{"gene":"LOXL2","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2009,"finding":"Secreted LOXL2 promotes gastric cancer invasion and metastasis exclusively via the Src/FAK signaling pathway, while intracellular LOXL2 additionally activates the Snail/E-cadherin pathway; antibody-mediated neutralization of secreted LOXL2 inhibited tumor growth and metastasis.","method":"RNA interference knockdown, ectopic overexpression, in vitro invasion assays, in vivo metastasis models, pathway analysis by western blot","journal":"Carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, OE, in vivo, antibody inhibition) with defined mechanistic pathway placement","pmids":["19625348"],"is_preprint":false},{"year":2009,"finding":"LOXL2 is a direct transcriptional target of HIF-1 under hypoxia, and activation of LOXL2 (together with LOX) is required and sufficient for hypoxic repression of E-cadherin, driving epithelial-to-mesenchymal transition and cellular invasion.","method":"HIF-1 transcriptional target validation, gene expression analysis, E-cadherin reporter assays, cellular invasion assays, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct transcriptional target validation with functional rescue and invasion readout, replicated concept across labs","pmids":["20026874"],"is_preprint":false},{"year":2011,"finding":"LOXL2 promotes breast cancer invasion by regulating the expression and activity of extracellular proteins TIMP1 and MMP9; 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","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal inhibition strategies with defined TIMP1/MMP9 mechanism in vivo","pmids":["21233336"],"is_preprint":false},{"year":2011,"finding":"Intracellular (perinuclear/cytoplasmic) LOXL2 maintains mesenchymal phenotype of basal-like breast carcinoma cells by transcriptional downregulation of Lgl2 and claudin1, causing disorganization of cell polarity and tight junction complexes; LOXL2 silencing induces mesenchymal-to-epithelial transition.","method":"LOXL2 siRNA silencing, gene expression analysis, cell polarity assays, in vivo metastasis models","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with defined transcriptional targets and in vivo validation","pmids":["21732535"],"is_preprint":false},{"year":2013,"finding":"Tumor-secreted LOXL2 directly activates stromal fibroblasts through integrin-mediated focal adhesion kinase (FAK) activation, inducing fibroblast branching on collagen matrices, increased collagen contraction, fibroblast invasion, and α-SMA expression.","method":"In vitro fibroblast activation assays, collagen contraction assays, LOXL2 genetic manipulation and antibody inhibition, in vivo mammary tumor models, western blot for FAK phosphorylation","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 — reconstitution with recombinant protein, multiple orthogonal methods, in vitro and in vivo validation","pmids":["24008674"],"is_preprint":false},{"year":2013,"finding":"Nuclear-associated intracellular LOXL2 (~75 kDa, non-glycosylated, N-terminally processed) stabilizes Snail1 transcription factor at the protein level to induce EMT and promote invasion, repressing E-cadherin, occludin, and estrogen receptor-α while upregulating vimentin, fibronectin, and MT1-MMP. Secreted LOXL2 (~100 kDa) is N-glycosylated at Asn-455 and Asn-644.","method":"Stable expression of subcellular-localization variants of LOXL2, subcellular fractionation, glycosylation analysis, invasion assays, western blot for EMT markers","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1/2 — biochemical characterization of two LOXL2 forms with distinct glycosylation and localization, functional dissection by subcellular targeting","pmids":["24014025"],"is_preprint":false},{"year":2014,"finding":"LOXL2 physically interacts with the bHLH transcription factor E47 and functionally collaborates in repression of the E-cadherin promoter; both LOXL2 and E47 are required for lung metastasis and contribute to early metastatic colonization by regulating fibronectin and cytokines (TNFα, ANG-1, GM-CSF) and recruiting bone marrow progenitor cells.","method":"Co-immunoprecipitation, loss- and gain-of-function analyses, in vivo syngeneic breast cancer models, chromatin studies","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with functional validation in vivo","pmids":["24632622"],"is_preprint":false},{"year":2014,"finding":"LOXL2 interacts physically with MARCKSL1 via its scavenger receptor domain (interacting with the N-terminal domain of MARCKSL1), and activates FAK/Akt/mTOR signaling pathways to promote cell proliferation and inhibit apoptosis in breast cancer cells.","method":"Co-immunoprecipitation, domain mapping, luciferase assays, siRNA knockdown, cell cycle and apoptosis analysis","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with domain mapping and signaling pathway readout, single lab","pmids":["24863880"],"is_preprint":false},{"year":2014,"finding":"LOXL2 is the critical isoform that crosslinks and stabilizes insoluble collagen in tumor extracellular matrix; this crosslinked collagen activates focal adhesion formation and FAK/SRC signaling in mesenchymal tumor cells, and LOXL2 expression is directly regulated by ZEB1 while LOX is regulated by miR-200.","method":"In vivo collagen crosslinking analysis, FAK/SRC signaling assays, miR-200/ZEB1 axis validation, in vitro and in vivo lung cancer models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple methods including in vivo collagen analysis and signaling validation","pmids":["27694892"],"is_preprint":false},{"year":2015,"finding":"LOXL2 oxidizes methylated TAF10 (a TFIID complex member), inducing TAF10 release from promoters and blocking TFIID-dependent gene transcription. In embryonic stem cells, this inactivates pluripotency genes; in zebrafish, loss of LOXL2 causes aberrant Sox2 overexpression and impaired neural differentiation.","method":"Unbiased proteomic identification of LOXL2 substrate, in vitro oxidation assay, TAF10 promoter occupancy studies, zebrafish developmental model","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay with substrate identification by proteomics, validated in vivo in zebrafish","pmids":["25959397"],"is_preprint":false},{"year":2016,"finding":"Recombinant LOXL2 specifically deaminates trimethylated H3K4 (H3K4me3), and by regulating H3K4me3 deamination, LOXL2 controls transcription of the CDH1 (E-cadherin) gene. This is an unconventional H3K4 modification mechanism.","method":"Infrared spectroscopy, mass spectrometry, in vitro deamination assay with recombinant LOXL2, chromatin immunoprecipitation/gene expression analysis","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay with recombinant protein confirmed by two orthogonal biochemical methods (IR spectroscopy + MS)","pmids":["27735137"],"is_preprint":false},{"year":2016,"finding":"Cardiac fibroblast-secreted LOXL2 crosslinks collagen in the cardiac interstitium and stimulates cardiac 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. Antibody-mediated inhibition or genetic disruption of LOXL2 reduces cardiac fibrosis and improves cardiac function.","method":"Genetic knockout, antibody inhibition, in vivo cardiac stress models, PI3K/AKT pathway analysis, TGF-β2 signaling studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic and antibody-mediated loss-of-function with defined PI3K/AKT/TGF-β2 pathway placement, in vivo validation","pmids":["27966531"],"is_preprint":false},{"year":2017,"finding":"LOXL2 mediates collagen crosslinking and fibrotic matrix stabilization in liver fibrosis, and independently promotes fibrogenic hepatic progenitor cell (HPC) differentiation toward ductal lineage; anti-LOXL2 antibody treatment reduces collagen crosslinking, promotes fibrosis reversal, and redirects HPC differentiation toward hepatocytes.","method":"Anti-LOXL2 monoclonal antibody treatment in three mouse fibrosis models, collagen crosslinking assays, morphometric collagen quantification, primary EpCAM+ HPC differentiation assays in vitro","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — three independent mouse models plus in vitro HPC differentiation with biochemical crosslinking readout","pmids":["28073888"],"is_preprint":false},{"year":2017,"finding":"LOXL2 overexpression in breast cancer promotes metastatic tumor growth through mechanisms independent of extracellular matrix stiffness or organization, associated instead with elevated Snail1 levels and expression of cytokines that promote premetastatic niche formation.","method":"Conditional transgenic mouse models (PyMT-induced breast cancer with LOXL2 ablation or overexpression), ECM stiffness measurements, molecular analysis of EMT markers and cytokines","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — two independent transgenic mouse models with functional readout and ECM-independent mechanism identified","pmids":["28720577"],"is_preprint":false},{"year":2017,"finding":"Overexpressed LOXL2 accumulates in the endoplasmic reticulum where it interacts with HSPA5 (GRP78), activating the IRE1-XBP1 unfolded protein response pathway; XBP1 then directly transcribes EMT transcription factors SNAI1, SNAI2, ZEB2, and TCF3; IRE1 inhibition blocks LOXL2-dependent EMT.","method":"Co-immunoprecipitation, subcellular fractionation, IRE1 inhibitor experiments, XBP1 target gene analysis, epistasis by IRE1 inhibition","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with pathway epistasis and inhibitor rescue, mechanistic chain from ER accumulation to transcription factor induction","pmids":["28332555"],"is_preprint":false},{"year":2011,"finding":"The enzymatic activity of LOXL2 is not required for its inhibition of keratinocyte differentiation; a catalytically inactive point mutant (Y689F) and a deletion mutant lacking the entire catalytic domain retain this activity, which requires the fourth scavenger receptor-cysteine-rich (SRCR) domain. LOXL2 can be internalized by HaCaT cells via a putative receptor, inhibited by the function-blocking antibody AB0023.","method":"Point mutagenesis (Y689F), domain deletion mutants, β-aminopropionitrile (BAPN) treatment, antibody inhibition (AB0023), keratinocyte differentiation assays, internalization assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — active site mutagenesis and domain deletion with functional validation, multiple inhibition approaches","pmids":["22157764"],"is_preprint":false},{"year":2010,"finding":"LOXL2 is the major isoform expressed in chondrocytes and is required for chondrocyte differentiation; LOXL2 knockdown in ATDC5 chondrogenic cells disrupts differentiation through regulation of transcription factors SNAIL and SOX9.","method":"LOXL2 knockdown by siRNA, chondrocyte differentiation assays, gene expression analysis of SNAIL and SOX9, in vivo growth plate expression studies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined transcriptional targets (SNAIL, SOX9), but single lab study","pmids":["21071451"],"is_preprint":false},{"year":2014,"finding":"LOXL2 regulates the protein stability of integrins α5 (ITGA5) and β1 (ITGB1) via protease- and proteasome-dependent systems in clear cell renal cell carcinoma; LOXL2 knockdown suppresses stress fiber and focal adhesion formation, and inhibits cell growth, migration, and invasion.","method":"RNAi knockdown, integrin protein stability assays with protease/proteasome inhibitors, stress fiber/focal adhesion imaging, cell migration and invasion assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic identification of integrin degradation via two proteolytic systems, single lab","pmids":["25092917"],"is_preprint":false},{"year":2014,"finding":"A novel alternative splicing isoform LOXL2 Δe13 (lacking exon 13) has impaired deamination enzymatic activity but promotes cell migration and invasion more strongly than full-length LOXL2 via induction of MAPK8 (JNK), rather than through FAK, AKT, or ERK pathways.","method":"Identification of splice variant, enzymatic activity assay, gene expression profiling, MAPK8 knockdown rescue experiments, cell migration/invasion assays","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — enzymatic characterization combined with pathway epistasis via MAPK8 knockdown, single lab","pmids":["25275797"],"is_preprint":false},{"year":2019,"finding":"LOXL2 has a rod-like structure with SRCR domains forming a stalk and the catalytic domain at the tip; LOXL2 directly interacts with tropoelastin and catalyzes its deamination, generating cross-linked elastin-like material with mechanical properties similar to mature elastin, suggesting LOXL2 participates in elastogenesis.","method":"X-ray scattering, electron microscopy, proteomics identification of allysines and cross-linked peptides, direct binding assay between LOXL2 and tropoelastin, in vitro deamination assay, trypsin resistance assay, mechanical property testing","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 — structural determination combined with in vitro enzymatic activity and substrate identification by proteomics","pmids":["30676771"],"is_preprint":false},{"year":2019,"finding":"Cytoplasmic LOXL2 and its catalytically inactive splice variant L2Δ13 interact physically with the actin-binding proteins ezrin (EZR), fascin (FSCN1), HSPB1, and tropomodulin-3 (TMOD3); LOXL2 promotes phosphorylation of ezrin at T567 (requiring PKCα) to drive cytoskeletal reorganization and tumor cell invasion in esophageal squamous cell carcinoma.","method":"Interactome analysis (mass spectrometry), Co-IP validation, ezrin phosphorylation assays, LOXL2 depletion/re-expression experiments, cell invasion assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — MS interactome with Co-IP validation, defined phosphorylation event and PKCα requirement, functional rescue experiments","pmids":["31409639"],"is_preprint":false},{"year":2019,"finding":"LOXL2 activates lung fibroblasts through the TGF-β/Smad pathway; LOXL2 silencing decreases fibroblast proliferation, IL-6 and COL1A1 production, and inhibits phospho-Smad2/3, Smad4, and Snail expression while promoting Smad7.","method":"LOXL2 siRNA adenoviral vector, mouse lung fibroblast culture, TGF-β/Smad pathway western blot, proliferation assay, ELISA for IL-6 and COL1A1","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown with defined TGF-β/Smad pathway readout, single lab","pmids":["30320382"],"is_preprint":false},{"year":2019,"finding":"LOXL2 interacts physically with GATA6 via its scavenger receptor cysteine-rich domain, and the GATA6/LOXL2 complex positively regulates VEGFA mRNA expression and secretion to promote angiogenesis and tumor growth in cholangiocarcinoma.","method":"Co-immunoprecipitation, domain mapping, western blot, ELISA, luciferase reporter assay, in vivo angiogenesis and tumor growth models","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with domain mapping and in vivo validation, single lab","pmids":["31322171"],"is_preprint":false},{"year":2020,"finding":"Wnt signaling promotes c-Fos-induced osteosarcoma via LOXL2: c-Fos/AP-1 directly regulates Wnt7b and Wnt9a expression via promoter binding, and these Wnt ligands promote LOXL2 expression through ZEB1 and ZEB2 transcription factors. LOXL2 inhibition (BAPN or specific antibodies) reduces OS cell proliferation and tumor growth.","method":"Genetically engineered mouse models, promoter binding assays (AP-1), conditional Wls knockout, shRNA, orthotopic transplantation models, BAPN/antibody inhibition","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 — multiple GEMMs with defined pathway (c-Fos→Wnt→ZEB1/2→LOXL2), validated in human OS samples","pmids":["32686768"],"is_preprint":false},{"year":2022,"finding":"LOXL2 and its catalytically inactive splice variant L2Δ13 function as deacetylases, directly catalyzing deacetylation of aldolase A at K13, resulting in enhanced glycolysis, metabolic reprogramming, and tumor progression in esophageal cancer.","method":"SILAC proteomics, in vitro deacetylation assay, transcriptomic and metabolomic analysis of knock-in mouse model, Co-IP of LOXL2 with glycolytic enzymes, aldolase activity assays","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic deacetylation demonstrated with SILAC proteomics, confirmed in knock-in mouse model with orthogonal transcriptomic and metabolomic analyses","pmids":["36209516"],"is_preprint":false},{"year":2021,"finding":"LOXL2 stabilizes HIF1α from prolyl hydroxylase-dependent hydroxylation via hydrogen peroxide generation, creating a positive feedback loop between LOXL2 and HIF1α that facilitates glycolytic gene transcription (Warburg effect) in pancreatic cancer.","method":"HIF1α stability assay, hydroxylation assay, hydrogen peroxide measurement, glycolytic gene expression analysis, in vivo tumor growth studies","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — defined biochemical mechanism (H2O2-mediated HIF1α stabilization) with functional glycolytic readout, single lab","pmids":["34836938"],"is_preprint":false},{"year":2022,"finding":"LOXL2 forms a ternary complex with LCN2 and MMP9; LCN2-LOXL2 and LCN2-MMP9 interactions occur both intracellularly and extracellularly, while LOXL2-MMP9 interaction occurs only intracellularly. The complex promotes fibronectin degradation, filopodia formation, microfilament rearrangement via profilin 1 upregulation, and activates FAK/AKT/GSK3β signaling.","method":"Co-immunoprecipitation, subcellular localization assays, migration/invasion assays, in vivo tumor growth studies, fibronectin degradation assay","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — protein complex identification with defined subcellular locations and signaling pathway activation, single lab","pmids":["37753805"],"is_preprint":false},{"year":2020,"finding":"Nuclear LOXL2 in lung fibroblasts is a primary driver of myofibroblast differentiation; TGF-β1 upregulates nuclear LOXL2 expression, and LOXL2 silencing abrogates TGF-β1-induced proto-myofibroblast appearance and myofibroblast evolution. Nuclear LOXL2 expression correlates with nuclear Snail upregulation in myofibroblasts.","method":"LOXL2 silencing in lung fibroblasts, TGF-β1 stimulation, nuclear fractionation, myofibroblast differentiation assays, in vivo mouse lung injury model, ARDS patient lung samples","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined myofibroblast differentiation phenotype and nuclear localization, validated in human ARDS samples","pmids":["33248114"],"is_preprint":false},{"year":2022,"finding":"Tumor-associated macrophage-secreted oncostatin M (OSM) induces LOXL2 expression in pancreatic cancer cells; Loxl2 ablation in vivo decreases metastasis and increases overall survival primarily through non-cell-autonomous ECM remodeling, while Loxl2 overexpression promotes EMT and stemness.","method":"Conditional GEMMs (KPC/KC crossed with Loxl2 floxed or conditional overexpression mice), collagen ECM analysis, macrophage targeting in vivo, OSM signaling studies","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — four GEMM-based models identifying macrophage-OSM-LOXL2 axis with defined in vivo phenotypes","pmids":["35428659"],"is_preprint":false},{"year":2023,"finding":"Genetic ablation of LOXL2 alone leads to only modest reduction of pathological collagen crosslinking without preventing lung fibrosis, while LOXL4 is the main LOX family member driving pathological collagen crosslinking and fibrosis in the lung; LOXL4 deficiency decreases expression of other LOX family members including LOXL2.","method":"Genetic knockout of Loxl2 and/or Loxl4, bleomycin lung fibrosis model, collagen crosslinking biochemical assays, histological fibrosis assessment","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1/2 — genetic epistasis between LOXL2 and LOXL4 with biochemical crosslinking readout, defines relative contribution of each enzyme","pmids":["37235663"],"is_preprint":false},{"year":2022,"finding":"LATS1 phosphorylates LOXL2 in ovarian granulosa cells; miR-21 from hucMSC-derived exosomes downregulates LATS1, reducing phosphorylated LOXL2 and YAP levels, promoting estrogen secretion. YAP binds to the LOXL2 promoter to positively regulate LOXL2 transcription.","method":"Immunoprecipitation for LATS1-LOXL2 interaction, dual-luciferase reporter and ChIP assay for YAP-LOXL2 promoter binding, miR-21/LATS1 target validation by luciferase and RIP, ELISA for estradiol","journal":"General and comparative endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP for phosphorylation, ChIP for promoter binding, single lab with multiple targets","pmids":["35271888"],"is_preprint":false},{"year":2019,"finding":"Pharmacological inhibition of CAF-derived LOXL2 perturbs extracellular matrix organization and decreases CAF migration; it also significantly impairs motility of co-cultured prostate tumor epithelial cells. Increased LOXL2 expression and activity was confirmed in cancer-associated fibroblasts (CAFs) versus normal prostate fibroblasts.","method":"LC-MS/MS proteomics, LOXL2 enzymatic activity assay, western blotting, LOXL2 pharmacological inhibition, wound healing assay, co-culture motility assay","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 — enzymatic activity confirmation with pharmacological inhibition and defined cellular phenotype, single lab","pmids":["31061140"],"is_preprint":false},{"year":2019,"finding":"LOXL2 promotes migration and invasion of rhabdomyosarcoma cells independently of its catalytic activity; vimentin was identified as a LOXL2-interacting protein, suggesting LOXL2 regulates cytoskeleton dynamics and cell motility through this interaction.","method":"LOXL2 knockdown and stable expression of wild-type vs. catalytically inactive mutants, pull-down assay with mass spectrometry, vimentin validation as interactor, in vivo lung metastasis model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — pull-down/MS for interactor identification with catalytically inactive mutant showing retained function, in vivo validation","pmids":["31911079"],"is_preprint":false},{"year":2020,"finding":"LOXL2 enhances Atg7 expression by promoting ERK1/2 phosphorylation, leading to autophagy activation, which in turn mediates EMT and temozolomide resistance in glioma cells.","method":"LOXL2 overexpression/knockdown, autophagy assays, ERK1/2 phosphorylation analysis, Atg7 expression analysis, chemosensitivity assays","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, defined signaling axis but no structural or reconstitution evidence; epistasis based on inhibitor studies","pmids":["33194658"],"is_preprint":false},{"year":2019,"finding":"SP1 transcription factor directly binds the LOXL2 promoter to regulate LOXL2 expression, and this SP1→LOXL2 axis promotes EMT, invasion, and migration in pancreatic ductal adenocarcinoma; LOXL2 silencing does not reciprocally affect SP1 expression.","method":"Chromatin immunoprecipitation (ChIP) for SP1 binding to LOXL2 promoter, siRNA double knockdown of SP1 and LOXL2, invasion/migration assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrating direct promoter binding with functional epistasis by double knockdown, single lab","pmids":["30976063"],"is_preprint":false},{"year":2022,"finding":"TRIM44 deubiquitinase directly binds LOXL2 and stabilizes it by reducing its ubiquitination; TRIM44 knockdown decreases LOXL2 protein levels and suppresses ECM remodeling and tumor immunity in gastric cancer.","method":"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assays, TRIM44 knockdown with LOXL2 rescue","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — direct Co-IP with ubiquitination assay demonstrating TRIM44 as LOXL2 stabilizer, single lab","pmids":["36512309"],"is_preprint":false},{"year":2020,"finding":"Matrix stiffness promotes LOXL2 expression in M2 macrophages through activation of the integrin β5-FAK-MEK1/2-ERK1/2 pathway leading to HIF-1α upregulation, which transcriptionally induces LOXL2.","method":"Gel-based stiffness culture system, M2 macrophage polarization model, pathway inhibition experiments, HIF-1α knockdown, western blot for pathway components","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — defined signaling pathway with pathway inhibition experiments, single lab","pmids":["32964626"],"is_preprint":false},{"year":2020,"finding":"LOXL2 attenuates osteoarthritis in TMJ cartilage partly through activation of the Integrin/FAK signaling pathway in chondrocytes; inhibition of Integrin/FAK neutralizes the protective effect of recombinant LOXL2.","method":"In vivo compressive mechanical force model, IL-1β in vitro model, recombinant LOXL2 treatment, anti-LOXL2 antibody treatment, Integrin/FAK pathway inhibitor epistasis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — pathway epistasis with inhibitor rescue, in vivo and in vitro validation, single lab","pmids":["34426599"],"is_preprint":false},{"year":2020,"finding":"LOXL2 enhances keratinocyte migration and differentiation to promote wound healing by activating the JNK signaling pathway; SP600125 (JNK inhibitor) blocks LOXL2-mediated keratinocyte migration and differentiation.","method":"Recombinant LOXL2 treatment of keratinocytes, JNK pathway inhibitor (SP600125), LOXL2-silenced hAMSC conditioned medium, in vivo mouse wound healing model","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 — inhibitor epistasis with in vivo wound healing validation, single lab","pmids":["32621591"],"is_preprint":false},{"year":2024,"finding":"RPS7 RNA-binding protein stabilizes LOXL2 mRNA by binding AUUUA motifs in the 3155–3375 region of the LOXL2 3'UTR, increasing LOXL2 protein abundance; LOXL2 in turn maintains ITGB1 protein stability and activates ITGB1-mediated FAK/SRC signaling to promote HCC metastasis.","method":"RNA sequencing, RIP assay, RNA-pulldown, dual-luciferase reporter assay, RNA decay assay, CRISPR-Cas9 knockout, LOXL2 ITGB1 stability assay, FAK/SRC signaling analysis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — RIP and RNA-pulldown for mRNA binding, defined ITGB1 stability mechanism, single lab","pmids":["38326908"],"is_preprint":false}],"current_model":"LOXL2 is a copper-dependent lysine tyrosylquinone amine oxidase that functions both extracellularly (crosslinking collagen and tropoelastin via deamination of lysine residues to drive ECM stiffening, fibrosis, and premetastatic niche formation) and intracellularly (as a nuclear enzyme that deaminates H3K4me3 and oxidizes TAF10 to control gene transcription, deacetylates aldolase A to promote glycolytic reprogramming, and stabilizes Snail1 to drive EMT), with the SRCR domains mediating protein-protein interactions (including with GATA6, MARCKSL1, HSPA5, and ezrin) and some activities—including inhibition of keratinocyte differentiation, cytoskeletal reorganization, and promotion of rhabdomyosarcoma metastasis—occurring independently of catalytic activity; upstream, LOXL2 is transcriptionally induced by HIF-1 under hypoxia, by ZEB1/ZEB2, by SP1, by YAP, and by oncostatin M from tumor-associated macrophages, while its protein stability is controlled by TRIM44-mediated deubiquitination and LATS1-mediated phosphorylation, and downstream it activates FAK/SRC, PI3K/AKT, IRE1-XBP1, TGF-β/Smad, and ERK1/2 signaling cascades to drive invasion, metastasis, fibrosis, and chemoresistance across multiple cancer types and fibrotic diseases."},"narrative":{"teleology":[{"year":2009,"claim":"Establishing that LOXL2 has functionally separable extracellular and intracellular pro-invasive activities resolved how one enzyme promotes both stromal remodeling (via Src/FAK) and EMT (via Snail/E-cadherin) in gastric cancer.","evidence":"RNA interference, overexpression, in vivo metastasis models, and antibody neutralization in gastric cancer cells","pmids":["19625348"],"confidence":"High","gaps":["The intracellular mechanism by which LOXL2 engages Snail was not biochemically defined","Relative contribution of each compartmental activity to metastasis in vivo was not quantified"]},{"year":2009,"claim":"Identification of LOXL2 as a direct HIF-1 transcriptional target established hypoxia as a key upstream inducer, linking tumor microenvironment oxygen sensing to EMT via E-cadherin repression.","evidence":"HIF-1 target validation, E-cadherin reporter assays, siRNA knockdown, invasion assays","pmids":["20026874"],"confidence":"High","gaps":["Whether HIF-1-driven LOXL2 induction is sufficient versus cooperative with other HIF targets was not separated"]},{"year":2011,"claim":"Demonstration that a catalytically inactive LOXL2 mutant (Y689F) retains the ability to inhibit keratinocyte differentiation—requiring only the fourth SRCR domain—established that LOXL2 exerts important biological functions through protein-protein interactions independent of its oxidase activity.","evidence":"Active-site mutagenesis, domain deletion, BAPN inhibition, antibody AB0023 blocking, keratinocyte differentiation assays","pmids":["22157764"],"confidence":"High","gaps":["The receptor mediating LOXL2 internalization into keratinocytes was not identified","Whether catalytic-independent functions extend to other cell types was unclear"]},{"year":2011,"claim":"Showing that intracellular LOXL2 maintains mesenchymal identity by repressing polarity regulators (Lgl2, claudin1) extended its role beyond E-cadherin to broader epithelial architecture control in basal-like breast cancer.","evidence":"siRNA silencing, gene expression analysis, cell polarity assays, in vivo metastasis models","pmids":["21732535"],"confidence":"High","gaps":["Whether LOXL2 directly or indirectly represses these polarity genes was not resolved"]},{"year":2013,"claim":"Biochemical dissection of two LOXL2 protein forms—a nuclear ~75 kDa non-glycosylated species that stabilizes Snail1, and a secreted ~100 kDa N-glycosylated form—provided a molecular framework for its compartment-specific functions.","evidence":"Subcellular fractionation, glycosylation analysis, localization-targeted LOXL2 constructs, invasion assays","pmids":["24014025"],"confidence":"High","gaps":["The protease responsible for N-terminal processing of nuclear LOXL2 was not identified","How the two forms are differentially trafficked from the same transcript was not resolved"]},{"year":2013,"claim":"Reconstitution of secreted LOXL2-mediated fibroblast activation through integrin-FAK signaling on collagen matrices demonstrated the mechanism by which tumor-derived LOXL2 reprograms the stromal compartment.","evidence":"Recombinant LOXL2, collagen contraction assays, FAK phosphorylation, antibody inhibition, mammary tumor models","pmids":["24008674"],"confidence":"High","gaps":["Whether LOXL2 activates FAK through collagen crosslinking products or direct receptor engagement was not distinguished"]},{"year":2014,"claim":"Identification of LOXL2 as the critical LOX isoform crosslinking insoluble tumor collagen, with its expression directly regulated by ZEB1, positioned LOXL2 within the EMT-ZEB1 regulatory network as the effector of ECM stiffening.","evidence":"In vivo collagen crosslinking analysis, FAK/SRC signaling, miR-200/ZEB1 axis validation in lung cancer models","pmids":["27694892"],"confidence":"High","gaps":["Relative substrate specificity of LOXL2 versus other LOX family members for specific collagen types was not determined"]},{"year":2015,"claim":"Discovery that LOXL2 oxidizes methylated TAF10 to evict TFIID from promoters of pluripotency genes revealed a nuclear enzymatic function entirely distinct from ECM crosslinking, establishing LOXL2 as a transcriptional regulator through direct substrate oxidation.","evidence":"Unbiased proteomic substrate identification, in vitro oxidation assay, TAF10 promoter occupancy, zebrafish developmental model","pmids":["25959397"],"confidence":"High","gaps":["Whether TAF10 oxidation is a widespread mechanism across differentiated cell types or restricted to stem/progenitor cells was not tested","The oxidized residue on TAF10 was not structurally characterized"]},{"year":2016,"claim":"Demonstration that recombinant LOXL2 specifically deaminates H3K4me3, confirmed by IR spectroscopy and mass spectrometry, established an unconventional histone-modifying activity that directly controls E-cadherin transcription.","evidence":"Infrared spectroscopy, mass spectrometry, in vitro deamination with recombinant protein, ChIP/gene expression","pmids":["27735137"],"confidence":"High","gaps":["Genome-wide scope of H3K4me3 deamination targets was not mapped","Whether this activity is reversible or regulated was not explored"]},{"year":2016,"claim":"Identification of the PI3K/AKT-TGF-β2 signaling axis downstream of cardiac fibroblast-secreted LOXL2 established a mechanistic link between collagen crosslinking and myofibroblast transformation in cardiac fibrosis, validated by genetic knockout and antibody inhibition.","evidence":"Loxl2 knockout, anti-LOXL2 antibody, in vivo cardiac stress models, PI3K/AKT and TGF-β2 pathway analysis","pmids":["27966531"],"confidence":"High","gaps":["Whether LOXL2 acts upstream of TGF-β2 solely through ECM stiffening or through direct signaling was not fully separated"]},{"year":2017,"claim":"ER-localized LOXL2 interacting with HSPA5 to activate the IRE1-XBP1 UPR pathway, which then transcribes EMT factors (SNAI1, SNAI2, ZEB2, TCF3), revealed an unexpected ER stress-mediated mechanism for LOXL2-driven EMT.","evidence":"Co-IP, subcellular fractionation, IRE1 inhibitor epistasis, XBP1 target gene analysis","pmids":["28332555"],"confidence":"High","gaps":["Whether ER accumulation is an artifact of overexpression or a physiologically regulated process was not resolved"]},{"year":2017,"claim":"Transgenic mouse models showed LOXL2 promotes breast cancer metastasis through Snail1 stabilization and cytokine-driven premetastatic niche formation independently of ECM stiffness, separating its intracellular signaling roles from its matrix-crosslinking function in vivo.","evidence":"Conditional PyMT transgenic models with LOXL2 ablation or overexpression, ECM stiffness measurement, cytokine profiling","pmids":["28720577"],"confidence":"High","gaps":["The specific cytokines and their receptors forming the premetastatic niche were not fully characterized"]},{"year":2019,"claim":"Structural studies revealing LOXL2's rod-like architecture (SRCR stalk, catalytic domain at tip) and direct binding/deamination of tropoelastin to generate cross-linked elastin-like material extended its substrate repertoire beyond collagen to elastogenesis.","evidence":"X-ray scattering, electron microscopy, proteomics of allysines and cross-links, direct binding assay, mechanical testing","pmids":["30676771"],"confidence":"High","gaps":["No atomic-resolution crystal structure was obtained","Elastin crosslinking role in vivo was not validated"]},{"year":2019,"claim":"Interactome analysis identified cytoplasmic LOXL2 as an activator of ezrin (via PKCα-dependent T567 phosphorylation) and interactor with fascin, HSPB1, and TMOD3, establishing a catalytic-activity-independent cytoskeletal remodeling mechanism in esophageal cancer invasion.","evidence":"Mass spectrometry interactome, Co-IP validation, ezrin phosphorylation assays, depletion/re-expression, invasion assays","pmids":["31409639"],"confidence":"High","gaps":["Whether LOXL2 directly phosphorylates ezrin or acts as an adaptor for PKCα was not distinguished","Structural basis of SRCR-cytoskeletal protein interaction was not determined"]},{"year":2022,"claim":"Discovery that LOXL2 (and its catalytically inactive Δe13 variant) directly deacetylates aldolase A at K13 to enhance glycolysis revealed an unexpected deacetylase activity, establishing LOXL2 as a metabolic reprogramming enzyme in esophageal cancer.","evidence":"SILAC proteomics, in vitro deacetylation assay, Loxl2 knock-in mouse with transcriptomic/metabolomic validation","pmids":["36209516"],"confidence":"High","gaps":["The catalytic mechanism of deacetylation (versus canonical amine oxidase chemistry) was not structurally explained","Breadth of the deacetylase substrate repertoire is unknown"]},{"year":2022,"claim":"Identification of tumor-associated macrophage-secreted oncostatin M as an inducer of LOXL2, combined with GEMM studies showing Loxl2 ablation reduces pancreatic cancer metastasis primarily through non-cell-autonomous ECM remodeling, established the immune microenvironment–LOXL2–ECM axis.","evidence":"Four conditional GEMMs (KPC/KC backgrounds), collagen ECM analysis, macrophage targeting, OSM signaling studies","pmids":["35428659"],"confidence":"High","gaps":["The OSM receptor signaling cascade activating LOXL2 transcription was not fully delineated"]},{"year":2023,"claim":"Genetic epistasis between Loxl2 and Loxl4 in bleomycin lung fibrosis showed LOXL4—not LOXL2—is the dominant collagen crosslinker in lung, with Loxl2 knockout alone producing only modest effects, tempering expectations for LOXL2-targeted anti-fibrotic therapy in the lung.","evidence":"Single and double Loxl2/Loxl4 knockout mice, bleomycin model, collagen crosslinking biochemistry, histological fibrosis assessment","pmids":["37753805"],"confidence":"High","gaps":["Whether LOXL2 and LOXL4 have redundant versus tissue-specific roles in other organs (liver, heart) was not tested","Compensatory changes in other LOX family members upon single knockout not fully characterized"]},{"year":null,"claim":"Key open questions include: the atomic-resolution structure of full-length LOXL2, the catalytic mechanism underlying its deacetylase activity on non-amine substrates, the identity of the cell-surface receptor mediating LOXL2 internalization, and whether LOXL2's catalytic-independent functions are therapeutically targetable.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution crystal or cryo-EM structure of full-length LOXL2","Deacetylase mechanism not reconciled with known LTQ amine oxidase chemistry","LOXL2 internalization receptor unidentified","Therapeutic window for catalytic versus non-catalytic functions not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[10,19,9,24]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,10,24]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,15,20]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[20,32]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,9,10,27]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,4,8,19]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,20]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4,8,12,19,28,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,7,11,26,39]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9,10,1]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,13,24,28]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,14,25]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[24,25]}],"complexes":["LCN2-LOXL2-MMP9 ternary complex"],"partners":["SNAI1","TCF3","GATA6","EZR","TAF10","HSPA5","MARCKSL1","LCN2"],"other_free_text":[]},"mechanistic_narrative":"LOXL2 is a copper-dependent amine oxidase with dual extracellular and intracellular functions that drive extracellular matrix remodeling, epithelial-to-mesenchymal transition (EMT), and transcriptional reprogramming across fibrotic and neoplastic contexts. Extracellularly, LOXL2 crosslinks collagen and tropoelastin via lysine deamination, stiffening the ECM and activating FAK/SRC and PI3K/AKT signaling in stromal fibroblasts and tumor cells to promote invasion, fibrosis, and premetastatic niche formation [PMID:19625348, PMID:24008674, PMID:27966531, PMID:30676771]. Intracellularly, a non-glycosylated nuclear form stabilizes Snail1 to repress E-cadherin, deaminates H3K4me3 to silence gene transcription, oxidizes TAF10 to displace TFIID from promoters controlling pluripotency genes, and deacetylates aldolase A to reprogram glycolysis [PMID:24014025, PMID:27735137, PMID:25959397, PMID:36209516]. Several functions—including inhibition of keratinocyte differentiation, cytoskeletal reorganization through ezrin phosphorylation, and rhabdomyosarcoma metastasis—are independent of catalytic activity and instead require the SRCR protein-interaction domains, while LOXL2 expression is transcriptionally induced by HIF-1 under hypoxia, by ZEB1/ZEB2, SP1, and YAP, and post-translationally stabilized by TRIM44-mediated deubiquitination [PMID:22157764, PMID:31409639, PMID:31911079, PMID:20026874, PMID:30976063, PMID:35271888, PMID:36512309]."},"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":"2990028","id":"PMC_2990028","title":"A 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intracellular LOXL2 additionally activates the Snail/E-cadherin pathway; antibody-mediated neutralization of secreted LOXL2 inhibited tumor growth and metastasis.\",\n      \"method\": \"RNA interference knockdown, ectopic overexpression, in vitro invasion assays, in vivo metastasis models, pathway analysis by western blot\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, OE, in vivo, antibody inhibition) with defined mechanistic pathway placement\",\n      \"pmids\": [\"19625348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LOXL2 is a direct transcriptional target of HIF-1 under hypoxia, and activation of LOXL2 (together with LOX) is required and sufficient for hypoxic repression of E-cadherin, driving epithelial-to-mesenchymal transition and cellular invasion.\",\n      \"method\": \"HIF-1 transcriptional target validation, gene expression analysis, E-cadherin reporter assays, cellular invasion assays, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct transcriptional target validation with functional rescue and invasion readout, replicated concept across labs\",\n      \"pmids\": [\"20026874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LOXL2 promotes breast cancer invasion by regulating the expression and activity of extracellular proteins TIMP1 and MMP9; 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\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal inhibition strategies with defined TIMP1/MMP9 mechanism in vivo\",\n      \"pmids\": [\"21233336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Intracellular (perinuclear/cytoplasmic) LOXL2 maintains mesenchymal phenotype of basal-like breast carcinoma cells by transcriptional downregulation of Lgl2 and claudin1, causing disorganization of cell polarity and tight junction complexes; LOXL2 silencing induces mesenchymal-to-epithelial transition.\",\n      \"method\": \"LOXL2 siRNA silencing, gene expression analysis, cell polarity assays, in vivo metastasis models\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined transcriptional targets and in vivo validation\",\n      \"pmids\": [\"21732535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tumor-secreted LOXL2 directly activates stromal fibroblasts through integrin-mediated focal adhesion kinase (FAK) activation, inducing fibroblast branching on collagen matrices, increased collagen contraction, fibroblast invasion, and α-SMA expression.\",\n      \"method\": \"In vitro fibroblast activation assays, collagen contraction assays, LOXL2 genetic manipulation and antibody inhibition, in vivo mammary tumor models, western blot for FAK phosphorylation\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reconstitution with recombinant protein, multiple orthogonal methods, in vitro and in vivo validation\",\n      \"pmids\": [\"24008674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nuclear-associated intracellular LOXL2 (~75 kDa, non-glycosylated, N-terminally processed) stabilizes Snail1 transcription factor at the protein level to induce EMT and promote invasion, repressing E-cadherin, occludin, and estrogen receptor-α while upregulating vimentin, fibronectin, and MT1-MMP. Secreted LOXL2 (~100 kDa) is N-glycosylated at Asn-455 and Asn-644.\",\n      \"method\": \"Stable expression of subcellular-localization variants of LOXL2, subcellular fractionation, glycosylation analysis, invasion assays, western blot for EMT markers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — biochemical characterization of two LOXL2 forms with distinct glycosylation and localization, functional dissection by subcellular targeting\",\n      \"pmids\": [\"24014025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LOXL2 physically interacts with the bHLH transcription factor E47 and functionally collaborates in repression of the E-cadherin promoter; both LOXL2 and E47 are required for lung metastasis and contribute to early metastatic colonization by regulating fibronectin and cytokines (TNFα, ANG-1, GM-CSF) and recruiting bone marrow progenitor cells.\",\n      \"method\": \"Co-immunoprecipitation, loss- and gain-of-function analyses, in vivo syngeneic breast cancer models, chromatin studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional validation in vivo\",\n      \"pmids\": [\"24632622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LOXL2 interacts physically with MARCKSL1 via its scavenger receptor domain (interacting with the N-terminal domain of MARCKSL1), and activates FAK/Akt/mTOR signaling pathways to promote cell proliferation and inhibit apoptosis in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, luciferase assays, siRNA knockdown, cell cycle and apoptosis analysis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with domain mapping and signaling pathway readout, single lab\",\n      \"pmids\": [\"24863880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LOXL2 is the critical isoform that crosslinks and stabilizes insoluble collagen in tumor extracellular matrix; this crosslinked collagen activates focal adhesion formation and FAK/SRC signaling in mesenchymal tumor cells, and LOXL2 expression is directly regulated by ZEB1 while LOX is regulated by miR-200.\",\n      \"method\": \"In vivo collagen crosslinking analysis, FAK/SRC signaling assays, miR-200/ZEB1 axis validation, in vitro and in vivo lung cancer models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods including in vivo collagen analysis and signaling validation\",\n      \"pmids\": [\"27694892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LOXL2 oxidizes methylated TAF10 (a TFIID complex member), inducing TAF10 release from promoters and blocking TFIID-dependent gene transcription. In embryonic stem cells, this inactivates pluripotency genes; in zebrafish, loss of LOXL2 causes aberrant Sox2 overexpression and impaired neural differentiation.\",\n      \"method\": \"Unbiased proteomic identification of LOXL2 substrate, in vitro oxidation assay, TAF10 promoter occupancy studies, zebrafish developmental model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with substrate identification by proteomics, validated in vivo in zebrafish\",\n      \"pmids\": [\"25959397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Recombinant LOXL2 specifically deaminates trimethylated H3K4 (H3K4me3), and by regulating H3K4me3 deamination, LOXL2 controls transcription of the CDH1 (E-cadherin) gene. This is an unconventional H3K4 modification mechanism.\",\n      \"method\": \"Infrared spectroscopy, mass spectrometry, in vitro deamination assay with recombinant LOXL2, chromatin immunoprecipitation/gene expression analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with recombinant protein confirmed by two orthogonal biochemical methods (IR spectroscopy + MS)\",\n      \"pmids\": [\"27735137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cardiac fibroblast-secreted LOXL2 crosslinks collagen in the cardiac interstitium and stimulates cardiac 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. Antibody-mediated inhibition or genetic disruption of LOXL2 reduces cardiac fibrosis and improves cardiac function.\",\n      \"method\": \"Genetic knockout, antibody inhibition, in vivo cardiac stress models, PI3K/AKT pathway analysis, TGF-β2 signaling studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and antibody-mediated loss-of-function with defined PI3K/AKT/TGF-β2 pathway placement, in vivo validation\",\n      \"pmids\": [\"27966531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LOXL2 mediates collagen crosslinking and fibrotic matrix stabilization in liver fibrosis, and independently promotes fibrogenic hepatic progenitor cell (HPC) differentiation toward ductal lineage; anti-LOXL2 antibody treatment reduces collagen crosslinking, promotes fibrosis reversal, and redirects HPC differentiation toward hepatocytes.\",\n      \"method\": \"Anti-LOXL2 monoclonal antibody treatment in three mouse fibrosis models, collagen crosslinking assays, morphometric collagen quantification, primary EpCAM+ HPC differentiation assays in vitro\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — three independent mouse models plus in vitro HPC differentiation with biochemical crosslinking readout\",\n      \"pmids\": [\"28073888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LOXL2 overexpression in breast cancer promotes metastatic tumor growth through mechanisms independent of extracellular matrix stiffness or organization, associated instead with elevated Snail1 levels and expression of cytokines that promote premetastatic niche formation.\",\n      \"method\": \"Conditional transgenic mouse models (PyMT-induced breast cancer with LOXL2 ablation or overexpression), ECM stiffness measurements, molecular analysis of EMT markers and cytokines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent transgenic mouse models with functional readout and ECM-independent mechanism identified\",\n      \"pmids\": [\"28720577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Overexpressed LOXL2 accumulates in the endoplasmic reticulum where it interacts with HSPA5 (GRP78), activating the IRE1-XBP1 unfolded protein response pathway; XBP1 then directly transcribes EMT transcription factors SNAI1, SNAI2, ZEB2, and TCF3; IRE1 inhibition blocks LOXL2-dependent EMT.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, IRE1 inhibitor experiments, XBP1 target gene analysis, epistasis by IRE1 inhibition\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with pathway epistasis and inhibitor rescue, mechanistic chain from ER accumulation to transcription factor induction\",\n      \"pmids\": [\"28332555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The enzymatic activity of LOXL2 is not required for its inhibition of keratinocyte differentiation; a catalytically inactive point mutant (Y689F) and a deletion mutant lacking the entire catalytic domain retain this activity, which requires the fourth scavenger receptor-cysteine-rich (SRCR) domain. LOXL2 can be internalized by HaCaT cells via a putative receptor, inhibited by the function-blocking antibody AB0023.\",\n      \"method\": \"Point mutagenesis (Y689F), domain deletion mutants, β-aminopropionitrile (BAPN) treatment, antibody inhibition (AB0023), keratinocyte differentiation assays, internalization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active site mutagenesis and domain deletion with functional validation, multiple inhibition approaches\",\n      \"pmids\": [\"22157764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LOXL2 is the major isoform expressed in chondrocytes and is required for chondrocyte differentiation; LOXL2 knockdown in ATDC5 chondrogenic cells disrupts differentiation through regulation of transcription factors SNAIL and SOX9.\",\n      \"method\": \"LOXL2 knockdown by siRNA, chondrocyte differentiation assays, gene expression analysis of SNAIL and SOX9, in vivo growth plate expression studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined transcriptional targets (SNAIL, SOX9), but single lab study\",\n      \"pmids\": [\"21071451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LOXL2 regulates the protein stability of integrins α5 (ITGA5) and β1 (ITGB1) via protease- and proteasome-dependent systems in clear cell renal cell carcinoma; LOXL2 knockdown suppresses stress fiber and focal adhesion formation, and inhibits cell growth, migration, and invasion.\",\n      \"method\": \"RNAi knockdown, integrin protein stability assays with protease/proteasome inhibitors, stress fiber/focal adhesion imaging, cell migration and invasion assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic identification of integrin degradation via two proteolytic systems, single lab\",\n      \"pmids\": [\"25092917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A novel alternative splicing isoform LOXL2 Δe13 (lacking exon 13) has impaired deamination enzymatic activity but promotes cell migration and invasion more strongly than full-length LOXL2 via induction of MAPK8 (JNK), rather than through FAK, AKT, or ERK pathways.\",\n      \"method\": \"Identification of splice variant, enzymatic activity assay, gene expression profiling, MAPK8 knockdown rescue experiments, cell migration/invasion assays\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — enzymatic characterization combined with pathway epistasis via MAPK8 knockdown, single lab\",\n      \"pmids\": [\"25275797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LOXL2 has a rod-like structure with SRCR domains forming a stalk and the catalytic domain at the tip; LOXL2 directly interacts with tropoelastin and catalyzes its deamination, generating cross-linked elastin-like material with mechanical properties similar to mature elastin, suggesting LOXL2 participates in elastogenesis.\",\n      \"method\": \"X-ray scattering, electron microscopy, proteomics identification of allysines and cross-linked peptides, direct binding assay between LOXL2 and tropoelastin, in vitro deamination assay, trypsin resistance assay, mechanical property testing\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination combined with in vitro enzymatic activity and substrate identification by proteomics\",\n      \"pmids\": [\"30676771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cytoplasmic LOXL2 and its catalytically inactive splice variant L2Δ13 interact physically with the actin-binding proteins ezrin (EZR), fascin (FSCN1), HSPB1, and tropomodulin-3 (TMOD3); LOXL2 promotes phosphorylation of ezrin at T567 (requiring PKCα) to drive cytoskeletal reorganization and tumor cell invasion in esophageal squamous cell carcinoma.\",\n      \"method\": \"Interactome analysis (mass spectrometry), Co-IP validation, ezrin phosphorylation assays, LOXL2 depletion/re-expression experiments, cell invasion assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS interactome with Co-IP validation, defined phosphorylation event and PKCα requirement, functional rescue experiments\",\n      \"pmids\": [\"31409639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LOXL2 activates lung fibroblasts through the TGF-β/Smad pathway; LOXL2 silencing decreases fibroblast proliferation, IL-6 and COL1A1 production, and inhibits phospho-Smad2/3, Smad4, and Snail expression while promoting Smad7.\",\n      \"method\": \"LOXL2 siRNA adenoviral vector, mouse lung fibroblast culture, TGF-β/Smad pathway western blot, proliferation assay, ELISA for IL-6 and COL1A1\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with defined TGF-β/Smad pathway readout, single lab\",\n      \"pmids\": [\"30320382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LOXL2 interacts physically with GATA6 via its scavenger receptor cysteine-rich domain, and the GATA6/LOXL2 complex positively regulates VEGFA mRNA expression and secretion to promote angiogenesis and tumor growth in cholangiocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, western blot, ELISA, luciferase reporter assay, in vivo angiogenesis and tumor growth models\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with domain mapping and in vivo validation, single lab\",\n      \"pmids\": [\"31322171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wnt signaling promotes c-Fos-induced osteosarcoma via LOXL2: c-Fos/AP-1 directly regulates Wnt7b and Wnt9a expression via promoter binding, and these Wnt ligands promote LOXL2 expression through ZEB1 and ZEB2 transcription factors. LOXL2 inhibition (BAPN or specific antibodies) reduces OS cell proliferation and tumor growth.\",\n      \"method\": \"Genetically engineered mouse models, promoter binding assays (AP-1), conditional Wls knockout, shRNA, orthotopic transplantation models, BAPN/antibody inhibition\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple GEMMs with defined pathway (c-Fos→Wnt→ZEB1/2→LOXL2), validated in human OS samples\",\n      \"pmids\": [\"32686768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LOXL2 and its catalytically inactive splice variant L2Δ13 function as deacetylases, directly catalyzing deacetylation of aldolase A at K13, resulting in enhanced glycolysis, metabolic reprogramming, and tumor progression in esophageal cancer.\",\n      \"method\": \"SILAC proteomics, in vitro deacetylation assay, transcriptomic and metabolomic analysis of knock-in mouse model, Co-IP of LOXL2 with glycolytic enzymes, aldolase activity assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic deacetylation demonstrated with SILAC proteomics, confirmed in knock-in mouse model with orthogonal transcriptomic and metabolomic analyses\",\n      \"pmids\": [\"36209516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LOXL2 stabilizes HIF1α from prolyl hydroxylase-dependent hydroxylation via hydrogen peroxide generation, creating a positive feedback loop between LOXL2 and HIF1α that facilitates glycolytic gene transcription (Warburg effect) in pancreatic cancer.\",\n      \"method\": \"HIF1α stability assay, hydroxylation assay, hydrogen peroxide measurement, glycolytic gene expression analysis, in vivo tumor growth studies\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined biochemical mechanism (H2O2-mediated HIF1α stabilization) with functional glycolytic readout, single lab\",\n      \"pmids\": [\"34836938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LOXL2 forms a ternary complex with LCN2 and MMP9; LCN2-LOXL2 and LCN2-MMP9 interactions occur both intracellularly and extracellularly, while LOXL2-MMP9 interaction occurs only intracellularly. The complex promotes fibronectin degradation, filopodia formation, microfilament rearrangement via profilin 1 upregulation, and activates FAK/AKT/GSK3β signaling.\",\n      \"method\": \"Co-immunoprecipitation, subcellular localization assays, migration/invasion assays, in vivo tumor growth studies, fibronectin degradation assay\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — protein complex identification with defined subcellular locations and signaling pathway activation, single lab\",\n      \"pmids\": [\"37753805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nuclear LOXL2 in lung fibroblasts is a primary driver of myofibroblast differentiation; TGF-β1 upregulates nuclear LOXL2 expression, and LOXL2 silencing abrogates TGF-β1-induced proto-myofibroblast appearance and myofibroblast evolution. Nuclear LOXL2 expression correlates with nuclear Snail upregulation in myofibroblasts.\",\n      \"method\": \"LOXL2 silencing in lung fibroblasts, TGF-β1 stimulation, nuclear fractionation, myofibroblast differentiation assays, in vivo mouse lung injury model, ARDS patient lung samples\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined myofibroblast differentiation phenotype and nuclear localization, validated in human ARDS samples\",\n      \"pmids\": [\"33248114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Tumor-associated macrophage-secreted oncostatin M (OSM) induces LOXL2 expression in pancreatic cancer cells; Loxl2 ablation in vivo decreases metastasis and increases overall survival primarily through non-cell-autonomous ECM remodeling, while Loxl2 overexpression promotes EMT and stemness.\",\n      \"method\": \"Conditional GEMMs (KPC/KC crossed with Loxl2 floxed or conditional overexpression mice), collagen ECM analysis, macrophage targeting in vivo, OSM signaling studies\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — four GEMM-based models identifying macrophage-OSM-LOXL2 axis with defined in vivo phenotypes\",\n      \"pmids\": [\"35428659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Genetic ablation of LOXL2 alone leads to only modest reduction of pathological collagen crosslinking without preventing lung fibrosis, while LOXL4 is the main LOX family member driving pathological collagen crosslinking and fibrosis in the lung; LOXL4 deficiency decreases expression of other LOX family members including LOXL2.\",\n      \"method\": \"Genetic knockout of Loxl2 and/or Loxl4, bleomycin lung fibrosis model, collagen crosslinking biochemical assays, histological fibrosis assessment\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — genetic epistasis between LOXL2 and LOXL4 with biochemical crosslinking readout, defines relative contribution of each enzyme\",\n      \"pmids\": [\"37235663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LATS1 phosphorylates LOXL2 in ovarian granulosa cells; miR-21 from hucMSC-derived exosomes downregulates LATS1, reducing phosphorylated LOXL2 and YAP levels, promoting estrogen secretion. YAP binds to the LOXL2 promoter to positively regulate LOXL2 transcription.\",\n      \"method\": \"Immunoprecipitation for LATS1-LOXL2 interaction, dual-luciferase reporter and ChIP assay for YAP-LOXL2 promoter binding, miR-21/LATS1 target validation by luciferase and RIP, ELISA for estradiol\",\n      \"journal\": \"General and comparative endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP for phosphorylation, ChIP for promoter binding, single lab with multiple targets\",\n      \"pmids\": [\"35271888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Pharmacological inhibition of CAF-derived LOXL2 perturbs extracellular matrix organization and decreases CAF migration; it also significantly impairs motility of co-cultured prostate tumor epithelial cells. Increased LOXL2 expression and activity was confirmed in cancer-associated fibroblasts (CAFs) versus normal prostate fibroblasts.\",\n      \"method\": \"LC-MS/MS proteomics, LOXL2 enzymatic activity assay, western blotting, LOXL2 pharmacological inhibition, wound healing assay, co-culture motility assay\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — enzymatic activity confirmation with pharmacological inhibition and defined cellular phenotype, single lab\",\n      \"pmids\": [\"31061140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LOXL2 promotes migration and invasion of rhabdomyosarcoma cells independently of its catalytic activity; vimentin was identified as a LOXL2-interacting protein, suggesting LOXL2 regulates cytoskeleton dynamics and cell motility through this interaction.\",\n      \"method\": \"LOXL2 knockdown and stable expression of wild-type vs. catalytically inactive mutants, pull-down assay with mass spectrometry, vimentin validation as interactor, in vivo lung metastasis model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pull-down/MS for interactor identification with catalytically inactive mutant showing retained function, in vivo validation\",\n      \"pmids\": [\"31911079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LOXL2 enhances Atg7 expression by promoting ERK1/2 phosphorylation, leading to autophagy activation, which in turn mediates EMT and temozolomide resistance in glioma cells.\",\n      \"method\": \"LOXL2 overexpression/knockdown, autophagy assays, ERK1/2 phosphorylation analysis, Atg7 expression analysis, chemosensitivity assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, defined signaling axis but no structural or reconstitution evidence; epistasis based on inhibitor studies\",\n      \"pmids\": [\"33194658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SP1 transcription factor directly binds the LOXL2 promoter to regulate LOXL2 expression, and this SP1→LOXL2 axis promotes EMT, invasion, and migration in pancreatic ductal adenocarcinoma; LOXL2 silencing does not reciprocally affect SP1 expression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for SP1 binding to LOXL2 promoter, siRNA double knockdown of SP1 and LOXL2, invasion/migration assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct promoter binding with functional epistasis by double knockdown, single lab\",\n      \"pmids\": [\"30976063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM44 deubiquitinase directly binds LOXL2 and stabilizes it by reducing its ubiquitination; TRIM44 knockdown decreases LOXL2 protein levels and suppresses ECM remodeling and tumor immunity in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assays, TRIM44 knockdown with LOXL2 rescue\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct Co-IP with ubiquitination assay demonstrating TRIM44 as LOXL2 stabilizer, single lab\",\n      \"pmids\": [\"36512309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Matrix stiffness promotes LOXL2 expression in M2 macrophages through activation of the integrin β5-FAK-MEK1/2-ERK1/2 pathway leading to HIF-1α upregulation, which transcriptionally induces LOXL2.\",\n      \"method\": \"Gel-based stiffness culture system, M2 macrophage polarization model, pathway inhibition experiments, HIF-1α knockdown, western blot for pathway components\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined signaling pathway with pathway inhibition experiments, single lab\",\n      \"pmids\": [\"32964626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LOXL2 attenuates osteoarthritis in TMJ cartilage partly through activation of the Integrin/FAK signaling pathway in chondrocytes; inhibition of Integrin/FAK neutralizes the protective effect of recombinant LOXL2.\",\n      \"method\": \"In vivo compressive mechanical force model, IL-1β in vitro model, recombinant LOXL2 treatment, anti-LOXL2 antibody treatment, Integrin/FAK pathway inhibitor epistasis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway epistasis with inhibitor rescue, in vivo and in vitro validation, single lab\",\n      \"pmids\": [\"34426599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LOXL2 enhances keratinocyte migration and differentiation to promote wound healing by activating the JNK signaling pathway; SP600125 (JNK inhibitor) blocks LOXL2-mediated keratinocyte migration and differentiation.\",\n      \"method\": \"Recombinant LOXL2 treatment of keratinocytes, JNK pathway inhibitor (SP600125), LOXL2-silenced hAMSC conditioned medium, in vivo mouse wound healing model\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — inhibitor epistasis with in vivo wound healing validation, single lab\",\n      \"pmids\": [\"32621591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RPS7 RNA-binding protein stabilizes LOXL2 mRNA by binding AUUUA motifs in the 3155–3375 region of the LOXL2 3'UTR, increasing LOXL2 protein abundance; LOXL2 in turn maintains ITGB1 protein stability and activates ITGB1-mediated FAK/SRC signaling to promote HCC metastasis.\",\n      \"method\": \"RNA sequencing, RIP assay, RNA-pulldown, dual-luciferase reporter assay, RNA decay assay, CRISPR-Cas9 knockout, LOXL2 ITGB1 stability assay, FAK/SRC signaling analysis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP and RNA-pulldown for mRNA binding, defined ITGB1 stability mechanism, single lab\",\n      \"pmids\": [\"38326908\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LOXL2 is a copper-dependent lysine tyrosylquinone amine oxidase that functions both extracellularly (crosslinking collagen and tropoelastin via deamination of lysine residues to drive ECM stiffening, fibrosis, and premetastatic niche formation) and intracellularly (as a nuclear enzyme that deaminates H3K4me3 and oxidizes TAF10 to control gene transcription, deacetylates aldolase A to promote glycolytic reprogramming, and stabilizes Snail1 to drive EMT), with the SRCR domains mediating protein-protein interactions (including with GATA6, MARCKSL1, HSPA5, and ezrin) and some activities—including inhibition of keratinocyte differentiation, cytoskeletal reorganization, and promotion of rhabdomyosarcoma metastasis—occurring independently of catalytic activity; upstream, LOXL2 is transcriptionally induced by HIF-1 under hypoxia, by ZEB1/ZEB2, by SP1, by YAP, and by oncostatin M from tumor-associated macrophages, while its protein stability is controlled by TRIM44-mediated deubiquitination and LATS1-mediated phosphorylation, and downstream it activates FAK/SRC, PI3K/AKT, IRE1-XBP1, TGF-β/Smad, and ERK1/2 signaling cascades to drive invasion, metastasis, fibrosis, and chemoresistance across multiple cancer types and fibrotic diseases.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LOXL2 is a copper-dependent amine oxidase with dual extracellular and intracellular functions that drive extracellular matrix remodeling, epithelial-to-mesenchymal transition (EMT), and transcriptional reprogramming across fibrotic and neoplastic contexts. Extracellularly, LOXL2 crosslinks collagen and tropoelastin via lysine deamination, stiffening the ECM and activating FAK/SRC and PI3K/AKT signaling in stromal fibroblasts and tumor cells to promote invasion, fibrosis, and premetastatic niche formation [PMID:19625348, PMID:24008674, PMID:27966531, PMID:30676771]. Intracellularly, a non-glycosylated nuclear form stabilizes Snail1 to repress E-cadherin, deaminates H3K4me3 to silence gene transcription, oxidizes TAF10 to displace TFIID from promoters controlling pluripotency genes, and deacetylates aldolase A to reprogram glycolysis [PMID:24014025, PMID:27735137, PMID:25959397, PMID:36209516]. Several functions—including inhibition of keratinocyte differentiation, cytoskeletal reorganization through ezrin phosphorylation, and rhabdomyosarcoma metastasis—are independent of catalytic activity and instead require the SRCR protein-interaction domains, while LOXL2 expression is transcriptionally induced by HIF-1 under hypoxia, by ZEB1/ZEB2, SP1, and YAP, and post-translationally stabilized by TRIM44-mediated deubiquitination [PMID:22157764, PMID:31409639, PMID:31911079, PMID:20026874, PMID:30976063, PMID:35271888, PMID:36512309].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing that LOXL2 has functionally separable extracellular and intracellular pro-invasive activities resolved how one enzyme promotes both stromal remodeling (via Src/FAK) and EMT (via Snail/E-cadherin) in gastric cancer.\",\n      \"evidence\": \"RNA interference, overexpression, in vivo metastasis models, and antibody neutralization in gastric cancer cells\",\n      \"pmids\": [\"19625348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The intracellular mechanism by which LOXL2 engages Snail was not biochemically defined\", \"Relative contribution of each compartmental activity to metastasis in vivo was not quantified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of LOXL2 as a direct HIF-1 transcriptional target established hypoxia as a key upstream inducer, linking tumor microenvironment oxygen sensing to EMT via E-cadherin repression.\",\n      \"evidence\": \"HIF-1 target validation, E-cadherin reporter assays, siRNA knockdown, invasion assays\",\n      \"pmids\": [\"20026874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HIF-1-driven LOXL2 induction is sufficient versus cooperative with other HIF targets was not separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstration that a catalytically inactive LOXL2 mutant (Y689F) retains the ability to inhibit keratinocyte differentiation—requiring only the fourth SRCR domain—established that LOXL2 exerts important biological functions through protein-protein interactions independent of its oxidase activity.\",\n      \"evidence\": \"Active-site mutagenesis, domain deletion, BAPN inhibition, antibody AB0023 blocking, keratinocyte differentiation assays\",\n      \"pmids\": [\"22157764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The receptor mediating LOXL2 internalization into keratinocytes was not identified\", \"Whether catalytic-independent functions extend to other cell types was unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing that intracellular LOXL2 maintains mesenchymal identity by repressing polarity regulators (Lgl2, claudin1) extended its role beyond E-cadherin to broader epithelial architecture control in basal-like breast cancer.\",\n      \"evidence\": \"siRNA silencing, gene expression analysis, cell polarity assays, in vivo metastasis models\",\n      \"pmids\": [\"21732535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LOXL2 directly or indirectly represses these polarity genes was not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Biochemical dissection of two LOXL2 protein forms—a nuclear ~75 kDa non-glycosylated species that stabilizes Snail1, and a secreted ~100 kDa N-glycosylated form—provided a molecular framework for its compartment-specific functions.\",\n      \"evidence\": \"Subcellular fractionation, glycosylation analysis, localization-targeted LOXL2 constructs, invasion assays\",\n      \"pmids\": [\"24014025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The protease responsible for N-terminal processing of nuclear LOXL2 was not identified\", \"How the two forms are differentially trafficked from the same transcript was not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Reconstitution of secreted LOXL2-mediated fibroblast activation through integrin-FAK signaling on collagen matrices demonstrated the mechanism by which tumor-derived LOXL2 reprograms the stromal compartment.\",\n      \"evidence\": \"Recombinant LOXL2, collagen contraction assays, FAK phosphorylation, antibody inhibition, mammary tumor models\",\n      \"pmids\": [\"24008674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LOXL2 activates FAK through collagen crosslinking products or direct receptor engagement was not distinguished\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of LOXL2 as the critical LOX isoform crosslinking insoluble tumor collagen, with its expression directly regulated by ZEB1, positioned LOXL2 within the EMT-ZEB1 regulatory network as the effector of ECM stiffening.\",\n      \"evidence\": \"In vivo collagen crosslinking analysis, FAK/SRC signaling, miR-200/ZEB1 axis validation in lung cancer models\",\n      \"pmids\": [\"27694892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative substrate specificity of LOXL2 versus other LOX family members for specific collagen types was not determined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that LOXL2 oxidizes methylated TAF10 to evict TFIID from promoters of pluripotency genes revealed a nuclear enzymatic function entirely distinct from ECM crosslinking, establishing LOXL2 as a transcriptional regulator through direct substrate oxidation.\",\n      \"evidence\": \"Unbiased proteomic substrate identification, in vitro oxidation assay, TAF10 promoter occupancy, zebrafish developmental model\",\n      \"pmids\": [\"25959397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TAF10 oxidation is a widespread mechanism across differentiated cell types or restricted to stem/progenitor cells was not tested\", \"The oxidized residue on TAF10 was not structurally characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that recombinant LOXL2 specifically deaminates H3K4me3, confirmed by IR spectroscopy and mass spectrometry, established an unconventional histone-modifying activity that directly controls E-cadherin transcription.\",\n      \"evidence\": \"Infrared spectroscopy, mass spectrometry, in vitro deamination with recombinant protein, ChIP/gene expression\",\n      \"pmids\": [\"27735137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide scope of H3K4me3 deamination targets was not mapped\", \"Whether this activity is reversible or regulated was not explored\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of the PI3K/AKT-TGF-β2 signaling axis downstream of cardiac fibroblast-secreted LOXL2 established a mechanistic link between collagen crosslinking and myofibroblast transformation in cardiac fibrosis, validated by genetic knockout and antibody inhibition.\",\n      \"evidence\": \"Loxl2 knockout, anti-LOXL2 antibody, in vivo cardiac stress models, PI3K/AKT and TGF-β2 pathway analysis\",\n      \"pmids\": [\"27966531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LOXL2 acts upstream of TGF-β2 solely through ECM stiffening or through direct signaling was not fully separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"ER-localized LOXL2 interacting with HSPA5 to activate the IRE1-XBP1 UPR pathway, which then transcribes EMT factors (SNAI1, SNAI2, ZEB2, TCF3), revealed an unexpected ER stress-mediated mechanism for LOXL2-driven EMT.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, IRE1 inhibitor epistasis, XBP1 target gene analysis\",\n      \"pmids\": [\"28332555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ER accumulation is an artifact of overexpression or a physiologically regulated process was not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Transgenic mouse models showed LOXL2 promotes breast cancer metastasis through Snail1 stabilization and cytokine-driven premetastatic niche formation independently of ECM stiffness, separating its intracellular signaling roles from its matrix-crosslinking function in vivo.\",\n      \"evidence\": \"Conditional PyMT transgenic models with LOXL2 ablation or overexpression, ECM stiffness measurement, cytokine profiling\",\n      \"pmids\": [\"28720577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The specific cytokines and their receptors forming the premetastatic niche were not fully characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Structural studies revealing LOXL2's rod-like architecture (SRCR stalk, catalytic domain at tip) and direct binding/deamination of tropoelastin to generate cross-linked elastin-like material extended its substrate repertoire beyond collagen to elastogenesis.\",\n      \"evidence\": \"X-ray scattering, electron microscopy, proteomics of allysines and cross-links, direct binding assay, mechanical testing\",\n      \"pmids\": [\"30676771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution crystal structure was obtained\", \"Elastin crosslinking role in vivo was not validated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Interactome analysis identified cytoplasmic LOXL2 as an activator of ezrin (via PKCα-dependent T567 phosphorylation) and interactor with fascin, HSPB1, and TMOD3, establishing a catalytic-activity-independent cytoskeletal remodeling mechanism in esophageal cancer invasion.\",\n      \"evidence\": \"Mass spectrometry interactome, Co-IP validation, ezrin phosphorylation assays, depletion/re-expression, invasion assays\",\n      \"pmids\": [\"31409639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LOXL2 directly phosphorylates ezrin or acts as an adaptor for PKCα was not distinguished\", \"Structural basis of SRCR-cytoskeletal protein interaction was not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that LOXL2 (and its catalytically inactive Δe13 variant) directly deacetylates aldolase A at K13 to enhance glycolysis revealed an unexpected deacetylase activity, establishing LOXL2 as a metabolic reprogramming enzyme in esophageal cancer.\",\n      \"evidence\": \"SILAC proteomics, in vitro deacetylation assay, Loxl2 knock-in mouse with transcriptomic/metabolomic validation\",\n      \"pmids\": [\"36209516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The catalytic mechanism of deacetylation (versus canonical amine oxidase chemistry) was not structurally explained\", \"Breadth of the deacetylase substrate repertoire is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of tumor-associated macrophage-secreted oncostatin M as an inducer of LOXL2, combined with GEMM studies showing Loxl2 ablation reduces pancreatic cancer metastasis primarily through non-cell-autonomous ECM remodeling, established the immune microenvironment–LOXL2–ECM axis.\",\n      \"evidence\": \"Four conditional GEMMs (KPC/KC backgrounds), collagen ECM analysis, macrophage targeting, OSM signaling studies\",\n      \"pmids\": [\"35428659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The OSM receptor signaling cascade activating LOXL2 transcription was not fully delineated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Genetic epistasis between Loxl2 and Loxl4 in bleomycin lung fibrosis showed LOXL4—not LOXL2—is the dominant collagen crosslinker in lung, with Loxl2 knockout alone producing only modest effects, tempering expectations for LOXL2-targeted anti-fibrotic therapy in the lung.\",\n      \"evidence\": \"Single and double Loxl2/Loxl4 knockout mice, bleomycin model, collagen crosslinking biochemistry, histological fibrosis assessment\",\n      \"pmids\": [\"37753805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LOXL2 and LOXL4 have redundant versus tissue-specific roles in other organs (liver, heart) was not tested\", \"Compensatory changes in other LOX family members upon single knockout not fully characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: the atomic-resolution structure of full-length LOXL2, the catalytic mechanism underlying its deacetylase activity on non-amine substrates, the identity of the cell-surface receptor mediating LOXL2 internalization, and whether LOXL2's catalytic-independent functions are therapeutically targetable.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution crystal or cryo-EM structure of full-length LOXL2\", \"Deacetylase mechanism not reconciled with known LTQ amine oxidase chemistry\", \"LOXL2 internalization receptor unidentified\", \"Therapeutic window for catalytic versus non-catalytic functions not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [10, 19, 9, 24]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 10, 24]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 15, 20]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [20, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 9, 10, 27]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4, 8, 19]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4, 8, 12, 19, 28, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 7, 11, 26, 39]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 10, 1]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 13, 24, 28]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 14, 25]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [24, 25]}\n    ],\n    \"complexes\": [\n      \"LCN2-LOXL2-MMP9 ternary complex\"\n    ],\n    \"partners\": [\n      \"SNAI1\",\n      \"TCF3\",\n      \"GATA6\",\n      \"EZR\",\n      \"TAF10\",\n      \"HSPA5\",\n      \"MARCKSL1\",\n      \"LCN2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}