, revealing a dual enzymatic/non-enzymatic biology that governs fibrosis, EMT, metastasis, and metabolic reprogramming."},"narrative":{"mechanistic_narrative":"LOXL2 is a copper-dependent lysyl oxidase-like amine oxidase that drives fibrosis, epithelial-to-mesenchymal transition (EMT), and metastasis through both catalytic and non-catalytic activities operating across extracellular, cytoplasmic, and nuclear compartments [PMID:10212285, PMID:19625348, PMID:28720577]. Structurally it forms a rod-like molecule with scavenger-receptor cysteine-rich (SRCR) domains forming a stalk and the catalytic domain at the tip; it binds and deaminates tropoelastin to generate crosslinked elastin-like material [PMID:30676771], and is the principal isoform crosslinking and stabilizing insoluble collagen in tumor tissue, thereby activating focal-adhesion/FAK/SRC signaling in mesenchymal cells [PMID:27694892]. Extracellularly, secreted LOXL2 remodels the matrix and the metastatic niche by activating stromal fibroblasts via integrin/FAK signaling [PMID:24008674], modulating TIMP-1/MMP9 [PMID:21233336], and—in cardiac and hepatic fibrosis—stimulating PI3K/AKT and TGF-β2 to drive myofibroblast transformation and collagen crosslinking [PMID:27966531, PMID:28073888]. A central oncogenic axis is the stabilization and induction of the EMT transcription factor Snail1: LOXL2 attenuates GSK3β-dependent Snail1 degradation [PMID:16294032] and, when accumulated in the ER, binds HSPA5/GRP78 to activate IRE1-XBP1 signaling that transcriptionally induces SNAI1/SNAI2/ZEB2/TCF3 [PMID:28332555], repressing E-cadherin in cooperation with E47 [PMID:24632622]. Several of these intracellular functions are independent of catalytic activity, as catalytically inactive mutants and the L2Δ13 isoform still repress E-cadherin, activate FAK/Src, and promote invasion [PMID:22157764, PMID:24414204, PMID:31911079]. Catalytic activities include unconventional chemistry: oxidative deamination of trimethylated TAF10 to release it from TFIID-controlled promoters [PMID:25959397], deamination of H3K4me3 (H3K4ox) that organizes heterochromatin and restrains the DNA-damage response [PMID:27735137, PMID:31462706], and deacetylation of aldolase A at K13 to reprogram glycolysis [PMID:36209516]. LOXL2 expression is itself controlled by hypoxia/HIF-1, ZEB1/miR-200, SMYD3, and Wnt signaling [PMID:20026874, PMID:27694892, PMID:26980013, PMID:32686768], and its protein and mRNA levels are tuned by TRIM44-mediated ubiquitination and RPS7-mediated mRNA stabilization [PMID:36512309, PMID:38326908]. Genetic ablation studies indicate that in lung fibrosis LOXL2 is dispensable for pathological collagen crosslinking—LOXL4 being the critical isoform—while in mammary and pancreatic metastasis LOXL2 acts through ECM-independent niche-forming and Snail1-linked mechanisms [PMID:28720577, PMID:37235663, PMID:35428659].","teleology":[{"year":1999,"claim":"Established LOXL2 as a distinct lysyl oxidase-family amine oxidase and raised the possibility of non-canonical processing/localization because its first exon lacks a signal sequence.","evidence":"cDNA cloning, gene structure analysis, in situ hybridization, and sequence homology","pmids":["10212285"],"confidence":"High","gaps":["No functional substrate identified at this stage","Subcellular localization inferred from sequence, not measured","Catalytic activity not biochemically demonstrated"]},{"year":2005,"claim":"Connected LOXL2 to EMT by showing it stabilizes Snail1 against GSK3β-dependent degradation, providing a transcriptional route to E-cadherin repression.","evidence":"Co-immunoprecipitation and functional interaction assays linking LOXL2, GSK3β, and Snail1","pmids":["16294032"],"confidence":"Medium","gaps":["Whether catalytic activity is required not addressed here","Single-lab interaction without reciprocal structural mapping","Mechanism of GSK3β attenuation unresolved"]},{"year":2009,"claim":"Resolved that LOXL2 acts in two compartments—secreted LOXL2 drives invasion via Src/FAK while intracellular LOXL2 engages the Snail/E-cadherin pathway—and showed antibody blockade of secreted LOXL2 is therapeutically tractable.","evidence":"RNAi, overexpression, Src/FAK western blot, xenografts, and anti-LOXL2 antibody in gastric cancer","pmids":["19625348"],"confidence":"High","gaps":["Molecular target of secreted LOXL2 on the cell surface not defined","Catalytic dependence of each compartmental activity untested"]},{"year":2009,"claim":"Placed LOXL2 downstream of hypoxia by identifying it as a direct HIF-1 target necessary and sufficient for hypoxic E-cadherin repression and invasion.","evidence":"HIF-1 binding analysis, gain/loss-of-function, and invasion assays under hypoxia","pmids":["20026874"],"confidence":"High","gaps":["Mechanism linking LOXL2 to E-cadherin repression under hypoxia not dissected here","Relative contribution of LOX vs LOXL2 not separated"]},{"year":2010,"claim":"Extended LOXL2 function to normal development, showing it is the major chondrocyte lysyl oxidase required for differentiation via SNAIL/SOX9 regulation.","evidence":"LOX-isoform expression profiling in fracture healing and LOXL2 knockdown in ATDC5 cells","pmids":["21071451"],"confidence":"Medium","gaps":["Catalytic requirement not tested","In vivo developmental phenotype not established here"]},{"year":2011,"claim":"Demonstrated that LOXL2's pro-invasive and differentiation-suppressing activities can be catalytic-independent, mapping a non-enzymatic function to the fourth SRCR domain.","evidence":"Catalytically inactive Y689F and domain-deletion mutants, BAPN inhibitor, AB0023 antibody, and involucrin/TIMP1/MMP9 readouts","pmids":["22157764","21233336"],"confidence":"High","gaps":["Molecular partners of the SRCR domain not identified at this stage","How a non-catalytic LOXL2 modulates MMP9/TIMP1 not mechanistically defined"]},{"year":2011,"claim":"Showed cytoplasmic/perinuclear LOXL2 actively maintains the mesenchymal state by repressing polarity and tight-junction genes (Lgl2, claudin-1), with silencing reverting cells toward an epithelial phenotype.","evidence":"LOXL2 silencing, gene expression, polarity/tight-junction immunofluorescence, and tumorigenicity assays in basal-like breast cells","pmids":["21732535"],"confidence":"Medium","gaps":["Direct vs indirect transcriptional control of Lgl2/claudin-1 unresolved","Nuclear targeting mechanism not defined"]},{"year":2013,"claim":"Defined LOXL2 as a tumor-stroma signal: secreted LOXL2 activates fibroblasts through integrin/FAK and, through ROS, activates ErbB2 to disrupt epithelial morphogenesis.","evidence":"Recombinant LOXL2 on collagen matrices, FAK phosphorylation, α-SMA staining, 3D acinar cultures, ROS/ErbB2 analysis with pharmacologic rescue","pmids":["24008674","23971878"],"confidence":"High","gaps":["Integrin receptor identity engaged by LOXL2 not pinned down","Source of ROS (catalytic byproduct vs indirect) not defined here"]},{"year":2014,"claim":"Consolidated the non-catalytic, partner-dependent transcriptional role of LOXL2, showing inactive mutants cooperate with Snail1 and E47 to repress E-cadherin and that LOXL2 directly programs metastatic-niche cytokines.","evidence":"Catalytic-mutant overexpression, reciprocal Co-IP with E47, E-cadherin promoter luciferase, FAK/Src blots, and in vivo lung metastasis/BMDC recruitment assays","pmids":["24414204","24632622"],"confidence":"High","gaps":["Stoichiometry/architecture of LOXL2–E47 transcriptional complex unknown","Direct vs cofactor role at cytokine promoters not fully separated"]},{"year":2014,"claim":"Broadened the cytoplasmic interactome and downstream signaling, linking LOXL2 to integrin turnover, MARCKSL1-dependent survival signaling, and an enzymatically impaired splice isoform with distinct pro-invasive wiring.","evidence":"Co-IP/domain mapping (MARCKSL1, SRCR), protease/proteasome inhibitor experiments on integrins, FAK/Akt/mTOR blots, and Δe13 isoform MAPK8-dependent rescue","pmids":["24863880","25092917","25275797"],"confidence":"Medium","gaps":["Single-lab Co-IPs without structural validation","How LOXL2 controls integrin proteolysis mechanistically unclear","Generality of Δe13 isoform across tumors untested"]},{"year":2016,"claim":"Revealed an unconventional catalytic biology in which recombinant LOXL2 deaminates H3K4me3, providing a chemical mechanism for histone modification tied to CDH1 transcription.","evidence":"In vitro deamination with recombinant LOXL2, infrared spectroscopy, mass spectrometry, and CDH1 transcription analysis","pmids":["27735137"],"confidence":"High","gaps":["Genome-wide distribution of the mark not yet mapped here","Reader/effector of H3K4ox unidentified at this stage"]},{"year":2015,"claim":"Identified a non-histone nuclear substrate, showing LOXL2 oxidizes methylated TAF10 to evict it from TFIID-dependent promoters, with developmental consequences for pluripotency and neural differentiation.","evidence":"Unbiased proteomic substrate ID, in vitro oxidation, ChIP-seq, ES-cell pluripotency analysis, and zebrafish loss-of-function","pmids":["25959397"],"confidence":"High","gaps":["Breadth of methylated protein substrates beyond TAF10 unknown","How nuclear LOXL2 is targeted to specific promoters not defined"]},{"year":2016,"claim":"Established upstream control of LOXL2 by the ZEB1/miR-200 EMT axis and confirmed LOXL2 as the principal collagen-crosslinking isoform that feeds back into FAK/SRC signaling during metastasis.","evidence":"miR-200/ZEB1 gain/loss-of-function, collagen solubility assays, FAK/SRC blots, and in vivo metastasis; SMYD3 ChIP identifying direct promoter binding","pmids":["27694892","26980013"],"confidence":"High","gaps":["Whether crosslinking and signaling effects are separable not resolved","Tissue-context dependence of these regulators not mapped"]},{"year":2016,"claim":"Demonstrated LOXL2's pathogenic role in cardiac fibrosis, with secreted LOXL2 stimulating fibroblasts through PI3K/AKT to produce TGF-β2 and drive myofibroblast transformation.","evidence":"Genetic Loxl2 disruption and antibody inhibition in mice, PI3K/AKT-TGF-β2 pathway analysis, cardiac function and fibrosis quantification with human-sample replication","pmids":["27966531"],"confidence":"High","gaps":["Receptor mediating LOXL2-to-fibroblast signaling not identified","Catalytic dependence of the cardiac effect not tested"]},{"year":2017,"claim":"Defined an ER-stress route to EMT, in which accumulated LOXL2 binds HSPA5/GRP78 to activate IRE1-XBP1, which transcriptionally induces multiple EMT transcription factors.","evidence":"Reciprocal Co-IP, ER fractionation, IRE1/XBP1 pathway analysis, XBP1 ChIP at EMT-TF promoters, and IRE1 inhibitor rescue","pmids":["28332555"],"confidence":"High","gaps":["What triggers ER accumulation of LOXL2 unclear","Catalytic requirement of HSPA5 engagement untested"]},{"year":2017,"claim":"Distinguished LOXL2's metastasis-promoting function from canonical ECM crosslinking using conditional models in breast and showed a parallel ECM-crosslinking role in liver fibrosis and progenitor-cell fate.","evidence":"Conditional PyMT ablation/overexpression with ECM stiffness measurement; anti-LOXL2 antibody across TAA/Mdr2/DDC liver models with crosslinking assays and EpCAM+ HPC differentiation","pmids":["28720577","28073888"],"confidence":"High","gaps":["Mechanism of ECM-independent metastatic function not fully resolved","Whether liver and breast functions share effectors unknown"]},{"year":2018,"claim":"Closed a mechanotransduction loop in which matrix stiffness induces LOXL2 via integrin β1/β5→JNK/c-JUN, and secreted LOXL2 builds the pre-metastatic niche through MMP9, fibronectin, CXCL12, and BMDC recruitment.","evidence":"Tunable-stiffness substrates, integrin shRNA, JNK inhibitor, c-JUN knockdown, conditioned-medium experiments, and effector quantification in HCC","pmids":["29728125"],"confidence":"High","gaps":["Direct vs indirect transcriptional control of niche factors not separated","Single-lab characterization"]},{"year":2019,"claim":"Provided the structural basis for LOXL2 architecture and demonstrated direct tropoelastin binding and deamination producing elastin-like crosslinked material, defining a bona fide ECM crosslinking substrate.","evidence":"X-ray scattering, electron microscopy, binding assay, in vitro deamination, and proteomic identification of crosslinked peptides","pmids":["30676771"],"confidence":"High","gaps":["High-resolution catalytic-site structure not obtained","In vivo elastin crosslinking by LOXL2 not demonstrated here"]},{"year":2019,"claim":"Linked LOXL2 to cytoskeletal control by identifying actin-binding partners (ezrin, fascin, HSPB1, TMOD3, vimentin) and showing PKCα-dependent ezrin T567 phosphorylation drives invasion, including catalytic-independent metastasis.","evidence":"MS interactome with Co-IP validation, ezrin phosphorylation blots, PKCα inhibitor, vimentin pull-down/MS, and in vivo metastasis with catalytic-inactive mutants","pmids":["31409639","31911079"],"confidence":"Medium","gaps":["Direct vs indirect role of LOXL2 in ezrin phosphorylation unclear","Whether vimentin interaction is functionally required not established"]},{"year":2019,"claim":"Added a transcription-promoting partnership in which LOXL2 binds GATA6 via its SRCR domain to upregulate VEGFA and angiogenesis in cholangiocarcinoma.","evidence":"Co-IP, SRCR-domain mapping, VEGFA qRT-PCR/ELISA, tube formation, and in vivo tumor growth","pmids":["31322171"],"confidence":"Medium","gaps":["Single Co-IP-based interaction without structural validation","Direct LOXL2 action at VEGFA locus not shown"]},{"year":2019,"claim":"Mapped genome-wide H3K4ox to heterochromatin in triple-negative breast cancer and showed LOXL2 loss decompacts chromatin and sustains DNA-damage signaling, sensitizing cells to therapy.","evidence":"H3K4ox ChIP-seq, chromatin accessibility assays, DDR markers, drug-sensitivity, and PDX models","pmids":["31462706"],"confidence":"High","gaps":["Mechanism targeting LOXL2 to heterochromatin unknown","Reader of H3K4ox still unidentified"]},{"year":2020,"claim":"Connected LOXL2 to glycolytic reprogramming via a catalysis-dependent Snail-FBP1 axis that elevates HIF-1α/VEGF signaling, distinguishing intracellular from extracellular function.","evidence":"Overexpression/silencing, Y689F catalytic mutant, anti-LOXL2 antibody, FBP1 knockdown, and HIF-1α/VEGF readouts with LOXL2-IN-1 in HCC","pmids":["32323822"],"confidence":"Medium","gaps":["Direct enzymatic step in the Snail-FBP1 axis not pinpointed","Single-lab study"]},{"year":2020,"claim":"Identified upstream Wnt control of LOXL2 in osteosarcoma and a TGF-β1-driven nuclear LOXL2 requirement for myofibroblast differentiation, reinforcing both transcriptional regulation and a nuclear Snail-linked fibrotic role.","evidence":"GEMMs with c-Fos ChIP and Wls inactivation, BAPN/shRNA/antibody inhibition for osteosarcoma; nuclear LOXL2 fractionation, TGF-β1 treatment, and siRNA silencing in lung fibroblasts","pmids":["32686768","33248114"],"confidence":"High","gaps":["How nuclear LOXL2 controls Snail in fibroblasts not mechanistically defined","Catalytic dependence of nuclear fibrotic function untested"]},{"year":2021,"claim":"Established LOXL2 as a redox driver of the Warburg effect, generating hydrogen peroxide that stabilizes HIF-1α against PHD hydroxylation in a feedforward loop, and linked LOXL2 induction to macrophage-derived OSM in pancreatic cancer.","evidence":"Overexpression/knockdown with HIF-1α stability and H2O2 assays and metabolic flux in PDAC; conditional GEMMs (KPC/KCL2KO/KCL2KI) with OSM treatment, macrophage depletion, and ECM/metastasis analysis","pmids":["34836938","35428659"],"confidence":"High","gaps":["Whether H2O2 production is the catalytic byproduct of substrate oxidation not directly shown","Coupling between redox and ECM functions unclear"]},{"year":2021,"claim":"Reinforced the Snail-driven, non-ECM-crosslinking oncogenic outputs of LOXL2 by showing it promotes vasculogenic mimicry through SNAIL upregulation in HCC.","evidence":"Gain/loss-of-function, tube formation, SNAIL blots, xenografts, and CD31/PAS staining in patient samples","pmids":["30506621"],"confidence":"Medium","gaps":["Catalytic requirement not tested","Single-lab study"]},{"year":2022,"claim":"Uncovered a moonlighting deacetylase activity, showing LOXL2 (and L2Δ13) deacetylates aldolase A at K13 to mobilize it from actin and enhance glycolysis, broadening LOXL2's catalytic repertoire beyond amine oxidation.","evidence":"SILAC proteomics, in vitro deacetylation, K13-acetylation antibody, aldolase activity/fractionation, and knock-in mouse metabolomics/transcriptomics in esophageal cancer","pmids":["36209516"],"confidence":"High","gaps":["Catalytic mechanism for deacetylation by an amine oxidase fold unresolved","Substrate scope of LOXL2 deacetylase activity unknown"]},{"year":2022,"claim":"Defined post-translational control of LOXL2 levels by TRIM44-mediated ubiquitination, linking LOXL2 stability to ECM remodeling and antitumor immunity in gastric cancer.","evidence":"Co-IP, co-localization, ubiquitination assay, and in vivo tumor immunity assays","pmids":["36512309"],"confidence":"Medium","gaps":["Whether TRIM44 stabilizes or destabilizes LOXL2 ubiquitin chains needs clarification","Single-lab interaction"]},{"year":2023,"claim":"Showed LOXL2 functions within a LOXL2-MMP9-LCN2 ternary complex with compartment-specific assembly that drives matrix degradation, filopodia formation, and FAK/AKT/GSK3β signaling.","evidence":"Compartment-resolved Co-IP, migration/invasion assays, filopodia imaging, profilin-1 analysis, signaling blots, and in vivo tumor growth","pmids":["37753805"],"confidence":"Medium","gaps":["Direct vs bridged interactions within the ternary complex not fully resolved","Single-lab characterization"]},{"year":2023,"claim":"Refined isoform specificity in fibrosis by showing that, in lung, LOXL4—not LOXL2—is the critical determinant of pathological collagen crosslinking, with LOXL2 ablation giving only modest effects.","evidence":"Single and double Loxl2/Loxl4 knockouts in pulmonary fibrosis with crosslinking biochemistry and fibrosis quantification","pmids":["37235663"],"confidence":"High","gaps":["Whether LOXL2 contributes to non-crosslinking fibrotic functions in lung not addressed","Tissue-specific division of labor among LOX isoforms incompletely mapped"]},{"year":2024,"claim":"Added mRNA-level control, showing RPS7 binds AUUUA motifs in the LOXL2 3'UTR to stabilize its transcript, raising LOXL2 protein that sustains ITGB1 and activates ITGB1/FAK/SRC signaling in HCC metastasis.","evidence":"RIP, RNA-pulldown, luciferase, mRNA-decay and nascent-RNA assays, ITGB1 stability assays, FAK/SRC blots, and in vivo metastasis","pmids":["38326908"],"confidence":"High","gaps":["Whether RPS7 control of LOXL2 operates broadly across tissues unknown","Mechanism by which LOXL2 stabilizes ITGB1 protein not detailed"]},{"year":null,"claim":"How LOXL2's multiple catalytic activities (amine oxidation of ECM substrates, deamination of TAF10/H3K4me3, and deacetylation of aldolase A) and its catalytic-independent scaffolding functions are partitioned across subcellular compartments, and what governs its localization to ER, nucleus, cytoskeleton, and extracellular space, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model for compartmental targeting of LOXL2","Structural basis for how one fold catalyzes oxidation and deacetylation undefined","Which functions are therapeutically separable by enzyme inhibition vs antibody blockade unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,15,16,24,32]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[15,16,35]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11,26,27]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[16,27]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[25,37]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,8,24]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,25,38]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15,27,31]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[20]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[17,21,24]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[17,21,24,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,8,18,23,39]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[15,16,27]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,15]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[30,32,35]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,18,21,33]}],"complexes":["LOXL2-MMP9-LCN2 ternary complex"],"partners":["SNAI1","E47 (TCF3)","HSPA5","EZR","VIM","GATA6","TRIM44","MMP9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y4K0","full_name":"Lysyl oxidase homolog 2","aliases":["Lysyl oxidase-like protein 2","Lysyl oxidase-related protein 2","Lysyl oxidase-related protein WS9-14"],"length_aa":774,"mass_kda":86.7,"function":"Mediates the post-translational oxidative deamination of lysine residues on target proteins leading to the formation of deaminated lysine (allysine) (PubMed:27735137). Acts as a transcription corepressor and specifically mediates deamination of trimethylated 'Lys-4' of histone H3 (H3K4me3), a specific tag for epigenetic transcriptional activation (PubMed:27735137). Shows no activity against histone H3 when it is trimethylated on 'Lys-9' (H3K9me3) or 'Lys-27' (H3K27me3) or when 'Lys-4' is monomethylated (H3K4me1) or dimethylated (H3K4me2) (PubMed:27735137). Also mediates deamination of methylated TAF10, a member of the transcription factor IID (TFIID) complex, which induces release of TAF10 from promoters, leading to inhibition of TFIID-dependent transcription (PubMed:25959397). LOXL2-mediated deamination of TAF10 results in transcriptional repression of genes required for embryonic stem cell pluripotency including POU5F1/OCT4, NANOG, KLF4 and SOX2 (By similarity). Involved in epithelial to mesenchymal transition (EMT) via interaction with SNAI1 and participates in repression of E-cadherin CDH1, probably by mediating deamination of histone H3 (PubMed:16096638, PubMed:24414204, PubMed:27735137). During EMT, involved with SNAI1 in negatively regulating pericentromeric heterochromatin transcription (PubMed:24239292). SNAI1 recruits LOXL2 to pericentromeric regions to oxidize histone H3 and repress transcription which leads to release of heterochromatin component CBX5/HP1A, enabling chromatin reorganization and acquisition of mesenchymal traits (PubMed:24239292). Interacts with the endoplasmic reticulum protein HSPA5 which activates the IRE1-XBP1 pathway of the unfolded protein response, leading to expression of several transcription factors involved in EMT and subsequent EMT induction (PubMed:28332555). Involved in E-cadherin repression following hypoxia, a hallmark of EMT believed to amplify tumor aggressiveness, suggesting that it may play a role in tumor progression (PubMed:20026874). When secreted into the extracellular matrix, promotes cross-linking of extracellular matrix proteins by mediating oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin (PubMed:20306300). Acts as a regulator of sprouting angiogenesis, probably via collagen IV scaffolding (PubMed:21835952). Acts as a regulator of chondrocyte differentiation, probably by regulating expression of factors that control chondrocyte differentiation (By similarity)","subcellular_location":"Secreted, extracellular space, extracellular matrix, basement membrane; Nucleus; Chromosome; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q9Y4K0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LOXL2","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/LOXL2","total_profiled":1310},"omim":[{"mim_id":"619066","title":"ZINC FINGER PROTEIN 532; ZNF532","url":"https://www.omim.org/entry/619066"},{"mim_id":"610782","title":"MICRO RNA 29A; MIR29A","url":"https://www.omim.org/entry/610782"},{"mim_id":"607318","title":"LYSYL OXIDASE-LIKE 4; LOXL4","url":"https://www.omim.org/entry/607318"},{"mim_id":"607163","title":"LYSYL OXIDASE-LIKE 3; LOXL3","url":"https://www.omim.org/entry/607163"},{"mim_id":"606663","title":"LYSYL OXIDASE-LIKE 2; LOXL2","url":"https://www.omim.org/entry/606663"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"smooth muscle","ntpm":38.5}],"url":"https://www.proteinatlas.org/search/LOXL2"},"hgnc":{"alias_symbol":["WS9-14","LOR"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y4K0","domains":[{"cath_id":"3.10.250.10","chopping":"58-168","consensus_level":"high","plddt":91.541,"start":58,"end":168},{"cath_id":"3.10.250.10","chopping":"186-303","consensus_level":"high","plddt":85.0317,"start":186,"end":303},{"cath_id":"3.10.250.10","chopping":"327-426","consensus_level":"high","plddt":94.3537,"start":327,"end":426},{"cath_id":"3.10.250.10","chopping":"432-545","consensus_level":"high","plddt":90.0016,"start":432,"end":545},{"cath_id":"-","chopping":"551-753","consensus_level":"high","plddt":93.6975,"start":551,"end":753}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4K0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4K0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4K0-F1-predicted_aligned_error_v6.png","plddt_mean":86.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LOXL2","jax_strain_url":"https://www.jax.org/strain/search?query=LOXL2"},"sequence":{"accession":"Q9Y4K0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y4K0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y4K0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4K0"}},"corpus_meta":[{"pmid":"28073888","id":"PMC_28073888","title":"Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal.","date":"2017","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/28073888","citation_count":229,"is_preprint":false},{"pmid":"20026874","id":"PMC_20026874","title":"The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20026874","citation_count":218,"is_preprint":false},{"pmid":"21233336","id":"PMC_21233336","title":"LOXL2-mediated matrix remodeling in metastasis and mammary gland involution.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21233336","citation_count":212,"is_preprint":false},{"pmid":"27966531","id":"PMC_27966531","title":"Targeting LOXL2 for cardiac interstitial fibrosis and heart failure 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37275755","citation_count":15,"is_preprint":false},{"pmid":"37056396","id":"PMC_37056396","title":"Dihydroartemisinin Potentiates VEGFR-TKIs Antitumorigenic Effect on Osteosarcoma by Regulating Loxl2/VEGFA Expression and Lipid Metabolism Pathway.","date":"2023","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37056396","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56027,"output_tokens":10189,"usd":0.160458,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20759,"output_tokens":9756,"usd":0.173847,"stage2_stop_reason":"end_turn"},"total_usd":0.334305,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"LOXL2 encodes a new lysyl oxidase-like amine oxidase with conserved copper-binding and catalytic domains; unlike LOX and LOXL, exon 1 of LOXL2 does not encode a signal sequence, suggesting different processing and intracellular localization. The protein has four divergent N-terminal exons and five conserved C-terminal exons encoding the catalytic domain.\",\n      \"method\": \"cDNA cloning, gene structure analysis, in situ hybridization, sequence homology analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — primary molecular characterization with multiple orthogonal methods (sequencing, gene structure, expression), foundational paper replicated by subsequent work\",\n      \"pmids\": [\"10212285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LOXL2 physically interacts with and functionally stabilizes the EMT transcription factor Snail1 by attenuating GSK3β-dependent phosphorylation and subsequent ubiquitination/degradation of Snail1, thereby promoting E-cadherin repression and EMT.\",\n      \"method\": \"Co-immunoprecipitation, functional interaction assays, discussion of epistasis between LOXL2 and GSK3β in Snail regulation\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — physical interaction reported, mechanistic model described; single lab, limited orthogonal methods in this paper specifically\",\n      \"pmids\": [\"16294032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Secreted extracellular LOXL2 promotes gastric cancer invasion and metastasis via the Src/FAK signaling pathway, whereas intracellular LOXL2 also activates the Snail/E-cadherin pathway; antibody blockade of secreted LOXL2 inhibits tumor growth and metastasis.\",\n      \"method\": \"RNA interference knockdown, ectopic overexpression, Src/FAK western blot, in vivo xenograft, anti-LOXL2 antibody treatment\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function, in vivo validation, pathway analysis by western blot, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19625348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LOX and LOXL2 are direct transcriptional targets of HIF-1 under hypoxia; their activation is necessary and sufficient for hypoxic repression of E-cadherin, mediating epithelial-to-mesenchymal transition and cellular invasion.\",\n      \"method\": \"HIF-1 transcription factor binding analysis, gene expression assays, cellular invasion assays, gain/loss-of-function experiments under hypoxic conditions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional target identification, necessity and sufficiency demonstrated via gain/loss-of-function, functional invasion readout\",\n      \"pmids\": [\"20026874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LOXL2 is the major lysyl oxidase isoform expressed in chondrocytes during fracture healing; LOXL2 knockdown in ATDC5 chondrogenic cells impairs differentiation by altering expression of SNAIL and SOX9, demonstrating LOXL2 is required for chondrocyte differentiation.\",\n      \"method\": \"Expression profiling of LOX isoforms in fracture healing, in vitro LOXL2 knockdown in chondrogenic cell line, gene expression analysis of SNAIL and SOX9\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and downstream transcription factor readout, single lab\",\n      \"pmids\": [\"21071451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LOXL2 promotes breast cancer invasion by regulating expression and activity of TIMP-1 and MMP9 in the extracellular environment; genetic, chemical, or antibody-mediated inhibition of LOXL2 reduces metastasis in orthotopic and transgenic models.\",\n      \"method\": \"Genetic knockdown, chemical inhibition, antibody inhibition, in vivo orthotopic and transgenic breast cancer models, protein expression analysis of TIMP1/MMP9\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal inhibition strategies (genetic, chemical, antibody), in vivo validation, mechanistic effectors identified\",\n      \"pmids\": [\"21233336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cytoplasmic/perinuclear LOXL2 maintains mesenchymal phenotype in basal-like breast carcinoma cells through transcriptional downregulation of Lgl2 and claudin-1, causing disorganization of cell polarity and tight junction complexes; LOXL2 silencing induces mesenchymal-to-epithelial transition.\",\n      \"method\": \"LOXL2 silencing, gene expression analysis, immunofluorescence of polarity/tight junction markers, in vivo tumorigenicity assay\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotypic readout and downstream gene targets, single lab\",\n      \"pmids\": [\"21732535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LOXL2 inhibition in enzymatic activity assays using catalytically inactive mutants (LOXL2 Y689F) and deletion of catalytic domain still inhibits keratinocyte differentiation, demonstrating the enzymatic activity of LOXL2 is not required for inhibition of keratinocyte differentiation; this activity requires the fourth SRCR domain.\",\n      \"method\": \"Catalytically inactive point mutant (Y689F), catalytic domain deletion mutant, β-aminopropionitrile enzymatic inhibitor, AB0023 function-blocking antibody, involucrin expression as differentiation readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis with multiple mutants, chemical inhibitor controls, domain deletion, clear catalytic vs. non-catalytic function separation\",\n      \"pmids\": [\"22157764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tumor-secreted LOXL2 activates stromal fibroblasts through integrin-mediated focal adhesion kinase (FAK) activation, inducing α-SMA expression, fibroblast branching on collagen matrices, collagen contraction, and fibroblast invasion.\",\n      \"method\": \"In vitro fibroblast activation assays on collagen matrices, recombinant LOXL2 treatment, FAK phosphorylation western blot, α-SMA immunostaining, in vivo orthotopic tumor models with LOXL2 manipulation\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein functional assay, in vitro and in vivo validation, defined signaling pathway (integrin/FAK), multiple readouts\",\n      \"pmids\": [\"24008674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LOXL2 induces aberrant acinar morphogenesis in normal mammary epithelial cells through production of reactive oxygen species (ROS) that activates ErbB2; ErbB2 inhibition (Herceptin, lapatinib) abrogates LOXL2-induced abnormal proliferation, disrupted polarity and lumen formation.\",\n      \"method\": \"LOXL2 overexpression in MCF10A 3D acinar cultures, ROS measurement, ErbB2 phosphorylation analysis, pharmacological ErbB2 inhibition, invasion assays\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined mechanistic pathway (ROS→ErbB2), rescue experiments with inhibitors, single lab\",\n      \"pmids\": [\"23971878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Catalytically inactive LOXL2 mutants collaborate with Snail1 in E-cadherin gene repression and promote FAK/Src pathway activation to trigger EMT, demonstrating a non-catalytic role of LOXL2 in regulating epithelial cell plasticity.\",\n      \"method\": \"Catalytically inactive LOXL2 mutant overexpression, E-cadherin promoter activity assays, FAK/Src phosphorylation western blot, EMT marker analysis\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis approach, defined pathway activation, single lab\",\n      \"pmids\": [\"24414204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LOXL2 interacts with the bHLH transcription factor E47 and functionally collaborates in repression of the E-cadherin promoter; LOXL2 and E47 together regulate recruitment of bone marrow progenitor cells to lungs and directly transcriptionally regulate fibronectin and cytokines TNFα, ANG-1 and GM-CSF during metastatic colonization.\",\n      \"method\": \"Co-immunoprecipitation, E-cadherin promoter luciferase assay, loss/gain-of-function in syngeneic breast cancer models, in vivo lung metastasis assay, bone marrow progenitor cell recruitment assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, promoter functional assay, in vivo validation, multiple mechanistic readouts\",\n      \"pmids\": [\"24632622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LOXL2 regulates integrin α5 and integrin β1 protein levels via protease- and proteasome-dependent degradation systems, promoting stress fiber and focal adhesion formation in renal clear cell carcinoma cells.\",\n      \"method\": \"RNAi knockdown, protease/proteasome inhibitor experiments, integrin α5/β1 western blot, stress fiber and focal adhesion imaging\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined downstream mechanism, pharmacological dissection of degradation pathway, single lab\",\n      \"pmids\": [\"25092917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LOXL2 interacts with MARCKSL1 through its scavenger receptor domain (interacting with the N-terminal domain of MARCKSL1); LOXL2 activates FAK/Akt/mTOR signaling pathways and inhibits MARCKSL1-induced apoptosis, promoting cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, luciferase reporter assay, cell cycle and apoptosis analysis, FAK/Akt/mTOR phosphorylation western blot\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with domain mapping, defined signaling pathway, single lab\",\n      \"pmids\": [\"24863880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LOXL2 alternative splicing isoform LOXL2 Δe13, lacking exon 13, shows impaired deamination enzymatic activity but promotes cell migration and invasion of esophageal squamous cell carcinoma cells to greater degrees than full-length LOXL2, operating through MAPK8 rather than FAK/AKT/ERK pathways.\",\n      \"method\": \"Isoform identification and cloning, enzymatic deamination assay, gene expression profiling, MAPK8 knockdown rescue experiment, migration/invasion assays\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity measurement, isoform-specific pathway dissection, functional rescue experiment, single lab\",\n      \"pmids\": [\"25275797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LOXL2 oxidizes methylated TAF10 (a TFIID complex member), causing its release from promoters and blocking TFIID-dependent gene transcription; in embryonic stem cells this inactivates pluripotency genes, and in zebrafish loss of LOXL2 causes aberrant Sox2 overexpression and impaired neural differentiation.\",\n      \"method\": \"Unbiased proteomic substrate identification, in vitro oxidation assay, ChIP-seq, embryonic stem cell pluripotency gene analysis, zebrafish LOXL2 loss-of-function\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with substrate identification, ChIP-seq, in vivo vertebrate model validation, multiple orthogonal methods\",\n      \"pmids\": [\"25959397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Recombinant LOXL2 specifically deaminates trimethylated lysine 4 on histone H3 (H3K4me3), as shown by infrared spectroscopy and mass spectrometry; this LOXL2-catalyzed H3K4 deamination is linked to transcriptional control of the CDH1 (E-cadherin) gene, representing a novel unconventional chemical mechanism for histone modification.\",\n      \"method\": \"In vitro deamination assay with recombinant LOXL2, infrared spectroscopy, mass spectrometry, CDH1 transcription analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with recombinant protein, multiple biophysical methods (IR spectroscopy + MS), functional gene expression link\",\n      \"pmids\": [\"27735137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LOXL2 expression in metastatic lung cancer cells is directly regulated by ZEB1 (transcriptional activator) and repressed by the miR-200 family; LOXL2, as opposed to LOX, is the principal isoform crosslinking and stabilizing insoluble collagen deposition in tumor tissues, which activates focal adhesion/FAK/SRC signaling in mesenchymal tumor cells.\",\n      \"method\": \"miR-200/ZEB1 gain/loss-of-function, collagen solubility assay, FAK/SRC phosphorylation western blot, in vivo metastasis models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct regulatory axis (miR-200/ZEB1/LOXL2) with functional validation, isoform specificity demonstrated, downstream signaling defined, in vivo\",\n      \"pmids\": [\"27694892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In cardiac stress, LOXL2 secreted by activated fibroblasts into the interstitium promotes cardiac fibrosis by stimulating fibroblasts through PI3K/AKT signaling to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; LOXL2 also acts downstream of TGF-β2 to stimulate myofibroblast migration.\",\n      \"method\": \"Genetic Loxl2 disruption in mice, antibody-mediated inhibition, PI3K/AKT and TGF-β2 pathway analysis, cardiac function assessment, fibrosis quantification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus antibody inhibition, defined signaling pathway (PI3K/AKT→TGF-β2), in vivo cardiac phenotype, replicated in human samples\",\n      \"pmids\": [\"27966531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SMYD3 methyltransferase directly binds the promoter regions of EZR and LOXL2 and stimulates their transcription in esophageal squamous cell carcinoma, as demonstrated by chromatin immunoprecipitation assay.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) assay, RNAi knockdown, immunohistochemistry correlation analysis\",\n      \"journal\": \"Human pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-demonstrated direct promoter binding, single lab\",\n      \"pmids\": [\"26980013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LOXL2 overexpression accumulates in the endoplasmic reticulum where it interacts with HSPA5 (GRP78), leading to activation of the IRE1-XBP1 arm of the ER stress response; XBP1 then directly transcriptionally activates EMT transcription factors SNAI1, SNAI2, ZEB2, and TCF3; IRE1 inhibition blocks LOXL2-dependent EMT.\",\n      \"method\": \"Co-immunoprecipitation, ER fractionation, IRE1/XBP1 pathway analysis, ChIP for XBP1 at EMT-TF promoters, IRE1 pharmacological inhibition rescue experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, subcellular fractionation, defined pathway with rescue experiment, multiple downstream targets validated\",\n      \"pmids\": [\"28332555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LOXL2 mediates collagen crosslinking in fibrotic liver septa and promotes hepatic progenitor cell (HPC) differentiation towards ductal/fibrogenic fate; anti-LOXL2 antibody reduces collagen crosslinking, suppresses bridging fibrosis progression, and promotes fibrosis reversal; LOXL2 blockade in vitro directly shifts primary EpCAM+ HPC differentiation towards hepatocytes away from ductal lineage.\",\n      \"method\": \"Anti-LOXL2 monoclonal antibody treatment in multiple mouse fibrosis models (TAA, Mdr2-/-, DDC), collagen crosslinking biochemical assay, morphometric collagen quantification, primary EpCAM+ cell in vitro differentiation assay\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — antibody inhibition across 3 independent mouse models, biochemical crosslinking assay, in vitro mechanistic cell differentiation assay\",\n      \"pmids\": [\"28073888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LOXL2 ablation in conditional transgenic mouse models dramatically decreases lung metastasis without affecting primary tumor ECM stiffness or organization, indicating a function independent of conventional ECM crosslinking; LOXL2 action is associated with elevated Snail1 levels and expression of cytokines promoting premetastatic niche formation.\",\n      \"method\": \"Conditional transgenic PyMT mouse models with LOXL2 ablation or overexpression, ECM stiffness measurement, Snail1 and cytokine expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic models (ablation and overexpression), ECM-independent function rigorously established, in vivo metastasis readout\",\n      \"pmids\": [\"28720577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Higher matrix stiffness upregulates LOXL2 expression in HCC cells through the integrin β1/α5 → JNK/c-JUN signaling pathway; secreted LOXL2 promotes pre-metastatic niche formation by upregulating MMP9 and fibronectin production in lung fibroblasts via Akt pathway activation, and increasing CXCL12 expression and BMDC recruitment.\",\n      \"method\": \"Gel-based stiffness substrate system, integrin shRNA knockdown, JNK inhibitor treatment, shRNA-c-JUN knockdown, conditioned medium experiments, MMP9/fibronectin/CXCL12 western blot/ELISA\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with genetic and pharmacological inhibitors, multiple downstream effectors validated, single lab\",\n      \"pmids\": [\"29728125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Full-length LOXL2 has a rod-like structure with SRCR domains forming a stalk and the catalytic domain at the tip; LOXL2 directly binds tropoelastin and catalyzes its deamination to form crosslinked elastin-like material resistant to trypsin proteolysis with mechanical properties similar to mature elastin; specific allysine-containing cross-linked peptides were identified by proteomics.\",\n      \"method\": \"X-ray scattering, electron microscopy (low-resolution structure), surface plasmon resonance or equivalent binding assay, in vitro deamination assay, proteomics identification of crosslinked peptides\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural characterization combined with in vitro enzymatic reconstitution, substrate binding detection, and proteomics identification of reaction products\",\n      \"pmids\": [\"30676771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LOXL2 and its catalytically inactive isoform L2Δ13 interact physically with actin-binding proteins ezrin (EZR), fascin (FSCN1), HSPB1, and TMOD3 in the cytoplasm; LOXL2 promotes phosphorylation of ezrin at T567 (requiring PKCα co-activity), which is critical for cytoskeletal reorganization and tumor cell invasion in esophageal squamous cell carcinoma.\",\n      \"method\": \"Interactome analysis (mass spectrometry), Co-IP validation, ezrin T567 phosphorylation western blot after LOXL2 depletion/re-expression, PKCα inhibitor experiment, in vivo tumor progression assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic interactome validated by Co-IP, phosphorylation site defined, pharmacological dissection with PKCα inhibitor, in vivo validation\",\n      \"pmids\": [\"31409639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LOXL2 interacts physically with GATA6 via its scavenger receptor cysteine-rich domain; the LOXL2/GATA6 complex regulates VEGFA mRNA expression and protein secretion, promoting angiogenesis in cholangiocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (SRCR domain), qRT-PCR and ELISA for VEGFA, tube formation assay, in vivo tumor growth assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with domain mapping, functional downstream readout, single lab\",\n      \"pmids\": [\"31322171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LOXL2-mediated H3K4ox (oxidation of H3K4me3) is elevated in triple-negative breast cancer and is located primarily in heterochromatin; LOXL2 knockdown reduces H3K4ox, causing chromatin decompaction and sustained DNA damage response activation, increasing susceptibility to anticancer agents.\",\n      \"method\": \"ChIP-seq for H3K4ox, LOXL2 knockdown, ATAC-seq or chromatin accessibility assay, DNA damage response markers, drug sensitivity assays, patient-derived xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq genome-wide mapping, loss-of-function with defined chromatin and DDR phenotype, PDX validation, single lab\",\n      \"pmids\": [\"31462706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wnt signaling (via Wnt7b and Wnt9a, regulated by c-Fos/AP-1) promotes Loxl2 expression through transcription factors Zeb1 and Zeb2 in osteosarcoma; Loxl2 inhibition reduces osteosarcoma cell proliferation and decreases tumor growth and lung colonization in murine and human orthotopic models.\",\n      \"method\": \"Genetically modified mouse models (GEMMs), c-Fos promoter binding (ChIP), Wls gene inactivation, BAPN and specific Loxl2 shRNA/antibody inhibition, in vitro and in vivo proliferation and tumor assays\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — GEMM epistasis, direct promoter binding (ChIP), multiple inhibition modalities (chemical, genetic, antibody), in vivo tumor models\",\n      \"pmids\": [\"32686768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LOXL4 (not LOXL2) is the critical determinant of pathological collagen crosslinking and fibrosis in the lung; genetic ablation of LOXL2 alone leads to only modest reduction in pathological collagen crosslinking without reducing fibrosis, while LOXL4 deletion markedly disrupts both; double knockout offers no additive effect over LOXL4 deletion alone.\",\n      \"method\": \"Genetic knockout of Loxl2 and/or Loxl4 in mouse pulmonary fibrosis model, collagen crosslinking biochemical assay, fibrosis quantification\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic ablation with clean negative result for LOXL2, rigorous comparison with LOXL4, double-KO epistasis\",\n      \"pmids\": [\"37235663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LOXL2 upregulates HIF-1α signaling through the Snail-FBP1 axis in hepatocellular carcinoma: intracellular LOXL2 (requiring enzymatic activity, as the Y689F mutant lacks this effect) upregulates Snail, which represses FBP1, thereby enhancing glycolysis and HIF-1α/VEGF signaling; extracellular LOXL2 blockade by antibody does not abrogate this intracellular pathway.\",\n      \"method\": \"LOXL2 overexpression/silencing, LOXL2 Y689F catalytic mutant, anti-LOXL2 antibody, FBP1 knockdown, Snail western blot, HIF-1α/VEGF expression, LOXL2-IN-1 small molecule inhibitor\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant distinguishes mechanism, rescue experiments, intracellular vs. extracellular compartment distinction, single lab\",\n      \"pmids\": [\"32323822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nuclear LOXL2 in lung fibroblasts is upregulated by TGF-β1 treatment and is required for TGF-β1-induced proto-myofibroblast appearance and myofibroblast differentiation; LOXL2 silencing abrogates TGF-β1-induced nuclear Snail upregulation and myofibroblast evolution.\",\n      \"method\": \"Nuclear LOXL2 fractionation/immunostaining in vivo (ARDS model), TGF-β1 treatment of lung fibroblasts, LOXL2 siRNA silencing, Snail and myofibroblast marker expression\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular localization with functional consequence, loss-of-function with defined phenotype, in vivo and in vitro correlation, single lab\",\n      \"pmids\": [\"33248114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LOXL2 stabilizes HIF-1α from prolyl hydroxylase (PHD)-dependent hydroxylation via hydrogen peroxide generation, creating a positive feedback loop that facilitates transcription of glycolytic genes and the Warburg effect in pancreatic ductal adenocarcinoma.\",\n      \"method\": \"LOXL2 overexpression/knockdown, HIF-1α stability assay (PHD inhibitor comparison), H2O2 measurement, glycolytic gene expression, metabolic flux analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined biochemical mechanism (H2O2-mediated PHD inhibition), feedback loop characterization, single lab\",\n      \"pmids\": [\"34836938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tumor-associated macrophage-secreted oncostatin M (OSM) induces LOXL2 expression in pancreatic cancer cells; Loxl2 loss in PDAC mouse models significantly decreases metastasis through non-cell-autonomous ECM remodeling effects; targeting macrophages in vivo reduces Osm and Loxl2 expression and collagen fiber alignment.\",\n      \"method\": \"Conditional GEMM (KPC/KCL2KO and KCL2KI mice), OSM treatment and macrophage depletion in vivo, ECM collagen fiber alignment analysis, metastasis quantification, overall survival analysis\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — GEMM models with both KO and KI, identified upstream inducer (OSM from macrophages), defined non-cell-autonomous ECM mechanism, multiple in vivo models\",\n      \"pmids\": [\"35428659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LOXL2 promotes SNAIL expression to enable vasculogenic mimicry formation in hepatocellular carcinoma; LOXL2 overexpression significantly promotes migration, invasion, and tube formation in HCC cells.\",\n      \"method\": \"LOXL2 gain/loss-of-function in HCC cell lines, tube formation assay, SNAIL western blot, in vivo xenograft, CD31/PAS double staining in patient samples\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional assay with defined downstream effector (Snail), in vivo correlation, single lab\",\n      \"pmids\": [\"30506621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LOXL2 and its catalytically inactive L2Δ13 isoform function as novel deacetylases: they directly catalyze deacetylation of aldolase A at K13, stimulating aldolase mobilization from the actin cytoskeleton, enhancing glycolytic activity, and promoting metabolic reprogramming and tumor progression in esophageal cancer.\",\n      \"method\": \"SILAC proteomics, in vitro deacetylation assay, aldolase A K13 acetylation-specific antibody, aldolase activity assay, actin cytoskeleton fractionation, knock-in mouse model metabolomics/transcriptomics\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with substrate site identification, proteomic validation, knock-in mouse model with metabolomics, multiple orthogonal methods\",\n      \"pmids\": [\"36209516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM44 directly binds LOXL2 and regulates its protein stability via ubiquitination; TRIM44-mediated LOXL2 stabilization promotes ECM remodeling that modulates T-cell-mediated antitumor immunity in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay, in vivo tumor immunity assay\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay demonstrate binding and PTM regulation, functional in vivo immune readout, single lab\",\n      \"pmids\": [\"36512309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LOXL2 in rhabdomyosarcoma promotes cell migration, invasion, and lung metastasis independently of catalytic activity; vimentin was identified as a LOXL2-interacting cytoskeletal protein by pull-down/mass spectrometry, suggesting regulation of cytoskeleton dynamics as the mechanism.\",\n      \"method\": \"Stable LOXL2 knockdown, wild-type and catalytically inactive LOXL2 overexpression, in vivo metastasis assay, pull-down assay with mass spectrometry, vimentin validation\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant establishes independence from enzymatic activity, mass spectrometry interactor identification, in vivo metastasis, single lab\",\n      \"pmids\": [\"31911079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LOXL2, MMP9, and LCN2 form a ternary protein complex; LCN2-LOXL2 and LCN2-MMP9 interactions occur both intracellularly and extracellularly, while LOXL2-MMP9 interactions only occur intracellularly; the complex promotes fibronectin and Matrigel degradation, filopodia formation, microfilament rearrangement via profilin 1 upregulation, and activates FAK/AKT/GSK3β signaling.\",\n      \"method\": \"Co-immunoprecipitation (intracellular and extracellular fractions), cell migration/invasion assays, filopodia imaging, signaling pathway western blot, in vivo tumor growth assay\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with compartment distinction, defined complex, multiple downstream pathway readouts, single lab\",\n      \"pmids\": [\"37753805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RPS7 stabilizes LOXL2 mRNA by binding to AUUUA motifs in the 3155–3375 region of the LOXL2 3'UTR, increasing LOXL2 mRNA abundance; elevated LOXL2 then maintains ITGB1 protein stability and activates ITGB1-mediated FAK/SRC signaling, promoting HCC metastasis.\",\n      \"method\": \"RNA-binding protein immunoprecipitation (RIP), RNA-pulldown, dual luciferase reporter assay, LOXL2 mRNA decay assay, nascent RNA capture, ITGB1 protein stability assay, FAK/SRC phosphorylation western blot, in vivo lung metastasis model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal RNA binding assays (RIP, pulldown, luciferase, decay), defined mRNA stabilization mechanism, downstream signaling validated, in vivo\",\n      \"pmids\": [\"38326908\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LOXL2 is a multifunctional copper-dependent lysine tyrosylquinone amine oxidase that operates both extracellularly and intracellularly: extracellularly it crosslinks collagen (via lysine oxidation/deamination) and tropoelastin to remodel the ECM and drive fibrosis and metastatic niche formation; intracellularly it deaminates H3K4me3 and TAF10 to regulate gene transcription (including E-cadherin repression), deacetylates glycolytic enzymes (aldolase A at K13) to reprogram tumor metabolism, accumulates in the ER to activate IRE1-XBP1 signaling and induce EMT transcription factors, stabilizes Snail1 from GSK3β-dependent degradation, interacts with E47 to repress E-cadherin, promotes cytoskeletal reorganization via ezrin phosphorylation and vimentin interaction, and activates integrin/FAK/Src and PI3K/AKT signaling; many of these intracellular functions do not require its catalytic amine oxidase activity, revealing a dual enzymatic/non-enzymatic biology that governs fibrosis, EMT, metastasis, and metabolic reprogramming.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LOXL2 is a copper-dependent lysyl oxidase-like amine oxidase that drives fibrosis, epithelial-to-mesenchymal transition (EMT), and metastasis through both catalytic and non-catalytic activities operating across extracellular, cytoplasmic, and nuclear compartments [#0, #2, #22]. Structurally it forms a rod-like molecule with scavenger-receptor cysteine-rich (SRCR) domains forming a stalk and the catalytic domain at the tip; it binds and deaminates tropoelastin to generate crosslinked elastin-like material [#24], and is the principal isoform crosslinking and stabilizing insoluble collagen in tumor tissue, thereby activating focal-adhesion/FAK/SRC signaling in mesenchymal cells [#17]. Extracellularly, secreted LOXL2 remodels the matrix and the metastatic niche by activating stromal fibroblasts via integrin/FAK signaling [#8], modulating TIMP-1/MMP9 [#5], and—in cardiac and hepatic fibrosis—stimulating PI3K/AKT and TGF-β2 to drive myofibroblast transformation and collagen crosslinking [#18, #21]. A central oncogenic axis is the stabilization and induction of the EMT transcription factor Snail1: LOXL2 attenuates GSK3β-dependent Snail1 degradation [#1] and, when accumulated in the ER, binds HSPA5/GRP78 to activate IRE1-XBP1 signaling that transcriptionally induces SNAI1/SNAI2/ZEB2/TCF3 [#20], repressing E-cadherin in cooperation with E47 [#11]. Several of these intracellular functions are independent of catalytic activity, as catalytically inactive mutants and the L2Δ13 isoform still repress E-cadherin, activate FAK/Src, and promote invasion [#7, #10, #37]. Catalytic activities include unconventional chemistry: oxidative deamination of trimethylated TAF10 to release it from TFIID-controlled promoters [#15], deamination of H3K4me3 (H3K4ox) that organizes heterochromatin and restrains the DNA-damage response [#16, #27], and deacetylation of aldolase A at K13 to reprogram glycolysis [#35]. LOXL2 expression is itself controlled by hypoxia/HIF-1, ZEB1/miR-200, SMYD3, and Wnt signaling [#3, #17, #19, #28], and its protein and mRNA levels are tuned by TRIM44-mediated ubiquitination and RPS7-mediated mRNA stabilization [#36, #39]. Genetic ablation studies indicate that in lung fibrosis LOXL2 is dispensable for pathological collagen crosslinking—LOXL4 being the critical isoform—while in mammary and pancreatic metastasis LOXL2 acts through ECM-independent niche-forming and Snail1-linked mechanisms [#22, #29, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established LOXL2 as a distinct lysyl oxidase-family amine oxidase and raised the possibility of non-canonical processing/localization because its first exon lacks a signal sequence.\",\n      \"evidence\": \"cDNA cloning, gene structure analysis, in situ hybridization, and sequence homology\",\n      \"pmids\": [\"10212285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional substrate identified at this stage\", \"Subcellular localization inferred from sequence, not measured\", \"Catalytic activity not biochemically demonstrated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected LOXL2 to EMT by showing it stabilizes Snail1 against GSK3β-dependent degradation, providing a transcriptional route to E-cadherin repression.\",\n      \"evidence\": \"Co-immunoprecipitation and functional interaction assays linking LOXL2, GSK3β, and Snail1\",\n      \"pmids\": [\"16294032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether catalytic activity is required not addressed here\", \"Single-lab interaction without reciprocal structural mapping\", \"Mechanism of GSK3β attenuation unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved that LOXL2 acts in two compartments—secreted LOXL2 drives invasion via Src/FAK while intracellular LOXL2 engages the Snail/E-cadherin pathway—and showed antibody blockade of secreted LOXL2 is therapeutically tractable.\",\n      \"evidence\": \"RNAi, overexpression, Src/FAK western blot, xenografts, and anti-LOXL2 antibody in gastric cancer\",\n      \"pmids\": [\"19625348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of secreted LOXL2 on the cell surface not defined\", \"Catalytic dependence of each compartmental activity untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed LOXL2 downstream of hypoxia by identifying it as a direct HIF-1 target necessary and sufficient for hypoxic E-cadherin repression and invasion.\",\n      \"evidence\": \"HIF-1 binding analysis, gain/loss-of-function, and invasion assays under hypoxia\",\n      \"pmids\": [\"20026874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking LOXL2 to E-cadherin repression under hypoxia not dissected here\", \"Relative contribution of LOX vs LOXL2 not separated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended LOXL2 function to normal development, showing it is the major chondrocyte lysyl oxidase required for differentiation via SNAIL/SOX9 regulation.\",\n      \"evidence\": \"LOX-isoform expression profiling in fracture healing and LOXL2 knockdown in ATDC5 cells\",\n      \"pmids\": [\"21071451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic requirement not tested\", \"In vivo developmental phenotype not established here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that LOXL2's pro-invasive and differentiation-suppressing activities can be catalytic-independent, mapping a non-enzymatic function to the fourth SRCR domain.\",\n      \"evidence\": \"Catalytically inactive Y689F and domain-deletion mutants, BAPN inhibitor, AB0023 antibody, and involucrin/TIMP1/MMP9 readouts\",\n      \"pmids\": [\"22157764\", \"21233336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners of the SRCR domain not identified at this stage\", \"How a non-catalytic LOXL2 modulates MMP9/TIMP1 not mechanistically defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed cytoplasmic/perinuclear LOXL2 actively maintains the mesenchymal state by repressing polarity and tight-junction genes (Lgl2, claudin-1), with silencing reverting cells toward an epithelial phenotype.\",\n      \"evidence\": \"LOXL2 silencing, gene expression, polarity/tight-junction immunofluorescence, and tumorigenicity assays in basal-like breast cells\",\n      \"pmids\": [\"21732535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect transcriptional control of Lgl2/claudin-1 unresolved\", \"Nuclear targeting mechanism not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined LOXL2 as a tumor-stroma signal: secreted LOXL2 activates fibroblasts through integrin/FAK and, through ROS, activates ErbB2 to disrupt epithelial morphogenesis.\",\n      \"evidence\": \"Recombinant LOXL2 on collagen matrices, FAK phosphorylation, α-SMA staining, 3D acinar cultures, ROS/ErbB2 analysis with pharmacologic rescue\",\n      \"pmids\": [\"24008674\", \"23971878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integrin receptor identity engaged by LOXL2 not pinned down\", \"Source of ROS (catalytic byproduct vs indirect) not defined here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Consolidated the non-catalytic, partner-dependent transcriptional role of LOXL2, showing inactive mutants cooperate with Snail1 and E47 to repress E-cadherin and that LOXL2 directly programs metastatic-niche cytokines.\",\n      \"evidence\": \"Catalytic-mutant overexpression, reciprocal Co-IP with E47, E-cadherin promoter luciferase, FAK/Src blots, and in vivo lung metastasis/BMDC recruitment assays\",\n      \"pmids\": [\"24414204\", \"24632622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry/architecture of LOXL2–E47 transcriptional complex unknown\", \"Direct vs cofactor role at cytokine promoters not fully separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Broadened the cytoplasmic interactome and downstream signaling, linking LOXL2 to integrin turnover, MARCKSL1-dependent survival signaling, and an enzymatically impaired splice isoform with distinct pro-invasive wiring.\",\n      \"evidence\": \"Co-IP/domain mapping (MARCKSL1, SRCR), protease/proteasome inhibitor experiments on integrins, FAK/Akt/mTOR blots, and Δe13 isoform MAPK8-dependent rescue\",\n      \"pmids\": [\"24863880\", \"25092917\", \"25275797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IPs without structural validation\", \"How LOXL2 controls integrin proteolysis mechanistically unclear\", \"Generality of Δe13 isoform across tumors untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed an unconventional catalytic biology in which recombinant LOXL2 deaminates H3K4me3, providing a chemical mechanism for histone modification tied to CDH1 transcription.\",\n      \"evidence\": \"In vitro deamination with recombinant LOXL2, infrared spectroscopy, mass spectrometry, and CDH1 transcription analysis\",\n      \"pmids\": [\"27735137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide distribution of the mark not yet mapped here\", \"Reader/effector of H3K4ox unidentified at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a non-histone nuclear substrate, showing LOXL2 oxidizes methylated TAF10 to evict it from TFIID-dependent promoters, with developmental consequences for pluripotency and neural differentiation.\",\n      \"evidence\": \"Unbiased proteomic substrate ID, in vitro oxidation, ChIP-seq, ES-cell pluripotency analysis, and zebrafish loss-of-function\",\n      \"pmids\": [\"25959397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Breadth of methylated protein substrates beyond TAF10 unknown\", \"How nuclear LOXL2 is targeted to specific promoters not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established upstream control of LOXL2 by the ZEB1/miR-200 EMT axis and confirmed LOXL2 as the principal collagen-crosslinking isoform that feeds back into FAK/SRC signaling during metastasis.\",\n      \"evidence\": \"miR-200/ZEB1 gain/loss-of-function, collagen solubility assays, FAK/SRC blots, and in vivo metastasis; SMYD3 ChIP identifying direct promoter binding\",\n      \"pmids\": [\"27694892\", \"26980013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether crosslinking and signaling effects are separable not resolved\", \"Tissue-context dependence of these regulators not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated LOXL2's pathogenic role in cardiac fibrosis, with secreted LOXL2 stimulating fibroblasts through PI3K/AKT to produce TGF-β2 and drive myofibroblast transformation.\",\n      \"evidence\": \"Genetic Loxl2 disruption and antibody inhibition in mice, PI3K/AKT-TGF-β2 pathway analysis, cardiac function and fibrosis quantification with human-sample replication\",\n      \"pmids\": [\"27966531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating LOXL2-to-fibroblast signaling not identified\", \"Catalytic dependence of the cardiac effect not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined an ER-stress route to EMT, in which accumulated LOXL2 binds HSPA5/GRP78 to activate IRE1-XBP1, which transcriptionally induces multiple EMT transcription factors.\",\n      \"evidence\": \"Reciprocal Co-IP, ER fractionation, IRE1/XBP1 pathway analysis, XBP1 ChIP at EMT-TF promoters, and IRE1 inhibitor rescue\",\n      \"pmids\": [\"28332555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What triggers ER accumulation of LOXL2 unclear\", \"Catalytic requirement of HSPA5 engagement untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguished LOXL2's metastasis-promoting function from canonical ECM crosslinking using conditional models in breast and showed a parallel ECM-crosslinking role in liver fibrosis and progenitor-cell fate.\",\n      \"evidence\": \"Conditional PyMT ablation/overexpression with ECM stiffness measurement; anti-LOXL2 antibody across TAA/Mdr2/DDC liver models with crosslinking assays and EpCAM+ HPC differentiation\",\n      \"pmids\": [\"28720577\", \"28073888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ECM-independent metastatic function not fully resolved\", \"Whether liver and breast functions share effectors unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Closed a mechanotransduction loop in which matrix stiffness induces LOXL2 via integrin β1/β5→JNK/c-JUN, and secreted LOXL2 builds the pre-metastatic niche through MMP9, fibronectin, CXCL12, and BMDC recruitment.\",\n      \"evidence\": \"Tunable-stiffness substrates, integrin shRNA, JNK inhibitor, c-JUN knockdown, conditioned-medium experiments, and effector quantification in HCC\",\n      \"pmids\": [\"29728125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect transcriptional control of niche factors not separated\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the structural basis for LOXL2 architecture and demonstrated direct tropoelastin binding and deamination producing elastin-like crosslinked material, defining a bona fide ECM crosslinking substrate.\",\n      \"evidence\": \"X-ray scattering, electron microscopy, binding assay, in vitro deamination, and proteomic identification of crosslinked peptides\",\n      \"pmids\": [\"30676771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution catalytic-site structure not obtained\", \"In vivo elastin crosslinking by LOXL2 not demonstrated here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked LOXL2 to cytoskeletal control by identifying actin-binding partners (ezrin, fascin, HSPB1, TMOD3, vimentin) and showing PKCα-dependent ezrin T567 phosphorylation drives invasion, including catalytic-independent metastasis.\",\n      \"evidence\": \"MS interactome with Co-IP validation, ezrin phosphorylation blots, PKCα inhibitor, vimentin pull-down/MS, and in vivo metastasis with catalytic-inactive mutants\",\n      \"pmids\": [\"31409639\", \"31911079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect role of LOXL2 in ezrin phosphorylation unclear\", \"Whether vimentin interaction is functionally required not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Added a transcription-promoting partnership in which LOXL2 binds GATA6 via its SRCR domain to upregulate VEGFA and angiogenesis in cholangiocarcinoma.\",\n      \"evidence\": \"Co-IP, SRCR-domain mapping, VEGFA qRT-PCR/ELISA, tube formation, and in vivo tumor growth\",\n      \"pmids\": [\"31322171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP-based interaction without structural validation\", \"Direct LOXL2 action at VEGFA locus not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped genome-wide H3K4ox to heterochromatin in triple-negative breast cancer and showed LOXL2 loss decompacts chromatin and sustains DNA-damage signaling, sensitizing cells to therapy.\",\n      \"evidence\": \"H3K4ox ChIP-seq, chromatin accessibility assays, DDR markers, drug-sensitivity, and PDX models\",\n      \"pmids\": [\"31462706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism targeting LOXL2 to heterochromatin unknown\", \"Reader of H3K4ox still unidentified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected LOXL2 to glycolytic reprogramming via a catalysis-dependent Snail-FBP1 axis that elevates HIF-1α/VEGF signaling, distinguishing intracellular from extracellular function.\",\n      \"evidence\": \"Overexpression/silencing, Y689F catalytic mutant, anti-LOXL2 antibody, FBP1 knockdown, and HIF-1α/VEGF readouts with LOXL2-IN-1 in HCC\",\n      \"pmids\": [\"32323822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic step in the Snail-FBP1 axis not pinpointed\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified upstream Wnt control of LOXL2 in osteosarcoma and a TGF-β1-driven nuclear LOXL2 requirement for myofibroblast differentiation, reinforcing both transcriptional regulation and a nuclear Snail-linked fibrotic role.\",\n      \"evidence\": \"GEMMs with c-Fos ChIP and Wls inactivation, BAPN/shRNA/antibody inhibition for osteosarcoma; nuclear LOXL2 fractionation, TGF-β1 treatment, and siRNA silencing in lung fibroblasts\",\n      \"pmids\": [\"32686768\", \"33248114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear LOXL2 controls Snail in fibroblasts not mechanistically defined\", \"Catalytic dependence of nuclear fibrotic function untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established LOXL2 as a redox driver of the Warburg effect, generating hydrogen peroxide that stabilizes HIF-1α against PHD hydroxylation in a feedforward loop, and linked LOXL2 induction to macrophage-derived OSM in pancreatic cancer.\",\n      \"evidence\": \"Overexpression/knockdown with HIF-1α stability and H2O2 assays and metabolic flux in PDAC; conditional GEMMs (KPC/KCL2KO/KCL2KI) with OSM treatment, macrophage depletion, and ECM/metastasis analysis\",\n      \"pmids\": [\"34836938\", \"35428659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H2O2 production is the catalytic byproduct of substrate oxidation not directly shown\", \"Coupling between redox and ECM functions unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reinforced the Snail-driven, non-ECM-crosslinking oncogenic outputs of LOXL2 by showing it promotes vasculogenic mimicry through SNAIL upregulation in HCC.\",\n      \"evidence\": \"Gain/loss-of-function, tube formation, SNAIL blots, xenografts, and CD31/PAS staining in patient samples\",\n      \"pmids\": [\"30506621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic requirement not tested\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered a moonlighting deacetylase activity, showing LOXL2 (and L2Δ13) deacetylates aldolase A at K13 to mobilize it from actin and enhance glycolysis, broadening LOXL2's catalytic repertoire beyond amine oxidation.\",\n      \"evidence\": \"SILAC proteomics, in vitro deacetylation, K13-acetylation antibody, aldolase activity/fractionation, and knock-in mouse metabolomics/transcriptomics in esophageal cancer\",\n      \"pmids\": [\"36209516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism for deacetylation by an amine oxidase fold unresolved\", \"Substrate scope of LOXL2 deacetylase activity unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined post-translational control of LOXL2 levels by TRIM44-mediated ubiquitination, linking LOXL2 stability to ECM remodeling and antitumor immunity in gastric cancer.\",\n      \"evidence\": \"Co-IP, co-localization, ubiquitination assay, and in vivo tumor immunity assays\",\n      \"pmids\": [\"36512309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TRIM44 stabilizes or destabilizes LOXL2 ubiquitin chains needs clarification\", \"Single-lab interaction\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed LOXL2 functions within a LOXL2-MMP9-LCN2 ternary complex with compartment-specific assembly that drives matrix degradation, filopodia formation, and FAK/AKT/GSK3β signaling.\",\n      \"evidence\": \"Compartment-resolved Co-IP, migration/invasion assays, filopodia imaging, profilin-1 analysis, signaling blots, and in vivo tumor growth\",\n      \"pmids\": [\"37753805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs bridged interactions within the ternary complex not fully resolved\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Refined isoform specificity in fibrosis by showing that, in lung, LOXL4—not LOXL2—is the critical determinant of pathological collagen crosslinking, with LOXL2 ablation giving only modest effects.\",\n      \"evidence\": \"Single and double Loxl2/Loxl4 knockouts in pulmonary fibrosis with crosslinking biochemistry and fibrosis quantification\",\n      \"pmids\": [\"37235663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LOXL2 contributes to non-crosslinking fibrotic functions in lung not addressed\", \"Tissue-specific division of labor among LOX isoforms incompletely mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added mRNA-level control, showing RPS7 binds AUUUA motifs in the LOXL2 3'UTR to stabilize its transcript, raising LOXL2 protein that sustains ITGB1 and activates ITGB1/FAK/SRC signaling in HCC metastasis.\",\n      \"evidence\": \"RIP, RNA-pulldown, luciferase, mRNA-decay and nascent-RNA assays, ITGB1 stability assays, FAK/SRC blots, and in vivo metastasis\",\n      \"pmids\": [\"38326908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RPS7 control of LOXL2 operates broadly across tissues unknown\", \"Mechanism by which LOXL2 stabilizes ITGB1 protein not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LOXL2's multiple catalytic activities (amine oxidation of ECM substrates, deamination of TAF10/H3K4me3, and deacetylation of aldolase A) and its catalytic-independent scaffolding functions are partitioned across subcellular compartments, and what governs its localization to ER, nucleus, cytoskeleton, and extracellular space, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model for compartmental targeting of LOXL2\", \"Structural basis for how one fold catalyzes oxidation and deacetylation undefined\", \"Which functions are therapeutically separable by enzyme inhibition vs antibody blockade unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 15, 16, 24, 32]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [15, 16, 35]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11, 26, 27]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [16, 27]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [25, 37]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 8, 24]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 25, 38]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15, 27, 31]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [17, 21, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [17, 21, 24, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8, 18, 23, 39]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [15, 16, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 15]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [30, 32, 35]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 18, 21, 33]}\n    ],\n    \"complexes\": [\n      \"LOXL2-MMP9-LCN2 ternary complex\"\n    ],\n    \"partners\": [\n      \"SNAI1\",\n      \"E47 (TCF3)\",\n      \"HSPA5\",\n      \"EZR\",\n      \"VIM\",\n      \"GATA6\",\n      \"TRIM44\",\n      \"MMP9\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}