Affinage

LOXL2

Lysyl oxidase homolog 2 · UniProt Q9Y4K0

Length
774 aa
Mass
86.7 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2009 High

    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

    PMID:19625348

    Open questions at the time
    • 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
  2. 2009 High

    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

    PMID:20026874

    Open questions at the time
    • Whether HIF-1-driven LOXL2 induction is sufficient versus cooperative with other HIF targets was not separated
  3. 2011 High

    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

    PMID:22157764

    Open questions at the time
    • The receptor mediating LOXL2 internalization into keratinocytes was not identified
    • Whether catalytic-independent functions extend to other cell types was unclear
  4. 2011 High

    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

    PMID:21732535

    Open questions at the time
    • Whether LOXL2 directly or indirectly represses these polarity genes was not resolved
  5. 2013 High

    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

    PMID:24014025

    Open questions at the time
    • 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
  6. 2013 High

    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

    PMID:24008674

    Open questions at the time
    • Whether LOXL2 activates FAK through collagen crosslinking products or direct receptor engagement was not distinguished
  7. 2014 High

    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

    PMID:27694892

    Open questions at the time
    • Relative substrate specificity of LOXL2 versus other LOX family members for specific collagen types was not determined
  8. 2015 High

    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

    PMID:25959397

    Open questions at the time
    • 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
  9. 2016 High

    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

    PMID:27735137

    Open questions at the time
    • Genome-wide scope of H3K4me3 deamination targets was not mapped
    • Whether this activity is reversible or regulated was not explored
  10. 2016 High

    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

    PMID:27966531

    Open questions at the time
    • Whether LOXL2 acts upstream of TGF-β2 solely through ECM stiffening or through direct signaling was not fully separated
  11. 2017 High

    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

    PMID:28332555

    Open questions at the time
    • Whether ER accumulation is an artifact of overexpression or a physiologically regulated process was not resolved
  12. 2017 High

    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

    PMID:28720577

    Open questions at the time
    • The specific cytokines and their receptors forming the premetastatic niche were not fully characterized
  13. 2019 High

    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

    PMID:30676771

    Open questions at the time
    • No atomic-resolution crystal structure was obtained
    • Elastin crosslinking role in vivo was not validated
  14. 2019 High

    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

    PMID:31409639

    Open questions at the time
    • 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
  15. 2022 High

    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

    PMID:36209516

    Open questions at the time
    • The catalytic mechanism of deacetylation (versus canonical amine oxidase chemistry) was not structurally explained
    • Breadth of the deacetylase substrate repertoire is unknown
  16. 2022 High

    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

    PMID:35428659

    Open questions at the time
    • The OSM receptor signaling cascade activating LOXL2 transcription was not fully delineated
  17. 2023 High

    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

    PMID:37753805

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0008092 cytoskeletal protein binding 2 GO:0042393 histone binding 1
Localization
GO:0005576 extracellular region 4 GO:0005634 nucleus 4 GO:0005829 cytosol 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1474244 Extracellular matrix organization 6 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1430728 Metabolism 2 R-HSA-4839726 Chromatin organization 1
Partners
EZRGATA6HSPA5LCN2MARCKSL1SNAI1TAF10TCF3
Complex memberships
LCN2-LOXL2-MMP9 ternary complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 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. RNA interference knockdown, ectopic overexpression, in vitro invasion assays, in vivo metastasis models, pathway analysis by western blot Carcinogenesis High 19625348
2009 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. HIF-1 transcriptional target validation, gene expression analysis, E-cadherin reporter assays, cellular invasion assays, siRNA knockdown The Journal of biological chemistry High 20026874
2011 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. Genetic knockdown, chemical inhibition, antibody inhibition, in vivo orthotopic and transgenic breast cancer models, protein expression analysis Cancer research High 21233336
2011 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. LOXL2 siRNA silencing, gene expression analysis, cell polarity assays, in vivo metastasis models EMBO molecular medicine High 21732535
2013 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. In vitro fibroblast activation assays, collagen contraction assays, LOXL2 genetic manipulation and antibody inhibition, in vivo mammary tumor models, western blot for FAK phosphorylation Molecular cancer research : MCR High 24008674
2013 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. Stable expression of subcellular-localization variants of LOXL2, subcellular fractionation, glycosylation analysis, invasion assays, western blot for EMT markers The Journal of biological chemistry High 24014025
2014 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. Co-immunoprecipitation, loss- and gain-of-function analyses, in vivo syngeneic breast cancer models, chromatin studies Oncogene High 24632622
2014 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. Co-immunoprecipitation, domain mapping, luciferase assays, siRNA knockdown, cell cycle and apoptosis analysis Cellular signalling Medium 24863880
2014 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. In vivo collagen crosslinking analysis, FAK/SRC signaling assays, miR-200/ZEB1 axis validation, in vitro and in vivo lung cancer models Oncogene High 27694892
2015 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. Unbiased proteomic identification of LOXL2 substrate, in vitro oxidation assay, TAF10 promoter occupancy studies, zebrafish developmental model Molecular cell High 25959397
2016 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. Infrared spectroscopy, mass spectrometry, in vitro deamination assay with recombinant LOXL2, chromatin immunoprecipitation/gene expression analysis The FEBS journal High 27735137
2016 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. Genetic knockout, antibody inhibition, in vivo cardiac stress models, PI3K/AKT pathway analysis, TGF-β2 signaling studies Nature communications High 27966531
2017 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. Anti-LOXL2 monoclonal antibody treatment in three mouse fibrosis models, collagen crosslinking assays, morphometric collagen quantification, primary EpCAM+ HPC differentiation assays in vitro Gut High 28073888
2017 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. Conditional transgenic mouse models (PyMT-induced breast cancer with LOXL2 ablation or overexpression), ECM stiffness measurements, molecular analysis of EMT markers and cytokines Cancer research High 28720577
2017 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. Co-immunoprecipitation, subcellular fractionation, IRE1 inhibitor experiments, XBP1 target gene analysis, epistasis by IRE1 inhibition Scientific reports High 28332555
2011 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. Point mutagenesis (Y689F), domain deletion mutants, β-aminopropionitrile (BAPN) treatment, antibody inhibition (AB0023), keratinocyte differentiation assays, internalization assay The Journal of biological chemistry High 22157764
2010 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. LOXL2 knockdown by siRNA, chondrocyte differentiation assays, gene expression analysis of SNAIL and SOX9, in vivo growth plate expression studies The Journal of biological chemistry Medium 21071451
2014 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. RNAi knockdown, integrin protein stability assays with protease/proteasome inhibitors, stress fiber/focal adhesion imaging, cell migration and invasion assays Molecular cancer research : MCR Medium 25092917
2014 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. Identification of splice variant, enzymatic activity assay, gene expression profiling, MAPK8 knockdown rescue experiments, cell migration/invasion assays Biochemistry and cell biology Medium 25275797
2019 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. 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 FASEB journal High 30676771
2019 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. Interactome analysis (mass spectrometry), Co-IP validation, ezrin phosphorylation assays, LOXL2 depletion/re-expression experiments, cell invasion assays Cancer research High 31409639
2019 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. LOXL2 siRNA adenoviral vector, mouse lung fibroblast culture, TGF-β/Smad pathway western blot, proliferation assay, ELISA for IL-6 and COL1A1 International journal of molecular medicine Medium 30320382
2019 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. Co-immunoprecipitation, domain mapping, western blot, ELISA, luciferase reporter assay, in vivo angiogenesis and tumor growth models International journal of oncology Medium 31322171
2020 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. Genetically engineered mouse models, promoter binding assays (AP-1), conditional Wls knockout, shRNA, orthotopic transplantation models, BAPN/antibody inhibition Cell research High 32686768
2022 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. 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 Redox biology High 36209516
2021 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. HIF1α stability assay, hydroxylation assay, hydrogen peroxide measurement, glycolytic gene expression analysis, in vivo tumor growth studies Cell death & disease Medium 34836938
2022 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. Co-immunoprecipitation, subcellular localization assays, migration/invasion assays, in vivo tumor growth studies, fibronectin degradation assay Molecular oncology Medium 37753805
2020 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. LOXL2 silencing in lung fibroblasts, TGF-β1 stimulation, nuclear fractionation, myofibroblast differentiation assays, in vivo mouse lung injury model, ARDS patient lung samples European journal of pharmacology Medium 33248114
2022 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. Conditional GEMMs (KPC/KC crossed with Loxl2 floxed or conditional overexpression mice), collagen ECM analysis, macrophage targeting in vivo, OSM signaling studies Gut High 35428659
2023 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. Genetic knockout of Loxl2 and/or Loxl4, bleomycin lung fibrosis model, collagen crosslinking biochemical assays, histological fibrosis assessment Science advances High 37235663
2022 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. 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 General and comparative endocrinology Medium 35271888
2019 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. LC-MS/MS proteomics, LOXL2 enzymatic activity assay, western blotting, LOXL2 pharmacological inhibition, wound healing assay, co-culture motility assay Molecular & cellular proteomics : MCP Medium 31061140
2019 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. 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 Cancer letters Medium 31911079
2020 LOXL2 enhances Atg7 expression by promoting ERK1/2 phosphorylation, leading to autophagy activation, which in turn mediates EMT and temozolomide resistance in glioma cells. LOXL2 overexpression/knockdown, autophagy assays, ERK1/2 phosphorylation analysis, Atg7 expression analysis, chemosensitivity assays Frontiers in oncology Low 33194658
2019 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. Chromatin immunoprecipitation (ChIP) for SP1 binding to LOXL2 promoter, siRNA double knockdown of SP1 and LOXL2, invasion/migration assays Scientific reports Medium 30976063
2022 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. Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assays, TRIM44 knockdown with LOXL2 rescue Cellular oncology Medium 36512309
2020 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. Gel-based stiffness culture system, M2 macrophage polarization model, pathway inhibition experiments, HIF-1α knockdown, western blot for pathway components The FEBS journal Medium 32964626
2020 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. In vivo compressive mechanical force model, IL-1β in vitro model, recombinant LOXL2 treatment, anti-LOXL2 antibody treatment, Integrin/FAK pathway inhibitor epistasis Scientific reports Medium 34426599
2020 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. Recombinant LOXL2 treatment of keratinocytes, JNK pathway inhibitor (SP600125), LOXL2-silenced hAMSC conditioned medium, in vivo mouse wound healing model Aging Medium 32621591
2024 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. 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 of experimental & clinical cancer research Medium 38326908

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1985 A transcriptional activator protein encoded by the x-lor region of the human T-cell leukemia virus. Science (New York, N.Y.) 358 2990028
2017 Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. Gut 224 28073888
2009 The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1. The Journal of biological chemistry 215 20026874
2011 LOXL2-mediated matrix remodeling in metastasis and mammary gland involution. Cancer research 212 21233336
2016 Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nature communications 203 27966531
2017 HIF-1α promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment. Journal of experimental & clinical cancer research : CR 183 28449718
2016 ZEB1 induces LOXL2-mediated collagen stabilization and deposition in the extracellular matrix to drive lung cancer invasion and metastasis. Oncogene 180 27694892
2009 Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway. Carcinogenesis 156 19625348
2011 Lysyl oxidase-like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas. EMBO molecular medicine 133 21732535
2017 Lysyl Oxidase-like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer. Cancer research 124 28720577
2020 Wnt signaling and Loxl2 promote aggressive osteosarcoma. Cell research 98 32686768
2017 LOXL2 drives epithelial-mesenchymal transition via activation of IRE1-XBP1 signalling pathway. Scientific reports 95 28332555
2020 LOXL2 in cancer: regulation, downstream effectors and novel roles. Biochimica et biophysica acta. Reviews on cancer 94 32976981
2015 LOXL2 Is Highly Expressed in Cancer-Associated Fibroblasts and Associates to Poor Colon Cancer Survival. Clinical cancer research : an official journal of the American Association for Cancer Research 89 26206869
2013 Tumor-secreted LOXL2 activates fibroblasts through FAK signaling. Molecular cancer research : MCR 86 24008674
2021 LOXL2 Inhibitors and Breast Cancer Progression. Antioxidants (Basel, Switzerland) 84 33669630
2019 Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment. Molecular & cellular proteomics : MCP 80 31061140
2012 Cancer-associated fibroblasts up-regulate CCL2, CCL26, IL6 and LOXL2 genes related to promotion of cancer progression in hepatocellular carcinoma cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 80 22739041
2014 A microfluidic method to synthesize transferrin-lipid nanoparticles loaded with siRNA LOR-1284 for therapy of acute myeloid leukemia. Nanoscale 79 25003978
2012 LOXL2 in epithelial cell plasticity and tumor progression. Future oncology (London, England) 79 23030485
2015 The function and mechanisms of action of LOXL2 in cancer (Review). International journal of molecular medicine 77 26329904
2014 Lysyl oxidase-like 2 (LOXL2) and E47 EMT factor: novel partners in E-cadherin repression and early metastasis colonization. Oncogene 76 24632622
2023 Mesenchymal stem cell-derived exosomal miR-27b-3p alleviates liver fibrosis via downregulating YAP/LOXL2 pathway. Journal of nanobiotechnology 75 37328872
2016 Regulation of the collagen cross-linking enzymes LOXL2 and PLOD2 by tumor-suppressive microRNA-26a/b in renal cell carcinoma. International journal of oncology 73 26983694
2020 Matrix stiffness-mediated effects on macrophages polarization and their LOXL2 expression. The FEBS journal 71 32964626
2014 Lysyl oxidase-like 2 (LOXL2) from stromal fibroblasts stimulates the progression of gastric cancer. Cancer letters 71 25128648
2005 Switching on-off Snail: LOXL2 versus GSK3beta. Cell cycle (Georgetown, Tex.) 70 16294032
2022 Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma. Gut 68 35428659
2013 MCF-7 cells expressing nuclear associated lysyl oxidase-like 2 (LOXL2) exhibit an epithelial-to-mesenchymal transition (EMT) phenotype and are highly invasive in vitro. The Journal of biological chemistry 68 24014025
2013 LOXL2 expression is associated with invasiveness and negatively influences survival in breast cancer patients. Breast cancer research and treatment 67 23933800
2019 Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 61 30676771
2019 LOXL2 Upregulates Phosphorylation of Ezrin to Promote Cytoskeletal Reorganization and Tumor Cell Invasion. Cancer research 59 31409639
2019 LOXL2-A New Target in Antifibrogenic Therapy? International journal of molecular sciences 58 30986934
2016 Lysyl oxidase-like 2 (LOXL2) oxidizes trimethylated lysine 4 in histone H3. The FEBS journal 58 27735137
2017 Small Molecule Lysyl Oxidase-like 2 (LOXL2) Inhibitors: The Identification of an Inhibitor Selective for LOXL2 over LOX. ACS medicinal chemistry letters 55 28435530
2016 Regulation of LOXL2 and SERPINH1 by antitumor microRNA-29a in lung cancer with idiopathic pulmonary fibrosis. Journal of human genetics 53 27488440
2016 Dormant tumor cells expressing LOXL2 acquire a stem-like phenotype mediating their transition to proliferative growth. Oncotarget 52 27655685
2021 The pathological significance of LOXL2 in pre-metastatic niche formation of HCC and its related molecular mechanism. European journal of cancer (Oxford, England : 1990) 46 33618200
2016 Emerging role of LOXL2 in the promotion of pancreas cancer metastasis. Oncotarget 45 27285767
2009 Functional analysis of LOXL2 in pancreatic carcinoma. International journal of colorectal disease 45 20012301
2011 The enzymatic activity of lysyl oxidas-like-2 (LOXL2) is not required for LOXL2-induced inhibition of keratinocyte differentiation. The Journal of biological chemistry 44 22157764
2010 Lysyl oxidase-like-2 (LOXL2) is a major isoform in chondrocytes and is critically required for differentiation. The Journal of biological chemistry 44 21071451
2013 The role of LOX and LOXL2 in scar formation after glaucoma surgery. Investigative ophthalmology & visual science 43 23821193
2021 Blocking LOXL2 and TGFβ1 signalling induces collagen I turnover in precision-cut lung slices derived from patients with idiopathic pulmonary fibrosis. Thorax 42 33472968
2021 Novel mechanism for OSM-promoted extracellular matrix remodeling in breast cancer: LOXL2 upregulation and subsequent ECM alignment. Breast cancer research : BCR 42 34011405
2015 LOXL2 Oxidizes Methylated TAF10 and Controls TFIID-Dependent Genes during Neural Progenitor Differentiation. Molecular cell 42 25959397
2008 TIMP-1 expression in human colorectal cancer is associated with TGF-B1, LOXL2, INHBA1, TNF-AIP6 and TIMP-2 transcript profiles. Molecular oncology 42 19383344
2022 HucMSCs-exosomes containing miR-21 promoted estrogen production in ovarian granulosa cells via LATS1-mediated phosphorylation of LOXL2 and YAP. General and comparative endocrinology 41 35271888
2023 LOXL4, but not LOXL2, is the critical determinant of pathological collagen cross-linking and fibrosis in the lung. Science advances 39 37235663
2018 LOXL2 promotes vasculogenic mimicry and tumour aggressiveness in hepatocellular carcinoma. Journal of cellular and molecular medicine 38 30506621
2021 Nuclear IL-33 Plays an Important Role in the Suppression of FLG, LOR, Keratin 1, and Keratin 10 by IL-4 and IL-13 in Human Keratinocytes. The Journal of investigative dermatology 37 33865911
2014 LOXL2 status correlates with tumor stage and regulates integrin levels to promote tumor progression in ccRCC. Molecular cancer research : MCR 37 25092917
2021 Reciprocal regulation of LOXL2 and HIF1α drives the Warburg effect to support pancreatic cancer aggressiveness. Cell death & disease 35 34836938
2014 Identification of a novel lysyl oxidase-like 2 alternative splicing isoform, LOXL2 Δe13, in esophageal squamous cell carcinoma. Biochemistry and cell biology = Biochimie et biologie cellulaire 35 25275797
1986 Molecular analysis of a deletion mutant provirus of type I human T-cell lymphotropic virus: evidence for a doubly spliced x-lor mRNA. Proceedings of the National Academy of Sciences of the United States of America 35 3001724
2019 Specific protein 1(SP1) regulates the epithelial-mesenchymal transition via lysyl oxidase-like 2(LOXL2) in pancreatic ductal adenocarcinoma. Scientific reports 33 30976063
2017 Role of LOXL2 in the epithelial-mesenchymal transition and colorectal cancer metastasis. Oncotarget 33 29113306
2014 Lysyl oxidase-like 2 (LOXL2) controls tumor-associated cell proliferation through the interaction with MARCKSL1. Cellular signalling 33 24863880
2011 Down-regulation of lysyl oxidase-like 2 (LOXL2) is associated with disease progression in lung adenocarcinomas. Medical oncology (Northwood, London, England) 33 21519871
2019 The interaction of LOXL2 with GATA6 induces VEGFA expression and angiogenesis in cholangiocarcinoma. International journal of oncology 32 31322171
2021 LOXL2-enriched small extracellular vesicles mediate hypoxia-induced premetastatic niche and indicates poor outcome of head and neck cancer. Theranostics 31 34646366
2018 LOXL2, a copper-dependent monoamine oxidase, activates lung fibroblasts through the TGF-β/Smad pathway. International journal of molecular medicine 31 30320382
2019 miR-29a Is Repressed by MYC in Pancreatic Cancer and Its Restoration Drives Tumor-Suppressive Effects via Downregulation of LOXL2. Molecular cancer research : MCR 29 31662451
2004 Characterization of the loricrin (LOR) gene as a positional candidate for the PSORS4 psoriasis susceptibility locus. Annals of human genetics 29 15598222
2020 LOXL2 Expression Status Is Correlated With Molecular Characterizations of Cervical Carcinoma and Associated With Poor Cancer Survival via Epithelial-Mesenchymal Transition (EMT) Phenotype. Frontiers in oncology 27 32211324
2023 LOXL2 in Cancer: A Two-Decade Perspective. International journal of molecular sciences 26 37762708
2022 LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression. Redox biology 25 36209516
2020 Linking LOXL2 to Cardiac Interstitial Fibrosis. International journal of molecular sciences 25 32824630
2007 Systematic screening of lysyl oxidase-like (LOXL) family genes demonstrates that LOXL2 is a susceptibility gene to intracranial aneurysms. Human genetics 25 17287949
2018 Lysyl oxidase-like protein 2 (LOXL2) modulates barrier function in cholangiocytes in cholestasis. Journal of hepatology 24 29709678
2019 Inhibition of LOXL2 Enhances the Radiosensitivity of Castration-Resistant Prostate Cancer Cells Associated with the Reversal of the EMT Process. BioMed research international 23 30809541
2023 A protein complex of LCN2, LOXL2 and MMP9 facilitates tumour metastasis in oesophageal cancer. Molecular oncology 22 37753805
2019 Salidroside ameliorated hypoxia-induced tumorigenesis of BxPC-3 cells via downregulating hypoxia-inducible factor (HIF)-1α and LOXL2. Journal of cellular biochemistry 22 31162697
2017 Exome Sequencing Identifies LOXL2 Mutation as a Cause of Familial Intracranial Aneurysm. World neurosurgery 22 29107163
2015 The Role of LOX and LOXL2 in the Pathogenesis of an Experimental Model of Choroidal Neovascularization. Investigative ophthalmology & visual science 21 26258612
2024 RNA-binding protein RPS7 promotes hepatocellular carcinoma progression via LOXL2-dependent activation of ITGB1/FAK/SRC signaling. Journal of experimental & clinical cancer research : CR 20 38326908
2023 Hypoxia preconditioned DPSC-derived exosomes regulate angiogenesis via transferring LOXL2. Experimental cell research 20 36894050
2022 TRIM44 regulates tumor immunity in gastric cancer through LOXL2-dependent extracellular matrix remodeling. Cellular oncology (Dordrecht, Netherlands) 20 36512309
2018 A serological marker of the N-terminal neoepitope generated during LOXL2 maturation is elevated in patients with cancer or idiopathic pulmonary fibrosis. Biochemistry and biophysics reports 20 30555938
2022 GDNF Promotes Astrocyte Abnormal Proliferation and Migration Through the GFRα1/RET/MAPK/pCREB/LOXL2 Signaling Axis. Molecular neurobiology 19 35925441
2021 ZEB1 promotes colorectal cancer cell invasion and disease progression by enhanced LOXL2 transcription. International journal of clinical and experimental pathology 19 33532019
2021 MIR29A Impedes Metastatic Behaviors in Hepatocellular Carcinoma via Targeting LOX, LOXL2, and VEGFA. International journal of molecular sciences 19 34206143
2016 Escin Ia suppresses the metastasis of triple-negative breast cancer by inhibiting epithelial-mesenchymal transition via down-regulating LOXL2 expression. Oncotarget 19 27008697
2021 Deubiquitinase ZRANB1 drives hepatocellular carcinoma progression through SP1-LOXL2 axis. American journal of cancer research 18 34765294
2020 LOXL2 Upregulation in Gliomas Drives Tumorigenicity by Activating Autophagy to Promote TMZ Resistance and Trigger EMT. Frontiers in oncology 18 33194658
2016 Baicalein Inhibits Epithelial to Mesenchymal Transition via Downregulation of Cyr61 and LOXL-2 in MDA-MB231 Breast Cancer Cells. Molecules and cells 18 28008161
2023 Multiple Roles of LOXL2 in the Progression of Hepatocellular Carcinoma and Its Potential for Therapeutic Targeting. International journal of molecular sciences 17 37511503
2020 LOXL2 promotes oncogenic progression in alveolar rhabdomyosarcoma independently of its catalytic activity. Cancer letters 17 31911079
2020 LOXL2 from human amniotic mesenchymal stem cells accelerates wound epithelialization by promoting differentiation and migration of keratinocytes. Aging 17 32621591
2020 Significance of nuclear LOXL2 inhibition in fibroblasts and myofibroblasts in the fibrotic process of acute respiratory distress syndrome. European journal of pharmacology 17 33248114
2016 The effect of LOXL2 in hepatocellular carcinoma. Molecular medicine reports 17 27430160
2023 Salidroside attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin-II through inhibition of LOXL2-TGF-β1-Smad2/3 pathway. Heliyon 16 37920527
2021 LOXL2 attenuates osteoarthritis through inactivating Integrin/FAK signaling. Scientific reports 16 34426599
2020 LOXL2 promotes aggrecan and gender-specific anabolic differences to TMJ cartilage. Scientific reports 16 33214607
2019 Withaferin A reverses bile duct ligation-induced liver fibrosis by modulating extracellular matrix deposition: Role of LOXL2/Snail1, vimentin, and NFκB signaling. BioFactors (Oxford, England) 16 31336025
2023 Irisin attenuates angiotensin II-induced atrial fibrillation and atrial fibrosis via LOXL2 and TGFβ1/Smad2/3 signaling pathways. Iranian journal of basic medical sciences 15 37275755
2022 LncRNA KCNQ1OT1-mediated cervical cancer progression by sponging miR-1270 as a ceRNA of LOXL2 through PI3k/Akt pathway. The journal of obstetrics and gynaecology research 15 35218109
2022 LOXL2 small molecule inhibitor restrains malignant transformation of cervical cancer cells by repressing LOXL2-induced epithelial-mesenchymal transition (EMT). Cell cycle (Georgetown, Tex.) 15 35509127
2021 Azithromycin Attenuates Bleomycin-Induced Pulmonary Fibrosis Partly by Inhibiting the Expression of LOX and LOXL-2. Frontiers in pharmacology 15 34803671
2019 A novel splice variant of LOXL2 promotes progression of human papillomavirus-negative head and neck squamous cell carcinoma. Cancer 15 31721164