Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004720 protein-lysine 6-oxidase activity	IBA GO_REF:0000033	ACCEPT	Summary: The IBA annotation assigns protein-lysine 6-oxidase activity to LOXL2. Reason: The phylogenetic inference agrees with direct recombinant-human LOXL2 assays showing oxidation of collagen and elastin substrates and copper-dependent LTQ formation; protein-lysine 6-oxidase is the conserved core activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0034660 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. FB:FBgn0039848 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. MGI:MGI:106096 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. MGI:MGI:1337004 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. MGI:MGI:1914823 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. MGI:MGI:96817 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. PANTHER:PTN002550804 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. RGD:3015 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:P28300 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:P58215 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:Q05063 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:Q95L39 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:Q96JB6 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:Q9Y4K0 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. Supporting Evidence: PMID:20306300 All of the purified recombinant LOXL2 proteins, with or without the SRCR domains in the N-terminus, showed significant amine oxidase activity toward several different types of collagen and elastin in in vitro amine oxidase assays.
GO:0005576 extracellular region	IBA GO_REF:0000033	ACCEPT	Summary: The IBA annotation assigns extracellular region to LOXL2. Reason: Conserved extracellular activity is corroborated by secretion of recombinant human LOXL2 and its recovery with extracellular-matrix material. This is the physiological compartment for the core collagen/elastin oxidase activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:106096 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. MGI:MGI:1337004 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. MGI:MGI:1914823 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. MGI:MGI:96817 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. PANTHER:PTN002550804 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. RGD:1308435 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. RGD:1308752 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. RGD:3015 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:P28300 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:P33072 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:P58215 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:Q08397 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:Q9Y4K0 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. Supporting Evidence: PMID:23319596 Disruption of N-glycosylation by site-directed mutagenesis or tunicamycin treatment completely inhibited secretion so that only small quantities of inclusion bodies were detected.
GO:0031012 extracellular matrix	IBA GO_REF:0000033	ACCEPT	Summary: The IBA annotation assigns extracellular matrix to LOXL2. Reason: The phylogenetic assignment is reinforced by direct human endothelial evidence for LOXL2-dependent matrix deposition and by recombinant-human-protein studies demonstrating secretion and extracellular matrix-substrate oxidation. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:106096 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. MGI:MGI:96817 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. PANTHER:PTN008698711 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. RGD:1308435 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. RGD:1308752 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. RGD:3015 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. Supporting Evidence: PMID:21835952 Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM.
GO:0002040 sprouting angiogenesis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: The IBA annotation assigns sprouting angiogenesis to LOXL2. Reason: Sprouting angiogenesis is directly supported by PMID:21835952 but is a contextual tissue program rather than LOXL2 core catalysis. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002910812 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:Q9Y4K0 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. ZFIN:ZDB-GENE-070818-1 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance.
GO:0030199 collagen fibril organization	IBA GO_REF:0000033	ACCEPT	Summary: The IBA annotation assigns collagen fibril organization to LOXL2. Reason: LOXL2 directly oxidizes collagen substrates, and loss/gain experiments show a requirement for LOXL2 in collagen-IV matrix assembly. These data support the conserved collagen-organization process represented by the IBA term. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:96817 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. PANTHER:PTN008698711 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. RGD:3015 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. UniProtKB:Q9Y4K0 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. Supporting Evidence: PMID:21835952 Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM.
GO:0004720 protein-lysine 6-oxidase activity	IEA GO_REF:0000120	ACCEPT	Summary: The IEA annotation assigns protein-lysine 6-oxidase activity to LOXL2. Reason: The Rhea/EC reaction mapping exactly matches LOXL2's experimentally established oxidative deamination of peptidyl lysines in collagen and elastin and is not merely a family-level prediction. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00088088 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. RHEA:24544 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. EC:1.4.3.13 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. Supporting Evidence: PMID:20306300 All of the purified recombinant LOXL2 proteins, with or without the SRCR domains in the N-terminus, showed significant amine oxidase activity toward several different types of collagen and elastin in in vitro amine oxidase assays.
GO:0005507 copper ion binding	IEA GO_REF:0000002	ACCEPT	Summary: The IEA annotation assigns copper ion binding to LOXL2. Reason: The InterPro copper-binding-domain mapping is corroborated by the human LOXL2 structure and biochemical copper loading, which restores LTQ formation and catalytic activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR001695 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. InterPro:IPR019828 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. Supporting Evidence: PMID:29581294 Biochemical analysis confirms that copper loading robustly activates hLOXL2 and supports LTQ formation.
GO:0005604 basement membrane	IEA GO_REF:0000044	ACCEPT	Summary: The IEA annotation assigns basement membrane to LOXL2. Reason: The UniProt subcellular-location mapping is supported by human endothelial studies placing LOXL2 in collagen-IV/fibronectin deposition and showing its role in vascular basement-membrane organization. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0025 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. Supporting Evidence: PMID:31759052 Neither enzyme activity nor catalytic domain were necessary for collagen IV deposition and angiogenesis, whereas the SRCR domains were effective for these processes.
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: The IEA annotation assigns nucleus to LOXL2. Reason: UniProt's nuclear-location mapping is corroborated by tumor-cell and tissue studies that detect a nuclear LOXL2 pool. Those observations are disease/context dependent and do not displace the core extracellular activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0191 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance.
GO:0005694 chromosome	IEA GO_REF:0000044	UNDECIDED	Summary: The IEA annotation assigns chromosome to LOXL2. Reason: This electronic row faithfully maps UniProt's chromosome location, but the underlying H3K4me3 evidence chain is disputed. The localization therefore cannot be independently verified and should not be used to support chromatin catalysis. Propagation Review Root cause: UNRESOLVED Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB-SubCell:SL-0468 SOURCE WEAK OR INFERRED The mapping is preserved, but its underlying chromosome evidence is disputed.
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: The IEA annotation assigns endoplasmic reticulum to LOXL2. Reason: Secretory-pathway transit makes ER localization plausible, and overexpressed LOXL2 accumulates in the ER in carcinoma cells. The observed accumulation is a maturation/overexpression context, not the mature enzyme's core site of action. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0095 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance.
GO:0016020 membrane	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: The IEA annotation assigns membrane to LOXL2. Reason: LOXL2 is secreted and lacks a transmembrane segment; an SRCR-domain mapping does not establish membrane residence. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: InterPro:IPR001190 SUPPORTS SOURCE BUT NOT TARGET InterPro source is present but does not establish membrane localization. InterPro:IPR036772 SUPPORTS SOURCE BUT NOT TARGET InterPro source is present but does not establish membrane localization.
GO:0016641 oxidoreductase activity, acting on the CH-NH2 group of donors, oxygen as acceptor	IEA GO_REF:0000002	MODIFY	Summary: The IEA annotation assigns the broad oxygen-dependent CH-NH2 oxidoreductase activity to LOXL2. Reason: LOXL2 substrate specificity is known, so replace this broad parent activity with protein-lysine 6-oxidase activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR001695 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. InterPro:IPR019828 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. Proposed replacements: protein-lysine 6-oxidase activity
GO:0071953 elastic fiber	IEA GO_REF:0000117	ACCEPT	Summary: The IEA annotation assigns elastic fiber to LOXL2. Reason: Although ARBA supplies this row, independent human-protein evidence shows direct tropoelastin binding, lysine oxidation, and cross-link formation, while vascular tissue places LOXL2 with elastin. Those data support elastic-fiber association. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00084594 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. Supporting Evidence: PMID:30676771 We detected direct interaction between LOXL2 and tropoelastin (TE) and also LOXL2-mediated deamination of TE. Using proteomics, we identified several allysines together with cross-linked TE peptides.
GO:0005515 protein binding	IPI PMID:24863880 Lysyl oxidase-like 2 (LOXL2) controls tumor-associated cell ...	UNDECIDED	Summary: The IPI annotation assigns protein binding to LOXL2. Reason: PMID:24863880 verifies an SRCR-region interaction with the actin-regulatory protein MARCKSL1, but MARCKSL1 is not itself a cytoskeletal structural component. The accessible evidence does not justify a more informative GO molecular-function term than generic protein binding, so no inaccurate replacement is proposed.
GO:0005515 protein binding	IPI PMID:30676771 Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropo...	MODIFY	Summary: The IPI annotation assigns protein binding to LOXL2. Reason: PMID:30676771 directly demonstrates tropoelastin binding and oxidation; extracellular matrix protein binding is the informative term. Proposed replacements: extracellular matrix protein binding
GO:0005515 protein binding	IPI PMID:31759052 Scavenger Receptor Cysteine-Rich domains of Lysyl Oxidase-Li...	MODIFY	Summary: The IPI annotation assigns protein binding to LOXL2. Reason: PMID:31759052 directly demonstrates fibronectin binding through LOXL2 SRCR domains; use extracellular matrix protein binding. Proposed replacements: extracellular matrix protein binding
GO:0005515 protein binding	IPI PMID:31911079 LOXL2 promotes oncogenic progression in alveolar rhabdomyosa...	MODIFY	Summary: The IPI annotation assigns protein binding to LOXL2. Reason: PMID:31911079 and the two IntAct partners identify vimentin and calpain-2. Intermediate-filament binding and protease binding describe those interactions more precisely than generic protein binding. Proposed replacements: intermediate filament binding protease binding
GO:0001666 response to hypoxia	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: The IEA annotation assigns response to hypoxia to LOXL2. Reason: Human LOXL2 is hypoxia inducible, but response to hypoxia is regulatory context rather than its core enzymatic function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P58022 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. ensembl:ENSMUSP00000022660 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance.
GO:0032332 positive regulation of chondrocyte differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: The IEA annotation assigns positive regulation of chondrocyte differentiation to LOXL2. Reason: Mouse orthology supports this developmental role, but chondrocyte differentiation is tissue-specific downstream biology. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P58022 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. ensembl:ENSMUSP00000022660 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance.
GO:1902455 negative regulation of stem cell population maintenance	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: The IEA annotation assigns negative regulation of stem cell population maintenance to LOXL2. Reason: TAF10 oxidation links LOXL2 to loss of pluripotency, but stem-cell maintenance is a contextual downstream process. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P58022 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. ensembl:ENSMUSP00000022660 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance.
GO:0071953 elastic fiber	TAS PMID:23962539 Elastic fibres in health and disease.	ACCEPT	Summary: The TAS annotation assigns elastic fiber to LOXL2. Reason: The broad review cited by this TAS row does not expose a LOXL2-specific statement in the cached abstract. Retain the biologically correct localization on independent PMID:30676771 evidence for direct tropoelastin binding/cross-linking and vascular codistribution, rather than treating PMID:23962539 as verification. Supporting Evidence: PMID:30676771 We detected direct interaction between LOXL2 and tropoelastin (TE) and also LOXL2-mediated deamination of TE. Using proteomics, we identified several allysines together with cross-linked TE peptides.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: The IDA annotation assigns nucleoplasm to LOXL2. Reason: This row comes from direct HPA immunofluorescence curation and therefore supports nucleoplasmic detection, but it does not establish a nuclear catalytic or transcriptional mechanism. The compartment is retained as non-core.
GO:0005694 chromosome	EXP PMID:27735137 Lysyl oxidase-like 2 (LOXL2) oxidizes trimethylated lysine 4...	UNDECIDED	Summary: The EXP annotation assigns chromosome to LOXL2. Reason: The cached PMID:27735137 record is abstract-only, and its H3K4me3 mechanism is disputed after retraction of the foundational same-group report. Chromosome localization cannot be independently verified from the accessible evidence, so curator deference requires an unresolved decision rather than a positive keep.
GO:0005515 protein binding	IPI PMID:27339457 Functional consequence of fibulin-4 missense mutations assoc...	MODIFY	Summary: The IPI annotation assigns protein binding to LOXL2. Reason: The reported partner is fibulin-4, so extracellular matrix protein binding is more informative than generic protein binding. Proposed replacements: extracellular matrix protein binding
GO:0031012 extracellular matrix	HDA PMID:28327460 Comprehensive proteomic characterization of stem cell-derive...	ACCEPT	Summary: The HDA annotation assigns extracellular matrix to LOXL2. Reason: The mesenchymal-cell proteomics record is retained with curator deference, while its cached narrative does not expose the LOXL2 peptide-level result. Extracellular matrix localization is independently established by IBA and PMID:23319596 and PMID:21835952; this reason does not claim PMID:28327460 was independently verified. Supporting Evidence: PMID:21835952 Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM.
GO:0004720 protein-lysine 6-oxidase activity	IDA PMID:29581294 Crystal structure of human lysyl oxidase-like 2 (hLOXL2) in ...	ACCEPT	Summary: The IDA annotation assigns protein-lysine 6-oxidase activity to LOXL2. Reason: PMID:29581294 directly shows that copper loading activates recombinant human LOXL2 and supports LTQ formation. Together with direct collagen/elastin substrate assays, this establishes the specific protein-lysine oxidase activity. Supporting Evidence: PMID:29581294 Biochemical analysis confirms that copper loading robustly activates hLOXL2 and supports LTQ formation. PMID:20306300 All of the purified recombinant LOXL2 proteins, with or without the SRCR domains in the N-terminus, showed significant amine oxidase activity toward several different types of collagen and elastin in in vitro amine oxidase assays.
GO:0005507 copper ion binding	IDA PMID:29581294 Crystal structure of human lysyl oxidase-like 2 (hLOXL2) in ...	ACCEPT	Summary: The IDA annotation assigns copper ion binding to LOXL2. Reason: The human LOXL2 structure defines the metal-binding site, and biochemical copper loading restores LTQ formation and catalytic activity whereas zinc occupancy traps an inactive precursor state. Supporting Evidence: PMID:29581294 Biochemical analysis confirms that copper loading robustly activates hLOXL2 and supports LTQ formation.
GO:0005509 calcium ion binding	IDA PMID:29581294 Crystal structure of human lysyl oxidase-like 2 (hLOXL2) in ...	ACCEPT	Summary: The IDA annotation assigns calcium ion binding to LOXL2. Reason: PMID:29581294 directly resolves a coordinated calcium ion in the recombinant human LOXL2 structure. The truncated precursor-state construct bounds the structural inference but still supports ion binding. Supporting Evidence: PMID:29581294 This octahedral coordination pattern is consistent with a bound calcium ion, which might play a role in local structure stabilization.
GO:0018057 peptidyl-lysine oxidation	IDA PMID:29581294 Crystal structure of human lysyl oxidase-like 2 (hLOXL2) in ...	ACCEPT	Summary: The IDA annotation assigns peptidyl-lysine oxidation to LOXL2. Reason: Copper-dependent LTQ formation in PMID:29581294 supplies the catalytic chemistry, and independent recombinant-human LOXL2 assays directly demonstrate oxidation of lysines in collagen and tropoelastin substrates. Supporting Evidence: PMID:20306300 All of the purified recombinant LOXL2 proteins, with or without the SRCR domains in the N-terminus, showed significant amine oxidase activity toward several different types of collagen and elastin in in vitro amine oxidase assays. PMID:30676771 We detected direct interaction between LOXL2 and tropoelastin (TE) and also LOXL2-mediated deamination of TE. Using proteomics, we identified several allysines together with cross-linked TE peptides.
GO:0031012 extracellular matrix	HDA PMID:23979707 SILAC-based proteomics of human primary endothelial cell mor...	ACCEPT	Summary: The HDA annotation assigns extracellular matrix to LOXL2. Reason: The endothelial proteomics record is retained with curator deference, while its cached narrative does not expose a LOXL2-specific result. Independent human endothelial loss/gain experiments and recombinant secretion establish ECM localization, so the action does not rely on claiming this dataset was verified. Supporting Evidence: PMID:21835952 Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:25959397 LOXL2 Oxidizes Methylated TAF10 and Controls TFIID-Dependent...	KEEP AS NON CORE	Summary: The IDA annotation assigns negative regulation of transcription by RNA polymerase II to LOXL2. Reason: PMID:25959397 identifies methylated TAF10 as an intracellular LOXL2 substrate and reports altered TFIID-dependent transcription during neural differentiation. This is a specific developmental context, not the core extracellular function.
GO:0004720 protein-lysine 6-oxidase activity	IDA PMID:25959397 LOXL2 Oxidizes Methylated TAF10 and Controls TFIID-Dependent...	ACCEPT	Summary: The IDA annotation assigns protein-lysine 6-oxidase activity to LOXL2. Reason: PMID:25959397 reports oxidation of a methylated protein lysine in TAF10, directly supporting the broad protein-lysine oxidase activity. The TAF10 context is non-core, but the enzymatic activity is independently established extracellularly. Supporting Evidence: PMID:25959397 Using an unbiased proteomic approach, we have identified methylated TAF10, a member of the TFIID complex, as a LOXL2 substrate.
GO:0005634 nucleus	IDA PMID:24414204 LOXL2 catalytically inactive mutants mediate epithelial-to-m...	KEEP AS NON CORE	Summary: The IDA annotation assigns nucleus to LOXL2. Reason: PMID:24414204 studies intracellular LOXL2/SNAI1-dependent EMT and catalytic-independent signaling in carcinoma cells. Nuclear localization is retained as a context-specific pool rather than a core catalytic compartment.
GO:0005783 endoplasmic reticulum	IDA PMID:28332555 LOXL2 drives epithelial-mesenchymal transition via activatio...	KEEP AS NON CORE	Summary: The IDA annotation assigns endoplasmic reticulum to LOXL2. Reason: PMID:28332555 directly shows that overexpressed LOXL2 accumulates in the ER and activates IRE1-XBP1 stress signaling in carcinoma cells. Because accumulation is overexpression-induced, it is retained as non-core maturation/disease context.
GO:0010718 positive regulation of epithelial to mesenchymal transition	IMP PMID:24239292 Regulation of heterochromatin transcription by Snail1/LOXL2 ...	KEEP AS NON CORE	Summary: The IMP annotation assigns positive regulation of epithelial to mesenchymal transition to LOXL2. Reason: PMID:24239292 directly reports LOXL2-dependent heterochromatin changes and mesenchymal-cell behavior during EMT, supporting this contextual phenotype as non-core. Its proposed H3K4-deaminase mechanism is disputed and is not accepted as the explanation for the observed EMT effect.
GO:0018057 peptidyl-lysine oxidation	IDA PMID:25959397 LOXL2 Oxidizes Methylated TAF10 and Controls TFIID-Dependent...	ACCEPT	Summary: The IDA annotation assigns peptidyl-lysine oxidation to LOXL2. Reason: PMID:25959397 identifies methylated TAF10 as a protein substrate oxidized by LOXL2. The neural-differentiation context is non-core, but oxidation of a peptidyl lysine directly supports this general process term. Supporting Evidence: PMID:25959397 Using an unbiased proteomic approach, we have identified methylated TAF10, a member of the TFIID complex, as a LOXL2 substrate.
GO:0070828 heterochromatin organization	IMP PMID:24239292 Regulation of heterochromatin transcription by Snail1/LOXL2 ...	KEEP AS NON CORE	Summary: The IMP annotation assigns heterochromatin organization to LOXL2. Reason: The abstract directly reports LOXL2-dependent HP1alpha release and major-satellite transcript downregulation during EMT, supporting a contextual heterochromatin phenotype. The proposed H3K4-deaminase mechanism is disputed and is not accepted as the biochemical basis of this non-core annotation.
GO:1902455 negative regulation of stem cell population maintenance	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: The ISS annotation assigns negative regulation of stem cell population maintenance to LOXL2. Reason: Mouse transfer agrees with human TAF10/pluripotency evidence but represents a contextual cell-state outcome. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P58022 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance.
GO:0000785 chromatin	IDA PMID:27735137 Lysyl oxidase-like 2 (LOXL2) oxidizes trimethylated lysine 4...	UNDECIDED	Summary: The IDA annotation assigns chromatin to LOXL2. Reason: The cached PMID:27735137 record is abstract-only, and its H3K4me3 mechanism is disputed after retraction of the foundational same-group report. Chromatin localization cannot be independently verified from the accessible evidence, so curator deference requires an unresolved decision rather than a positive keep.
GO:0004720 protein-lysine 6-oxidase activity	IDA PMID:27735137 Lysyl oxidase-like 2 (LOXL2) oxidizes trimethylated lysine 4...	ACCEPT	Summary: The IDA annotation assigns protein-lysine 6-oxidase activity to LOXL2. Reason: Protein-lysine 6-oxidase activity is independently established by recombinant human LOXL2 biochemistry, including copper-dependent LTQ formation and oxidation of collagen substrates. The specific H3K4me3 substrate claim in PMID:27735137 remains disputed and is not used to support this broader catalytic term. Supporting Evidence: PMID:20306300 All of the purified recombinant LOXL2 proteins, with or without the SRCR domains in the N-terminus, showed significant amine oxidase activity toward several different types of collagen and elastin in in vitro amine oxidase assays. PMID:29581294 Biochemical analysis confirms that copper loading robustly activates hLOXL2 and supports LTQ formation.
GO:0018057 peptidyl-lysine oxidation	IDA PMID:27735137 Lysyl oxidase-like 2 (LOXL2) oxidizes trimethylated lysine 4...	ACCEPT	Summary: The IDA annotation assigns peptidyl-lysine oxidation to LOXL2. Reason: Peptidyl-lysine oxidation is independently established for recombinant human LOXL2 acting on extracellular protein substrates. The disputed H3K4me3 substrate claim in PMID:27735137 is not used to support this broader process term. Supporting Evidence: PMID:20306300 All of the purified recombinant LOXL2 proteins, with or without the SRCR domains in the N-terminus, showed significant amine oxidase activity toward several different types of collagen and elastin in in vitro amine oxidase assays. PMID:30676771 We detected direct interaction between LOXL2 and tropoelastin (TE) and also LOXL2-mediated deamination of TE. Using proteomics, we identified several allysines together with cross-linked TE peptides.
GO:0005634 nucleus	IDA PMID:22204712 Reduced nuclear and ectopic cytoplasmic expression of lysyl ...	KEEP AS NON CORE	Summary: The IDA annotation assigns nucleus to LOXL2. Reason: Human esophageal-carcinoma immunohistochemistry in PMID:22204712 directly detects nuclear and cytoplasmic LOXL2. This supports compartmental detection in tumors, not a normal nuclear catalytic core function.
GO:0004720 protein-lysine 6-oxidase activity	IDA PMID:23319596 Post-translational modifications of recombinant human lysyl ...	ACCEPT	Summary: The IDA annotation assigns protein-lysine 6-oxidase activity to LOXL2. Reason: Recombinant human LOXL2 in PMID:23319596 contains the LTQ cross-link and directly oxidizes tropoelastin, establishing the specific protein-lysine oxidase activity despite the Drosophila S2 expression-system boundary. Supporting Evidence: PMID:23319596 The recombinant proteins also show activity in tropoelastin oxidation.
GO:0005576 extracellular region	IDA PMID:23319596 Post-translational modifications of recombinant human lysyl ...	ACCEPT	Summary: The IDA annotation assigns extracellular region to LOXL2. Reason: PMID:23319596 directly analyzes recombinant human LOXL2 recovered from S2-cell secretion medium and shows that N-glycosylation is required for efficient secretion. This supports extracellular localization with an explicit expression system boundary. Supporting Evidence: PMID:23319596 Disruption of N-glycosylation by site-directed mutagenesis or tunicamycin treatment completely inhibited secretion so that only small quantities of inclusion bodies were detected.
GO:0036211 protein modification process	IDA PMID:23319596 Post-translational modifications of recombinant human lysyl ...	MODIFY	Summary: The IDA annotation assigns protein modification process to LOXL2. Reason: PMID:23319596 supports the specific process peptidyl-lysine oxidation, not merely generic protein modification. Proposed replacements: peptidyl-lysine oxidation
GO:0046688 response to copper ion	IDA PMID:23319596 Post-translational modifications of recombinant human lysyl ...	UNDECIDED	Summary: The IDA annotation assigns response to copper ion to LOXL2. Reason: The accessible PMID:23319596 record establishes LTQ formation, glycosylation, and secretion but does not expose a cellular response-to-copper assay. Copper binding and copper-dependent activation are independently secure, yet they do not justify replacing this biological-process row across GO aspects; defer to the curator.
GO:0070492 oligosaccharide binding	IDA PMID:23319596 Post-translational modifications of recombinant human lysyl ...	UNDECIDED	Summary: The IDA annotation assigns oligosaccharide binding to LOXL2. Reason: The accessible PMID:23319596 record demonstrates N-linked glycosylation of LOXL2, not clearly oligosaccharide binding. Full-text curator evidence is unavailable, so defer.
GO:0001666 response to hypoxia	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: The ISS annotation assigns response to hypoxia to LOXL2. Reason: Human LOXL2 is hypoxia inducible, but this response is non-core context. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P58022 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance.
GO:0001837 epithelial to mesenchymal transition	IDA PMID:16096638 A molecular role for lysyl oxidase-like 2 enzyme in snail re...	KEEP AS NON CORE	Summary: The IDA annotation assigns epithelial to mesenchymal transition to LOXL2. Reason: PMID:16096638 directly supports LOXL2/SNAI1-dependent EMT, a contextual tumor/developmental program.
GO:0001935 endothelial cell proliferation	IMP PMID:21835952 Lysyl oxidase-like protein-2 regulates sprouting angiogenesi...	KEEP AS NON CORE	Summary: The IMP annotation assigns endothelial cell proliferation to LOXL2. Reason: PMID:21835952 supports the proliferation phenotype downstream of endothelial matrix organization.
GO:0002040 sprouting angiogenesis	IMP PMID:21835952 Lysyl oxidase-like protein-2 regulates sprouting angiogenesi...	KEEP AS NON CORE	Summary: The IMP annotation assigns sprouting angiogenesis to LOXL2. Reason: PMID:21835952 supports angiogenesis through collagen IV scaffolding, but this is downstream context.
GO:0005515 protein binding	IPI PMID:16096638 A molecular role for lysyl oxidase-like 2 enzyme in snail re...	MODIFY	Summary: The IPI annotation assigns protein binding to LOXL2. Reason: PMID:16096638 establishes functional interaction with SNAI1; transcription factor binding is more informative. Proposed replacements: transcription factor binding
GO:0005604 basement membrane	ISS GO_REF:0000024	ACCEPT	Summary: The ISS annotation assigns basement membrane to LOXL2. Reason: The orthology transfer is independently supported in human endothelial cells: LOXL2 is required for collagen-IV deposition and its SRCR domains organize vascular basement-membrane matrix. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:B5DF27 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance. Supporting Evidence: PMID:31759052 Neither enzyme activity nor catalytic domain were necessary for collagen IV deposition and angiogenesis, whereas the SRCR domains were effective for these processes.
GO:0005634 nucleus	TAS PMID:16096638 A molecular role for lysyl oxidase-like 2 enzyme in snail re...	KEEP AS NON CORE	Summary: The TAS annotation assigns nucleus to LOXL2. Reason: PMID:16096638 reports intracellular LOXL2 interaction with SNAI1 and repression of E-cadherin in carcinoma models, supporting a nuclear-context role. This is retained as non-core and does not establish the normal site of oxidase action.
GO:0030199 collagen fibril organization	IMP PMID:21835952 Lysyl oxidase-like protein-2 regulates sprouting angiogenesi...	ACCEPT	Summary: The IMP annotation assigns collagen fibril organization to LOXL2. Reason: Loss- and gain-of-function experiments in PMID:21835952 directly show that LOXL2 is required for collagen-IV assembly in endothelial ECM. Together with direct collagen oxidation, this supports a collagen-organization role. Supporting Evidence: PMID:21835952 Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM.
GO:0032332 positive regulation of chondrocyte differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: The ISS annotation assigns positive regulation of chondrocyte differentiation to LOXL2. Reason: Mouse orthology supports this plausible tissue-specific developmental role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P58022 SUPPORTS TRANSFER Identifier preserved exactly from live QuickGO WITH/FROM provenance.
GO:0043542 endothelial cell migration	IMP PMID:21835952 Lysyl oxidase-like protein-2 regulates sprouting angiogenesi...	KEEP AS NON CORE	Summary: The IMP annotation assigns endothelial cell migration to LOXL2. Reason: PMID:21835952 supports endothelial migration downstream of matrix organization.
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:16096638 A molecular role for lysyl oxidase-like 2 enzyme in snail re...	KEEP AS NON CORE	Summary: The IDA annotation assigns negative regulation of DNA-templated transcription to LOXL2. Reason: PMID:16096638 directly reports LOXL2/SNAI1-dependent E-cadherin repression in carcinoma models. The transcriptional phenotype is experimentally supported but remains a context-specific intracellular role rather than core matrix catalysis.
GO:0048251 elastic fiber assembly	IDA PMID:30676771 Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropo...	NEW	Summary: Recombinant full-length human LOXL2 binds, deaminates, and cross-links tropoelastin into an insoluble elastin-like material. Reason: Direct substrate binding, allysine formation, cross-linked tropoelastin peptides, and elastin-like material formation justify elastic fiber assembly as a specific process annotation. The demonstrated chemistry is in vitro, while vascular codistribution supports but does not by itself prove the in-vivo scope. Supporting Evidence: PMID:30676771 We detected direct interaction between LOXL2 and tropoelastin (TE) and also LOXL2-mediated deamination of TE. Using proteomics, we identified several allysines together with cross-linked TE peptides.
GO:0071711 basement membrane organization	IMP PMID:31759052 Scavenger Receptor Cysteine-Rich domains of Lysyl Oxidase-Li...	NEW	Summary: LOXL2 SRCR domains organize endothelial collagen IV and fibronectin deposition independently of the catalytic domain. Reason: Direct binding, loss-of-function, domain-deletion, and rescue evidence establish a non-catalytic LOXL2 scaffolding role in vascular basement-membrane organization. Angiogenesis is a downstream endothelial context and is not asserted as a separate molecular activity. Supporting Evidence: PMID:31759052 Neither enzyme activity nor catalytic domain were necessary for collagen IV deposition and angiogenesis, whereas the SRCR domains were effective for these processes.

Core Functions

Secreted LOXL2 uses copper and its lysine-tyrosylquinone cofactor to oxidatively deaminate peptidyl lysine residues in extracellular collagen and elastin precursors. The resulting allysines initiate spontaneous covalent cross-links that stabilize collagen fibrils and elastic fibers. Recombinant human LOXL2 directly oxidizes fibrillar type-I collagen and multiple collagen preparations, binds and deaminates tropoelastin, and generates cross-linked tropoelastin peptides. Copper loading activates LTQ formation; zinc-bound precursor-state protein is inactive. Full-length LOXL2 is catalytically competent, so cleavage between SRCR2 and SRCR3 is not treated as the activation step characteristic of LOX/LOXL1 propeptide removal. Nuclear, chromatin, hypoxia, EMT, and tumor-cell phenotypes are excluded from this core node, as are the retracted/disputed H3K4me3 claims. No stable protein-complex membership is asserted.

Molecular Function:

protein-lysine 6-oxidase activity

Directly Involved In:

peptidyl-lysine oxidation collagen fibril organization elastic fiber assembly

Cellular Locations:

extracellular matrix basement membrane elastic fiber

Supporting Evidence:

PMID:20306300
All of the purified recombinant LOXL2 proteins, with or without the SRCR domains in the N-terminus, showed significant amine oxidase activity toward several different types of collagen and elastin in in vitro amine oxidase assays.
PMID:20439985
In this report, we assessed the steady-state enzymatic activity of lysyl oxidase-like 2 (LOXL2) against the substrates 1,5-diaminopentane (DAP), spermine, and fibrillar type I collagen.
PMID:29581294
Biochemical analysis confirms that copper loading robustly activates hLOXL2 and supports LTQ formation.
PMID:30676771
We detected direct interaction between LOXL2 and tropoelastin (TE) and also LOXL2-mediated deamination of TE. Using proteomics, we identified several allysines together with cross-linked TE peptides.

LOXL2 also acts as a non-catalytic extracellular-matrix scaffold through its N-terminal SRCR domains. These domains directly bind collagen IV, while LOXL2 associates with collagen IV and fibronectin before their exocytic deposition, supporting endothelial basement-membrane organization independently of the catalytic domain. This is modeled separately from lysine oxidation because catalytic-dead and catalytic-domain-deleted proteins retain the relevant deposition activity. Sprouting angiogenesis is a downstream endothelial context, not a second molecular activity. The observed pairwise matrix interactions do not establish a single stable LOXL2-containing complex.

Molecular Function:

extracellular matrix protein binding

Directly Involved In:

basement membrane organization

Cellular Locations:

basement membrane

Supporting Evidence:

PMID:31759052
LOXL2 interacts intracellularly and directly with collagen IV and fibronectin before incorporation into ECM fibrillar structures upon exocytosis, as demonstrated by TIRF time-lapse microscopy.
PMID:31759052
Neither enzyme activity nor catalytic domain were necessary for collagen IV deposition and angiogenesis, whereas the SRCR domains were effective for these processes.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:16096638

A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression.

LOXL2 interacts and cooperates with SNAI1 to repress E-cadherin and promote epithelial-to-mesenchymal transition in carcinoma models.

"Here we show that lysyl-oxidase-like 2 and 3 (LOXL2 and LOXL3), two members of the lysyl-oxidase gene family, interact and cooperate with Snail to downregulate E-cadherin expression."

PMID:21835952

Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane.

LOXL2 accumulates in endothelial extracellular matrix and is required for collagen-IV assembly and sprouting angiogenesis.

"Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM."

PMID:22204712

Reduced nuclear and ectopic cytoplasmic expression of lysyl oxidase-like 2 is associated with lymph node metastasis and poor prognosis in esophageal squamous cell carcinoma.

LOXL2 protein was detected in nuclear and cytoplasmic compartments of human esophageal carcinoma samples, with altered distribution associated with progression.

"The protein manifested decreased nuclear expression and increased cytoplasmic expression."

PMID:23319596

Post-translational modifications of recombinant human lysyl oxidase-like 2 (rhLOXL2) secreted from Drosophila S2 cells.

Recombinant human LOXL2 contains LTQ at Lys653/Tyr689, oxidizes tropoelastin, and requires N-glycosylation for efficient secretion from Drosophila S2 cells.

"The recombinant proteins also show activity in tropoelastin oxidation. After phenylhydrazine derivatization and trypsin digestion, we used mass spectrometry to identify peptides containing the derivatized lysine tyrosylquinone cross-link at Lys-653 and Tyr-689, as well as N-linked glycans at Asn-455 and Asn-644."

PMID:23962539

Elastic fibres in health and disease.

PMID:23979707

SILAC-based proteomics of human primary endothelial cell morphogenesis unveils tumor angiogenic markers.

PMID:24239292

Regulation of heterochromatin transcription by Snail1/LOXL2 during epithelial-to-mesenchymal transition.

The paper attributes repression of mouse pericentromeric transcription during EMT to a SNAI1/LOXL2 pathway, but its H3K4-deaminase mechanism is disputed.

"Here, we show that the Snail1 transcription factor represses mouse pericentromeric transcription, acting through the H3K4 deaminase LOXL2."

PMID:24414204

LOXL2 catalytically inactive mutants mediate epithelial-to-mesenchymal transition.

Catalytically inactive LOXL2 mutants can cooperate with SNAI1 and activate FAK/Src signaling to drive EMT.

"Here we show that LOXL2 catalytic inactive mutants collaborate with Snail1 in E-cadherin gene repression to trigger EMT and, in addition, promote FAK/Src pathway activation to support EMT."

PMID:24863880

Lysyl oxidase-like 2 (LOXL2) controls tumor-associated cell proliferation through the interaction with MARCKSL1.

The LOXL2 SRCR region interacts with MARCKSL1 in human breast carcinoma cells and modulates proliferation/apoptosis signaling.

"The scavenger-receptor domain of LOXL2 was shown to interact with the N-terminal domain of MARCKSL1."

PMID:25959397

LOXL2 Oxidizes Methylated TAF10 and Controls TFIID-Dependent Genes during Neural Progenitor Differentiation.

Methylated TAF10 was reported as an intracellular LOXL2 substrate whose oxidation changes TFIID-dependent transcription during neural differentiation.

"Using an unbiased proteomic approach, we have identified methylated TAF10, a member of the TFIID complex, as a LOXL2 substrate."

PMID:27339457

Functional consequence of fibulin-4 missense mutations associated with vascular and skeletal abnormalities and cutis laxa.

PMID:27735137

Lysyl oxidase-like 2 (LOXL2) oxidizes trimethylated lysine 4 in histone H3.

The authors report recombinant LOXL2 oxidation of H3K4me3, but this claim is disputed and unsuitable as secure annotation evidence.

"Infrared spectroscopy and mass spectrometry analyses demonstrated that recombinant LOXL2 specifically deaminates trimethylated H3K4."

PMID:28327460

Comprehensive proteomic characterization of stem cell-derived extracellular matrices.

PMID:28332555

LOXL2 drives epithelial-mesenchymal transition via activation of IRE1-XBP1 signalling pathway.

Overexpressed LOXL2 accumulates in the endoplasmic reticulum and activates IRE1-XBP1 signaling in carcinoma-cell EMT models independently of catalytic activity.

"We demonstrate that overexpression of LOXL2 promotes its accumulation in the Endoplasmic Reticulum (ER), inducing ER stress and activating the IRE1-XBP1 signalling pathway of the ER-stress response."

PMID:29581294

Crystal structure of human lysyl oxidase-like 2 (hLOXL2) in a precursor state.

Copper loading activates human LOXL2 and supports LTQ formation, whereas zinc occupancy traps an inactive precursor state.

"Unexpectedly, the copper-binding site of hLOXL2 is occupied by zinc, which blocks LTQ generation and the enzymatic activity of hLOXL2 in our in vitro assay. Biochemical analysis confirms that copper loading robustly activates hLOXL2 and supports LTQ formation."
The crystallized human LOXL2 fragment is monomeric in solution and contains a structurally coordinated calcium ion.

"Despite the observation of two molecules in a single ASU, hLOXL2 is revealed as being in a monomeric state in solution."

PMID:30676771

Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin.

Full-length recombinant human LOXL2 directly binds and deaminates tropoelastin and creates allysines and cross-linked tropoelastin peptides in vitro.

"We detected direct interaction between LOXL2 and tropoelastin (TE) and also LOXL2-mediated deamination of TE. Using proteomics, we identified several allysines together with cross-linked TE peptides."
LOXL2 N-terminal processing is not required for catalytic activation, unlike propeptide cleavage of LOX and LOXL1.

"Our data suggest that SRCR domains 1 and 2 are located away from the catalytic domain, supporting the notion that LOXL2 processing is not associated with enzyme activation, as recently proposed in López-Jiménez et al. (4)."

PMID:31759052

Scavenger Receptor Cysteine-Rich domains of Lysyl Oxidase-Like2 regulate endothelial ECM and angiogenesis through non-catalytic scaffolding mechanisms.

LOXL2 SRCR domains directly bind collagen IV and support endothelial collagen-IV deposition and angiogenesis independently of the catalytic domain.

"Neither enzyme activity nor catalytic domain were necessary for collagen IV deposition and angiogenesis, whereas the SRCR domains were effective for these processes."

PMID:31911079

LOXL2 promotes oncogenic progression in alveolar rhabdomyosarcoma independently of its catalytic activity.

LOXL2 promotes rhabdomyosarcoma motility and metastasis independently of catalytic activity and was reported to interact with vimentin.

"The intermediated filament protein vimentin was validated as a LOXL2-interactor."

PMID:20026874

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.

LOXL2 is induced as a direct HIF-1 target and contributes to hypoxia-driven E-cadherin repression and EMT in cell models.

"In addition to the previously demonstrated LOX, we characterize LOXL2 as a direct transcriptional target of HIF-1."

PMID:20306300

The human lysyl oxidase-like 2 protein functions as an amine oxidase toward collagen and elastin.

Recombinant human LOXL2 oxidizes multiple collagen types and elastin in vitro, and its N-terminal SRCR domains are dispensable for this catalytic activity.

"All of the purified recombinant LOXL2 proteins, with or without the SRCR domains in the N-terminus, showed significant amine oxidase activity toward several different types of collagen and elastin in in vitro amine oxidase assays."

PMID:20439985

Modulation of lysyl oxidase-like 2 enzymatic activity by an allosteric antibody inhibitor.

LOXL2 oxidizes diamine substrates and fibrillar type-I collagen and is inhibited allosterically by an antibody binding SRCR4.

"In this report, we assessed the steady-state enzymatic activity of lysyl oxidase-like 2 (LOXL2) against the substrates 1,5-diaminopentane (DAP), spermine, and fibrillar type I collagen."

PMID:20818376

Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment.

LOXL2 inhibition reduces fibrotic and tumor-associated stromal remodeling in animal models.

"Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) was efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models."

PMID:22483618

Lysyl oxidase-like 2 deaminates lysine 4 in histone H3.

This paper's H3K4-deamination claim was retracted and must not support LOXL2 annotation.

"1. RETRACTED ARTICLE"

PMID:27392148

Retraction Notice to: Lysyl Oxidase-like 2 Deaminates Lysine 4 in Histone H3.

This notice retracts PMID:22483618.

"Retraction of Mol Cell. 2012 May 11;46(3):369-76. doi: 10.1016/j.molcel.2012.03.002."

file:human/LOXL2/LOXL2-uniprot.txt

UniProtKB record for human LOXL2 (Q9Y4K0)

UniProt curates LOXL2 as a precursor with extracellular matrix, basement-membrane, nuclear, chromosome, and endoplasmic-reticulum localizations.

"CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular CC matrix, basement membrane {ECO:0000269|PubMed:23319596}. Nucleus CC {ECO:0000269|PubMed:22204712, ECO:0000269|PubMed:24414204}. Chromosome CC {ECO:0000269|PubMed:27735137}. Endoplasmic reticulum CC {ECO:0000269|PubMed:28332555}."

file:human/LOXL2/LOXL2-deep-research-falcon.md

Falcon deep-research report for human LOXL2

The provider report prioritizes LOXL2 extracellular protein-lysine oxidation and collagen/elastin cross-link initiation as the most defensible core function.

"The most defensible functional annotation of human LOXL2 is **a secreted copper/LTQ-dependent protein-lysine oxidase that initiates collagen and elastin cross-linking in the extracellular matrix**."

Suggested Experiments

Experiment: Engineer an acute endogenous LOXL2 degron in primary human fibroblasts, endothelial cells, and matrix-producing organoids. Quantify site-resolved allysines, hydroxyallysines, and mature cross-links by targeted mass spectrometry, with wild-type and catalytic-dead rescue and parallel measurement or perturbation of LOX-family paralogs.

Hypothesis: LOXL2 oxidizes a defined subset of collagen and elastin sites in human matrix that is not redundantly modified by other LOX-family enzymes.

Type: endogenous protein degradation and matrix cross-link proteomics

Experiment: Create endogenous cleavage-resistant and cleavage-mimetic LOXL2 alleles in human endothelial cells and fibroblasts. Compare secretion kinetics, full-length and processed forms, copper/LTQ-dependent activity, collagen/tropoelastin oxidation, collagen-IV/fibronectin binding, and matrix deposition.

Hypothesis: SRCR1/2 cleavage changes LOXL2 substrate presentation and extracellular retention but is not required for catalytic activation.

Type: endogenous processing and substrate-targeting analysis

Experiment: Combine endogenous pulse-chase imaging, split-proximity labeling, cross-linking mass spectrometry, and single-molecule stoichiometry with purified SRCR-domain reconstitution. Compare wild-type, SRCR-deleted, and catalytic-dead LOXL2 while separately measuring deposition and angiogenic phenotypes.

Hypothesis: LOXL2 SRCR domains transiently coordinate collagen IV and fibronectin during exocytosis rather than forming a stable extracellular complex.

Type: matrix-scaffold interaction dynamics

Experiment: Endogenously tag LOXL2 on both sides of the signal peptide/processing boundaries in normal and matched tumor-derived cells, quantify intracellular forms by compartment-resolved proteomics, and test TAF10 and unbiased candidate substrates with wild-type versus catalytic-dead rescue. Treat H3K4me3 oxidation as a disputed claim requiring independent replication, not as an assay-positive control.

Hypothesis: Reported nuclear and chromatin-associated LOXL2 catalysis is context dependent and absent from normal human cells at endogenous abundance.

Type: endogenous localization and intracellular-substrate validation

Knowledge Gaps

What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).

Gap: The endogenous human collagen and elastin lysine/hydroxylysine sites modified specifically by LOXL2, rather than another LOX-family enzyme, and their tissue-specific partitioning are unresolved.

OPEN BIOLOGY RESIDUAL_SUBGAP

What is known: Recombinant human LOXL2 oxidizes several collagen preparations, fibrillar type-I collagen, and tropoelastin, but these assays do not define enzyme-specific sites or quantify LOXL2's share of cross-link formation in native human tissues.

Significance: Site- and enzyme-specific maps are needed to distinguish LOXL2 physiology from paralog redundancy and to interpret selective inhibition.

What would resolve it: Quantify site-resolved allysines, hydroxyallysines, and mature cross-links in primary human matrix-producing cells or organoids after selective endogenous LOXL2 degradation, with LOX/LOXL1/LOXL3/LOXL4 activity measured and controlled.

Provenance (the field's own admissions):

"although their specific functions and substrate preferences in vivo remain to be elucidated." — PMID:29581294

Gap: The physiological purpose and tissue regulation of LOXL2 cleavage between SRCR2 and SRCR3 remain unknown, including whether processing changes substrate choice, extracellular retention, or SRCR-dependent scaffolding without activating catalysis.

OPEN BIOLOGY RESIDUAL_SUBGAP

What is known: Full-length recombinant LOXL2 is active, and structural work places SRCR1/2 away from the catalytic domain. Cleavage therefore differs from activating propeptide removal in LOX and LOXL1, but its endogenous consequences are not defined.

Significance: Conflating processing with activation obscures which LOXL2 form performs catalysis versus matrix targeting and may misdirect form-selective interventions.

What would resolve it: Introduce endogenous cleavage-resistant and cleavage-mimetic alleles in human endothelial cells and fibroblasts, then compare secretion, matrix retention, substrate binding, site-resolved oxidation, and basement-membrane deposition.

Provenance (the field's own admissions):

"Our data suggest that SRCR domains 1 and 2 are located away from the catalytic domain, supporting the notion that LOXL2 processing is not associated with enzyme activation, as recently proposed in López-Jiménez et al. (4)." — PMID:30676771

Gap: The molecular architecture, stoichiometry, and dynamics by which LOXL2 SRCR domains organize collagen IV and fibronectin deposition are not known.

OPEN BIOLOGY MF_DARK

What is known: Direct binding and domain-rescue experiments establish a catalytic-independent matrix-scaffolding role, but they do not show whether LOXL2 simultaneously bridges substrates, acts sequentially during secretion, or forms a persistent complex.

Significance: Defining this mechanism is necessary to distinguish transient substrate handling from stable complex membership and to separate SRCR-targeted from catalytic interventions.

What would resolve it: Use endogenous split-proximity labeling, single-molecule stoichiometry, pulse-chase secretion imaging, and purified-domain reconstitution with collagen IV and fibronectin, including catalytic-dead and SRCR-deletion controls.

Provenance (the field's own admissions):

"LOXL2 interacts intracellularly and directly with collagen IV and fibronectin before incorporation into ECM fibrillar structures upon exocytosis, as demonstrated by TIRF time-lapse microscopy." — PMID:31759052

Gap: Whether endogenous LOXL2 has a reproducible normal intracellular catalytic substrate and how any intracellular pool bypasses or exits the secretory pathway remain unresolved.

OPEN BIOLOGYCURATION RESIDUAL_SUBGAP

What is known: Tumor immunohistochemistry and overexpression experiments detect nuclear, cytoplasmic, and endoplasmic-reticulum pools, and methylated TAF10 was reported as a substrate. The H3K4me3 oxidation evidence is retracted or disputed and cannot establish normal chromatin catalysis.

Significance: Resolving this boundary would prevent extracellular catalytic function from being conflated with tumor-specific localization or invalid histone chemistry.

What would resolve it: Tag endogenous LOXL2 in normal and matched tumor-derived human cells, quantify secretory and intracellular forms, and test candidate intracellular substrates by activity-dependent proteomics and catalytic-dead rescue without relying on H3K4me3 as a positive control.

Provenance (the field's own admissions):

"The protein manifested decreased nuclear expression and increased cytoplasmic expression." — PMID:22204712
"1. RETRACTED ARTICLE" — PMID:22483618

Deep Research

Falcon

(LOXL2-deep-research-falcon.md)

Human LOXL2 (UniProt Q9Y4K0): Functional-Annotation Research Report Falcon Edison Scientific Literature 31 citations 1 artifacts 2026-08-10T23:34:15.388743

Edison artifact artifact-00 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Human LOXL2 (UniProt Q9Y4K0): Functional-Annotation Research Report

Executive summary

Identity was verified before literature interpretation. LOXL2 is the human lysyl oxidase-like 2 gene product (UniProt Q9Y4K0), not a similarly named protein from another organism. The literature agrees with the supplied annotation: LOXL2 belongs to the lysyl-oxidase family and contains four N-terminal scavenger-receptor cysteine-rich (SRCR) domains followed by a conserved C-terminal lysyl-oxidase/amine-oxidase catalytic domain. No conflicting same-symbol literature was used. (meier2021oligomericstatesand pages 1-2, moon2014humanlysyloxidaselike pages 1-2)

LOXL2’s best-established primary function is extracellular: it is a secreted, copper- and lysine-tyrosylquinone (LTQ)-dependent amine oxidase that oxidatively deaminates selected lysine and hydroxylysine side chains in collagen and elastin precursors. The resulting aldehydes initiate spontaneous covalent cross-link formation, thereby stabilizing and mechanically remodeling extracellular matrix (ECM). Direct evidence is strongest for collagen IV and tropoelastin; oxidation of the extracellular domain of PDGFRβ has also been demonstrated. (meier2021oligomericstatesand pages 1-2, meier2021oligomericstatesand pages 10-12, schmelzer2019lysyloxidase–like2 pages 1-2)

LOXL2 remains a biologically credible fibrosis and cancer-stroma target, but therapeutic validation is unresolved. The anti-LOXL2 antibody simtuzumab failed in multiple phase 2 trials. Work published in 2023–2024 suggests that the antibody did not adequately inhibit catalytic cross-linking in disease-relevant models and, in some IPF models, produced counterproductive profibrotic effects. Thus, simtuzumab’s failure should not automatically be interpreted as proof that LOXL2 catalytic activity is irrelevant; it instead exposes target-engagement, model-selection, redundancy, and disease-stage problems. (espindola2023translationalstudiesreveal pages 1-2, bell2024spatialtranscriptomicvalidation pages 10-11)

topic	best-supported conclusion	evidence type/key quantitative detail	confidence/caveat
Identity and domains	The target is human LOXL2 (lysyl oxidase-like 2), a LOX-family secreted amine oxidase with four N-terminal SRCR domains and a conserved C-terminal catalytic domain.	Concordant biochemical/structural reviews and recombinant protein studies; UniProt-compatible architecture repeatedly reported. Full-length protein is ~100 kDa. (meier2021oligomericstatesand pages 1-2, moon2014humanlysyloxidaselike pages 1-2)	High; identity and domain architecture are well established.
Catalytic chemistry and cofactors	LOXL2 catalyzes oxidative deamination of peptidyl lysine/hydroxylysine to reactive aldehydes that drive covalent ECM cross-linking; activity is copper- and LTQ-dependent.	LTQ derives from Lys653 and Tyr689; catalytic domain contains the His-X-His-X-His copper-binding motif. Model-substrate kinetics reported for 1,5-diaminopentane/spermine: Km ~1 mM, kcat ~0.02 s^-1. (moon2014humanlysyloxidaselike pages 1-2, meier2021oligomericstatesand pages 1-2)	High for amine-oxidase chemistry/cofactor assignment; kinetic constants are mainly from model substrates rather than native fibrillar substrates.
Processing and localization	LOXL2 is synthesized as a precursor, secreted, and can be proteolytically processed by PACE4 to remove SRCR1-2 without abolishing in vitro amine-oxidase activity. The major functional site is extracellular matrix.	Cleavage site reported as Arg314-Phe315-Arg316-Lys317↓Ala318; processed form ~60 kDa. Full-length LOXL2 is mostly monomer, with some concentration-dependent dimerization/higher oligomers; at ≥0.88 mg/mL: 83.6% monomer, 11.6% dimer, 4.7% tetramer+pentamer. (meier2021oligomericstatesand pages 1-2, meier2021oligomericstatesand pages 10-12)	High for secretion/processing; physiological significance of SRCR cleavage remains incompletely resolved. Proposed intracellular roles exist but are less securely established than ECM-localized catalysis.
Physiological substrates	Best-supported physiological substrates are extracellular matrix proteins, especially collagen and elastin precursors; direct evidence is strongest for tropoelastin and collagen IV.	Proteomics demonstrated LOXL2-mediated tropoelastin deamination/cross-linking and formation of elastin-like material with mature-elastin-like mechanical properties; LOXL2 also oxidizes collagen IV and can oxidize lysines in PDGFRβ extracellular domain. (schmelzer2019lysyloxidase–like2 pages 1-2, meier2021oligomericstatesand pages 1-2, meier2021oligomericstatesand pages 10-12)	High for ECM substrate class; substrate-site specificity across all collagen isoforms is still incomplete. PDGFRβ oxidation broadens substrate scope beyond structural ECM proteins.
Pathways and disease mechanisms	LOXL2 primarily functions in ECM remodeling, matrix stiffening, and collagen/elastin cross-linking, influencing fibrosis, invasion, metastasis, angiogenesis, and mechanotransduction-related phenotypes.	Recent reviews and translational studies connect LOXL2 to fibrotic niche remodeling, myofibroblast biology, and tumor desmoplasia; Open Targets lists human disease associations including idiopathic pulmonary fibrosis. (immanuel2024loxl2innon‐alcoholic pages 4-4, OpenTargets Search: -LOXL2)	Moderate-high; disease linkage is strong, but many pathway assignments integrate direct and indirect effects of altered matrix mechanics.
2023-2024 simtuzumab re-evaluation	Recent work argues failure of simtuzumab/AB0023 may reflect incomplete or nonproductive target modulation rather than invalidation of LOXL2 biology.	Espindola 2023 found anti-LOXL2 enhanced fibroblast-to-myofibroblast differentiation/invasion in translational IPF models and worsened fibrosis in humanized mice; normal/IPF fibroblast studies used n=4 per group and mouse studies n=3-5. Bell 2024 reported AB0023 did not significantly inhibit LOXL2 catalytic activity, collagen cross-linking, or tissue stiffness in disease-relevant fibrosis models. (espindola2023translationalstudiesreveal pages 6-8, espindola2023translationalstudiesreveal pages 1-2, bell2024spatialtranscriptomicvalidation pages 10-11, espindola2023translationalstudiesreveal pages 18-21)	High that simtuzumab was ineffective; moderate that mechanism of failure is fully resolved. Negative antibody-trial results should not be overinterpreted as disproving LOXL2 as a target.
Clinical-stage inhibitors and trial status	Multiple LOXL2-directed or pan-LOX programs reached the clinic, but no LOX/LOXL2 inhibitor is yet approved. Simtuzumab failed in several phase 2 settings; newer small-molecule approaches remain under evaluation.	Simtuzumab IPF phase 2 RAINIER enrolled 544 and was terminated for lack of efficacy; PSC phase 2b enrolled 235; metastatic pancreatic cancer phase 2 enrolled 250; metastatic colorectal cancer phase 2 enrolled 266 and was terminated. Oral LOXL2 inhibitor GB2064 (formerly PAT-1251) phase IIa in myelofibrosis is active-not-recruiting, estimated n=21. Pan-LOX inhibitor PXS-5505 phase 1/2a in myelofibrosis completed with actual enrollment 43. (NCT01769196 chunk 1, NCT01672853 chunk 1, NCT01472198 chunk 1, NCT01479465 chunk 1, NCT04679870 chunk 1, NCT04676529 chunk 1)	High for trial status/enrollment. Caveat: some active programs are pan-LOX rather than LOXL2-selective, so clinical outcomes may not isolate LOXL2 biology alone.

Table: This table compacts the strongest available evidence for human LOXL2 functional annotation, from molecular mechanism and substrates to recent therapeutic re-evaluations. It is useful as a quick reference for separating well-established extracellular amine-oxidase functions from more tentative disease-mechanistic and translational claims.

1. Identity, nomenclature and domain verification

The target is Homo sapiens LOXL2, approved name lysyl oxidase like 2. Its architecture matches the supplied InterPro annotation:

an N-terminal signal-peptide/secretory precursor context;
four N-terminal SRCR domains, corresponding to the supplied SRCR and SRCR-like-superfamily assignments;
a conserved C-terminal lysyl-oxidase catalytic region, corresponding to the supplied LOX-like protein, lysyl-oxidase, and lysyl-oxidase conserved-site annotations.

The SRCR domains distinguish LOXL2 structurally from canonical LOX while potentially organizing substrate and partner recognition. The C-terminal domain has approximately 68% sequence similarity to the corresponding LOX catalytic region and contains the conserved copper-binding and LTQ machinery. (meier2021oligomericstatesand pages 1-2)

Structural studies describe full-length LOXL2 as an elongated or rod-like protein, with the SRCR domains forming a stalk and the catalytic domain positioned at one end. Full-length protein is predominantly monomeric in solution but can form concentration-dependent oligomers: at concentrations reported as at least 0.88 mg/mL, approximately 83.6% was monomer, 11.6% dimer, and 4.7% tetramer plus pentamer. Deleting SRCR1–2 abolished the detected oligomeric species, implicating these domains in self-association. (meier2021oligomericstatesand pages 10-12, schmelzer2019lysyloxidase–like2 pages 1-2)

2. Primary biochemical function

2.1 Catalyzed reaction

LOXL2 is classified as a protein-lysine 6-oxidase/lysyl oxidase, EC 1.4.3.13. Its net reaction can be represented as:

peptidyl-L-lysine + O₂ + H₂O → peptidyl-allysine + NH₃ + H₂O₂

Hydroxylysine residues can analogously yield hydroxyallysine. These reactive aldehydes then undergo non-enzymatic condensation with neighboring lysine, hydroxylysine, or aldehyde-bearing residues to create immature and subsequently mature collagen or elastin cross-links. LOXL2 therefore initiates cross-linking chemically; it does not directly catalyze every subsequent condensation step. Its structural consequence is increased ECM stability, protease resistance, organization and—when excessive—tissue stiffness. (immanuel2024loxl2innon‐alcoholic pages 4-4, moon2014humanlysyloxidaselike pages 1-2, schmelzer2019lysyloxidase–like2 pages 1-2)

2.2 Cofactors and active site

LOXL2 requires Cu²⁺ and the protein-derived quinone cofactor LTQ. The catalytic region contains a conserved His-X-His-X-His copper-binding motif. LTQ is generated post-translationally from Lys653 and Tyr689 in the human sequence. Structural comparisons indicate that LTQ maturation does not cause a major global rearrangement of LOXL2, and the principal set of disulfide bonds is retained between precursor and mature forms. (meier2021oligomericstatesand pages 1-2, moon2014humanlysyloxidaselike pages 1-2)

Molecular oxygen is the terminal oxidant, explaining production of hydrogen peroxide. Consequently, LOXL2 couples ECM cross-link generation to local redox chemistry, although many reported downstream “redox-signaling” effects are indirect and should not be treated as part of the minimal enzyme annotation.

2.3 Substrate specificity

The defensible annotation is peptidyl lysine/hydroxylysine oxidase with preference for structured extracellular protein substrates, rather than a narrowly sequence-specific enzyme.

Tropoelastin: Direct binding, oxidative deamination, allysine formation, and cross-linked peptides were demonstrated by biochemical and proteomic methods. The resulting elastin-like material resisted trypsin and had mechanical properties resembling mature elastin. Vascular-wall codistribution of LOXL2 and elastin supports, but does not alone prove, an in-vivo elastogenesis role. (schmelzer2019lysyloxidase–like2 pages 1-2)
Collagen: Collagen IV is a repeatedly documented substrate. The broader literature supports collagen cross-linking as a major function, but residue-level and isoform-by-isoform specificity remains incomplete. It is therefore safer to state that LOXL2 acts on multiple collagen contexts rather than that it is universally equivalent across all 28 collagen types. (meier2021oligomericstatesand pages 1-2)
PDGFRβ: LOXL2 can oxidize lysines in the receptor’s extracellular domain, showing that its protein-substrate scope extends beyond fibrillar structural proteins. The physiological importance of this reaction is less established than collagen/elastin cross-linking. (meier2021oligomericstatesand pages 10-12)
Small-amolecule assay substrates: 1,5-diaminopentane and spermine support activity assays, with reported approximate values of Km ≈1 mM and kcat ≈0.02 s⁻¹. These values are useful for assay development but should not be extrapolated directly to native collagen or elastin kinetics. β-Aminopropionitrile inhibited these assay reactions with IC₅₀ values of 5.0±1.4 and 3.8±0.2 µM, respectively. (moon2014humanlysyloxidaselike pages 1-2)

3. Biosynthesis, processing and site of action

LOXL2 is synthesized as a precursor and secreted through the conventional secretory pathway as an approximately 100-kDa full-length glycoprotein. Extracellular PACE4 processing at Arg314-Phe315-Arg316-Lys317↓Ala318 removes the first two SRCR domains and yields an approximately 60-kDa form. In vitro, this cleavage does not abolish amine-oxidase activity against cadaverine or tropoelastin, although it changes solubility and oligomeric behavior. The physiological purpose of this processing remains uncertain. (meier2021oligomericstatesand pages 1-2)

The strongest localization/function assignment is therefore the extracellular space and ECM, particularly sites of collagen and elastin maturation or pathological matrix deposition. Secreted LOXL2 can associate with vascular elastin, basement-membrane collagen, cell-surface receptors and other matrix partners. The SRCR domains likely contribute to localization, substrate presentation and protein interactions rather than housing the catalytic chemistry. (meier2021oligomericstatesand pages 10-12, schmelzer2019lysyloxidase–like2 pages 1-2)

Intracellular and nuclear LOXL2 pools have been reported in cancer and EMT studies, including proposed regulation of transcription, histones and signaling. These observations may be biologically important, but they are less consistently defined mechanistically than extracellular oxidation. Some alleged intracellular functions may also be catalytic-activity-independent. They should therefore be represented as context-dependent secondary functions, not as replacements for the primary extracellular amine-oxidase annotation. (immanuel2024loxl2innon‐alcoholic pages 4-4)

4. Biological pathways and processes

4.1 ECM assembly and mechanobiology

By introducing aldehydes into collagen and elastin, LOXL2 controls cross-link density, fibril/fiber architecture, matrix insolubility and stiffness. These material changes affect integrin engagement, focal adhesion signaling, cytoskeletal tension and fibroblast-to-myofibroblast differentiation. Thus, many effects attributed to “LOXL2 signaling” are better understood as a sequence:

LOXL2 secretion → lysine/hydroxylysine oxidation → ECM cross-linking/stiffening → altered receptor engagement and mechanotransduction.

This distinction matters because downstream proliferation, migration or transcriptional changes may result from matrix mechanics rather than direct intracellular signaling by LOXL2.

4.2 Fibrosis

LOXL2 is frequently elevated in fibrotic tissues and contributes to persistence of collagen-rich scar matrix. A 2024 NASH review identifies hepatic stellate-cell activation, ECM cross-linking, oxidative stress and altered inflammatory/metabolic states as interconnected LOXL2-associated processes. However, direct enzymatic cross-linking is the most secure mechanism; effects on lipid metabolism or inflammation may be secondary or context-specific. (immanuel2024loxl2innon‐alcoholic pages 4-4)

Open Targets associates human LOXL2 with idiopathic pulmonary fibrosis, although the displayed aggregate association score is modest (approximately 0.119) and reflects heterogeneous evidence. Database association scores should not be confused with causal effect sizes or clinical efficacy. (OpenTargets Search: -LOXL2)

4.3 Cancer and metastasis

In tumors, LOXL2-mediated collagen cross-linking can align and stiffen the matrix, facilitate invasion, compress vessels, limit drug penetration and remodel immune-cell access. Increased LOXL2 has accordingly been linked to desmoplasia, EMT-like states and metastasis. Nevertheless, cancer phenotypes are not uniformly catalytic or cell autonomous: macrophage-, fibroblast- and tumor-cell-derived LOXL2 can have different effects, and other LOX-family enzymes may compensate.

The clinically relevant interpretation is therefore that LOXL2 is a matrix-remodeling node, not a simple universal oncogenic switch. Its value is likely to depend on tumor type, producing cell, substrate environment, disease stage and combination therapy.

5. Recent developments, emphasizing 2023–2024

5.1 Re-evaluation of anti-LOXL2 therapy in pulmonary fibrosis

Espindola and colleagues, published November 2023, found elevated LOXL2 transcript and protein in IPF lungs. Slow-progressing IPF fibroblasts showed an approximately fourfold transcript increase relative to normal cells, while SSEA4-positive progenitors showed about 2.4–3.1-fold increases in slow- and rapid-IPF groups. Despite this association, simtuzumab did not reduce collagen production or fibroblast migration as nintedanib did; instead, it promoted myofibroblast differentiation and invasion in some assays. Preventive or delayed dosing at 15 mg/kg twice weekly worsened fibrosis in a humanized mouse model. Human-cell experiments included normal and IPF fibroblasts at n=4 per group, while mouse groups were small (n=3–5), so the direction of effect is important but precise effect-size generalization is limited. [Published November 2023; DOI: https://doi.org/10.35534/fibrosis.2023.10007] (espindola2023translationalstudiesreveal pages 6-8, espindola2023translationalstudiesreveal pages 1-2, espindola2023translationalstudiesreveal pages 18-21)

Bell and colleagues, published September 2024, used spatial transcriptomics to validate a three-dimensional fibrosis model against human fibroblast foci. In this disease-relevant system, AB0023—the precursor antibody to simtuzumab—did not significantly inhibit LOXL2 catalytic activity, collagen cross-linking or tissue stiffness. This finding challenges the assumption that prior antibody trials rigorously tested catalytic LOXL2 inhibition. [Published September 2024; DOI: https://doi.org/10.1016/j.xcrm.2024.101695] (bell2024spatialtranscriptomicvalidation pages 10-11)

Expert interpretation: these studies suggest at least three non-exclusive explanations for clinical failure: insufficient catalytic target engagement, potentially agonistic or compensatory effects of antibody binding, and biological redundancy among LOX-family enzymes. They also illustrate why target expression alone is an inadequate biomarker for response.

5.2 Other 2023–2024 directions

Recent work extends LOXL2 research beyond simple collagen abundance toward spatially resolved matrix architecture, cell-specific sources, and catalytic versus non-catalytic functions. Examples include macrophage-driven LOXL2 programs in pancreatic cancer, pan-LOX inhibition to decompress tumor vessels and improve chemotherapy, and proposed non-enzymatic LOXL2/HIF1A effects in ligament vascularization. These findings are promising mechanistic leads, but most remain preclinical and cannot yet be described as established human therapy.

The emerging consensus is that small-molecule catalytic inhibitors with verified tissue pharmacodynamics may provide a cleaner test than antibodies directed to non-catalytic SRCR epitopes. Conversely, pan-LOX inhibition may better overcome family redundancy but carries a greater risk of disturbing physiological collagen and elastin homeostasis.

6. Applications and real-world implementation

6.1 Drug development

No LOXL2 or pan-LOX inhibitor is established as an approved therapy in the evidence reviewed. Clinical development has included:

Simtuzumab/GS-6624, an anti-LOXL2 antibody. The randomized phase 2 RAINIER IPF study enrolled 544 participants and was terminated for lack of efficacy. Its endpoints included progression-free survival based on confirmed FVC decline or death, including analyses stratified by serum LOXL2. [NCT01769196; posted results April 13, 2017: https://clinicaltrials.gov/study/NCT01769196] (NCT01769196 chunk 1)
In primary sclerosing cholangitis, a randomized phase 2b trial enrolled 235 participants receiving 75 mg, 125 mg or placebo weekly for 96 weeks. [NCT01672853: https://clinicaltrials.gov/study/NCT01672853] (NCT01672853 chunk 1)
In metastatic pancreatic adenocarcinoma, simtuzumab plus gemcitabine was tested in a phase 2 study enrolling 250 participants. [NCT01472198: https://clinicaltrials.gov/study/NCT01472198] (NCT01472198 chunk 1)
In KRAS-mutant metastatic colorectal cancer, simtuzumab plus FOLFIRI was tested in a phase 2 study enrolling 266 participants; the study was terminated. [NCT01479465: https://clinicaltrials.gov/study/NCT01479465] (NCT01479465 chunk 1)
GB2064/PAT-1251, described as a high-affinity, selective, mechanism-based oral LOXL2 inhibitor, entered an open-label phase IIa myelofibrosis study at 1,000 mg twice daily, with 21 participants listed and active-not-recruiting status in the retrieved April 2024 record. [NCT04679870; last posted April 3, 2024: https://clinicaltrials.gov/study/NCT04679870] (NCT04679870 chunk 1)
PXS-5505/amsulostat, a pan-LOX inhibitor, entered a phase 1/2a myelofibrosis program with 43 actual participants, including monotherapy and ruxolitinib add-on cohorts. Its pharmacodynamic endpoints explicitly include plasma LOX/LOXL2 inhibition and changes in reticulin and collagen marrow fibrosis. Because it is pan-family rather than LOXL2-selective, outcomes cannot isolate LOXL2 alone. [NCT04676529: https://clinicaltrials.gov/study/NCT04676529] (NCT04676529 chunk 1)

6.2 Biomarkers

LOXL2 protein, transcript abundance, serum LOXL2 and matrix cross-link signatures have been explored as fibrosis or cancer biomarkers. Current evidence supports association more strongly than clinical utility. Serum abundance may not report local catalytic activity, substrate accessibility or drug engagement; future biomarkers should combine enzyme-activity measures with tissue cross-link chemistry and mechanical readouts.

6.3 Biomaterials and tissue engineering

Recombinant LOXL2 can cross-link tropoelastin into protease-resistant, mechanically mature-elastin-like material under cell-compatible conditions. This provides a concrete application in engineered elastic tissues, vascular constructs and biomimetic matrices, although manufacturing control, residual peroxide, cross-link uniformity and immunogenicity require evaluation. [Published January 2019; DOI: https://doi.org/10.1096/fj.201801860rr] (schmelzer2019lysyloxidase–like2 pages 1-2)

7. Evidence assessment and annotation recommendations

High-confidence annotation

Human LOXL2/Q9Y4K0 is a secreted lysyl-oxidase-family precursor with four SRCR domains and a C-terminal catalytic domain.
It is a Cu²⁺/LTQ-dependent amine oxidase using oxygen to convert peptidyl lysine or hydroxylysine into aldehydes, with ammonia and hydrogen peroxide as coproducts.
Its principal site of action is extracellular.
Collagen and tropoelastin are physiological substrate classes; direct tropoelastin cross-linking and collagen-IV oxidation are experimentally supported.
The principal biological role is initiation of ECM cross-linking and regulation of matrix stability and mechanics.

Moderate-confidence/context-dependent annotation

oxidation of non-matrix extracellular proteins such as PDGFRβ;
regulation of EMT, angiogenesis and immune behavior downstream of ECM mechanics;
intracellular or nuclear functions, including chromatin-associated effects;
disease-specific causal roles inferred mainly from expression correlations or perturbation models.

Important unresolved questions

Which lysine/hydroxylysine positions and collagen isoforms are preferred in vivo?
What is the physiological significance of PACE4 removal of SRCR1–2?
Which reported intracellular activities require the LTQ/copper catalytic mechanism?
Can selective catalytic inhibition achieve adequate tissue exposure without compensation by LOX, LOXL1, LOXL3 or LOXL4?
Which activity-based or cross-link biomarkers best identify patients likely to benefit?

Conclusion

The most defensible functional annotation of human LOXL2 is a secreted copper/LTQ-dependent protein-lysine oxidase that initiates collagen and elastin cross-linking in the extracellular matrix. Its direct chemistry is well established; many fibrosis, cancer, angiogenesis and EMT phenotypes are downstream consequences of altered matrix architecture or context-dependent non-catalytic functions. The 2023–2024 literature has shifted emphasis from simple LOXL2 expression toward catalytic target engagement, spatially faithful human models, family redundancy and cell-specific matrix biology. Simtuzumab’s failures substantially weaken that antibody strategy but do not constitute a definitive test of selective catalytic LOXL2 inhibition.

References

(meier2021oligomericstatesand pages 1-2): Alex A. Meier, Hee-Jung Moon, Ronald Toth, Ewa Folta-Stogniew, Krzysztof Kuczera, C. Russell Middaugh, and Minae Mure. Oligomeric states and hydrodynamic properties of lysyl oxidase-like 2. Dec 2021. URL: https://doi.org/10.3390/biom11121846, doi:10.3390/biom11121846. This article has 7 citations.
(moon2014humanlysyloxidaselike pages 1-2): Hee-Jung Moon, Joel Finney, Trey Ronnebaum, and Minae Mure. Human lysyl oxidase-like 2. Bioorganic chemistry, 57:231-41, Dec 2014. URL: https://doi.org/10.1016/j.bioorg.2014.07.003, doi:10.1016/j.bioorg.2014.07.003. This article has 196 citations and is from a peer-reviewed journal.
(meier2021oligomericstatesand pages 10-12): Alex A. Meier, Hee-Jung Moon, Ronald Toth, Ewa Folta-Stogniew, Krzysztof Kuczera, C. Russell Middaugh, and Minae Mure. Oligomeric states and hydrodynamic properties of lysyl oxidase-like 2. Dec 2021. URL: https://doi.org/10.3390/biom11121846, doi:10.3390/biom11121846. This article has 7 citations.
(schmelzer2019lysyloxidase–like2 pages 1-2): Christian E. H. Schmelzer, Andrea Heinz, Helen Troilo, Michael P. Lockhart‐Cairns, Thomas A. Jowitt, Marion F. Marchand, Laurent Bidault, Marine Bignon, Tobias Hedtke, Alain Barret, James C. McConnell, Michael J. Sherratt, Stéphane Germain, David J. S. Hulmes, Clair Baldock, and Laurent Muller. Lysyl oxidase–like 2 (loxl2)–mediated cross-linking of tropoelastin. The FASEB Journal, 33:5468-5481, Jan 2019. URL: https://doi.org/10.1096/fj.201801860rr, doi:10.1096/fj.201801860rr. This article has 94 citations.
(espindola2023translationalstudiesreveal pages 1-2): Milena S. Espindola, David M. Habiel, Ana Lucia Coelho, Tanyalak Parimon, Peter Chen, Amanda Mikels-Vigdal, and Cory M. Hogaboam. Translational studies reveal the divergent effects of simtuzumab targeting loxl2 in idiopathic pulmonary fibrosis. Fibrosis (Hong Kong, China), 1:1-12, Nov 2023. URL: https://doi.org/10.35534/fibrosis.2023.10007, doi:10.35534/fibrosis.2023.10007. This article has 13 citations.
(bell2024spatialtranscriptomicvalidation pages 10-11): Joseph A. Bell, Elizabeth R. Davies, Christopher J. Brereton, Milica Vukmirovic, James J.W. Roberts, Kerry Lunn, Leanne Wickens, Franco Conforti, Robert A. Ridley, Jessica Ceccato, Lucy N. Sayer, David A. Johnston, Andres F. Vallejo, Aiman Alzetani, Sanjay Jogai, Ben G. Marshall, Aurelie Fabre, Luca Richeldi, Phillip D. Monk, Paul Skipp, Naftali Kaminski, Emily Offer, Yihua Wang, Donna E. Davies, and Mark G. Jones. Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting loxl2. Sep 2024. URL: https://doi.org/10.1016/j.xcrm.2024.101695, doi:10.1016/j.xcrm.2024.101695. This article has 20 citations and is from a peer-reviewed journal.
(immanuel2024loxl2innon‐alcoholic pages 4-4): Joys Rachel Immanuel, Rajnish Kumar, Ashish Kumar Agrahari, and Shailendra Asthana. Loxl2 in non‐alcoholic steatohepatitis (nash): insights into fibrosis pathogenesis and therapeutic potential. Liver International Communications, Mar 2024. URL: https://doi.org/10.1002/lci2.85, doi:10.1002/lci2.85. This article has 4 citations.
(OpenTargets Search: -LOXL2): Open Targets Query (-LOXL2, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(espindola2023translationalstudiesreveal pages 6-8): Milena S. Espindola, David M. Habiel, Ana Lucia Coelho, Tanyalak Parimon, Peter Chen, Amanda Mikels-Vigdal, and Cory M. Hogaboam. Translational studies reveal the divergent effects of simtuzumab targeting loxl2 in idiopathic pulmonary fibrosis. Fibrosis (Hong Kong, China), 1:1-12, Nov 2023. URL: https://doi.org/10.35534/fibrosis.2023.10007, doi:10.35534/fibrosis.2023.10007. This article has 13 citations.
(espindola2023translationalstudiesreveal pages 18-21): Milena S. Espindola, David M. Habiel, Ana Lucia Coelho, Tanyalak Parimon, Peter Chen, Amanda Mikels-Vigdal, and Cory M. Hogaboam. Translational studies reveal the divergent effects of simtuzumab targeting loxl2 in idiopathic pulmonary fibrosis. Fibrosis (Hong Kong, China), 1:1-12, Nov 2023. URL: https://doi.org/10.35534/fibrosis.2023.10007, doi:10.35534/fibrosis.2023.10007. This article has 13 citations.
(NCT01769196 chunk 1): Study to Assess the Efficacy and Safety of Simtuzumab (GS-6624) in Adults With Idiopathic Pulmonary Fibrosis (IPF). Gilead Sciences. 2013. ClinicalTrials.gov Identifier: NCT01769196
(NCT01672853 chunk 1): Simtuzumab (GS-6624) in the Prevention of Progression of Liver Fibrosis in Adults With Primary Sclerosing Cholangitis (PSC). Gilead Sciences. 2013. ClinicalTrials.gov Identifier: NCT01672853
(NCT01472198 chunk 1): A Study to Evaluate the Efficacy and Safety of Simtuzumab Combined With Gemcitabine for Metastatic Pancreatic Adenocarcinoma. Gilead Sciences. 2011. ClinicalTrials.gov Identifier: NCT01472198
(NCT01479465 chunk 1): Efficacy and Safety of Simtuzumab (SIM) With FOLFIRI as Second Line Treatment in Colorectal Adenocarcinoma. Gilead Sciences. 2011. ClinicalTrials.gov Identifier: NCT01479465
(NCT04679870 chunk 1): A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral GB2064 in Participants With Myelofibrosis. Galecto Biotech AB. 2021. ClinicalTrials.gov Identifier: NCT04679870
(NCT04676529 chunk 1): Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis. Syntara. 2021. ClinicalTrials.gov Identifier: NCT04676529

Artifacts

Edison artifact artifact-00

Citations

meier2021oligomericstatesand pages 1-2
meier2021oligomericstatesand pages 10-12
moon2014humanlysyloxidaselike pages 1-2
bell2024spatialtranscriptomicvalidation pages 10-11
espindola2023translationalstudiesreveal pages 1-2
espindola2023translationalstudiesreveal pages 6-8
espindola2023translationalstudiesreveal pages 18-21
Published November 2023; DOI: https://doi.org/10.35534/fibrosis.2023.10007
Published September 2024; DOI: https://doi.org/10.1016/j.xcrm.2024.101695
NCT01769196; posted results April 13, 2017: https://clinicaltrials.gov/study/NCT01769196
NCT01672853: https://clinicaltrials.gov/study/NCT01672853
NCT01472198: https://clinicaltrials.gov/study/NCT01472198
NCT01479465: https://clinicaltrials.gov/study/NCT01479465
NCT04679870; last posted April 3, 2024: https://clinicaltrials.gov/study/NCT04679870
NCT04676529: https://clinicaltrials.gov/study/NCT04676529
Published January 2019; DOI: https://doi.org/10.1096/fj.201801860rr
https://doi.org/10.35534/fibrosis.2023.10007]
https://doi.org/10.1016/j.xcrm.2024.101695]
https://clinicaltrials.gov/study/NCT01769196]
https://clinicaltrials.gov/study/NCT01672853]
https://clinicaltrials.gov/study/NCT01472198]
https://clinicaltrials.gov/study/NCT01479465]
https://clinicaltrials.gov/study/NCT04679870]
https://clinicaltrials.gov/study/NCT04676529]
https://doi.org/10.1096/fj.201801860rr]
https://doi.org/10.3390/biom11121846,
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https://doi.org/10.1096/fj.201801860rr,
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https://doi.org/10.1016/j.xcrm.2024.101695,
https://doi.org/10.1002/lci2.85,

📚 Additional Documentation

Notes

(LOXL2-notes.md)

LOXL2 literature and provenance notes

Provenance and evidence boundary

No provider-generated deep-research file was present during the initial evidence audit. Falcon subsequently completed LOXL2-deep-research-falcon.md; it was inspected as a secondary lead source after the primary-paper findings had been assembled. Its central extracellular-enzyme framing agrees with the cached primary literature, but none of its claims is used here without checking a primary cache or the local UniProt record. These notes remain a manual evidence synthesis and are not presented as provider output. [file:human/LOXL2/LOXL2-deep-research-falcon.md, "The most defensible functional annotation of human LOXL2 is a secreted copper/LTQ-dependent protein-lysine oxidase that initiates collagen and elastin cross-linking in the extracellular matrix."]

All biochemical statements below distinguish recombinant human LOXL2 from ortholog loss-of-function evidence and distinguish full-length protein from engineered truncations. The local GOA contains no isoform field, and the reviewed UniProt record contains no ALTERNATIVE PRODUCTS block. Consequently, no finding is treated as isoform-specific. Experimental truncations and catalytically inactive mutants are constructs, not curated human isoforms.

Core catalytic activity and substrates

The strongest direct substrate evidence supports a copper/LTQ-dependent protein-lysine oxidase acting on extracellular collagen and elastin substrates.

Recombinant human LOXL2 constructs oxidized several collagen types and elastin in vitro: [PMID:20306300, "All of the purified recombinant LOXL2 proteins, with or without the SRCR domains in the N-terminus, showed significant amine oxidase activity toward several different types of collagen and elastin in in vitro amine oxidase assays"]
Enzymology included fibrillar type-I collagen as well as small diamines: [PMID:20439985, "In this report, we assessed the steady-state enzymatic activity of lysyl oxidase-like 2 (LOXL2) against the substrates 1,5-diaminopentane (DAP), spermine, and fibrillar type I collagen."] Small-diamine activity is an assay capability and should not displace protein substrates as the biologically informative function.
Recombinant human LOXL2 directly bound and deaminated tropoelastin and generated allysines and cross-linked peptides: [PMID:30676771, "We detected direct interaction between LOXL2 and tropoelastin (TE) and also LOXL2-mediated deamination of TE. Using proteomics, we identified several allysines together with cross-linked TE peptides."] This chemistry was demonstrated in vitro; vascular codistribution only suggests an in-vivo elastogenesis role.
Endothelial studies support collagen-IV assembly and vascular basement-membrane organization: [PMID:21835952, "Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM."]
Later work separates collagen-IV scaffolding from catalysis: [PMID:31759052, "Neither enzyme activity nor catalytic domain were necessary for collagen IV deposition and angiogenesis, whereas the SRCR domains were effective for these processes."] Thus collagen-IV deposition is not itself proof that LOXL2 oxidizes collagen IV under those conditions.

Cofactors, precursor state, processing, and domain boundary

Copper loading supports LTQ biogenesis and enzymatic activation: [PMID:29581294, "Biochemical analysis confirms that copper loading robustly activates hLOXL2 and supports LTQ formation."]
The crystal structure captured a zinc-bound inactive precursor-like state, not the mature active conformation: [PMID:29581294, "Unexpectedly, the copper-binding site of hLOXL2 is occupied by zinc, which blocks LTQ generation and the enzymatic activity of hLOXL2 in our in vitro assay."] The crystallized protein was an engineered residues-318–774 N455Q fragment.
Glycosylation and secretion were assessed using recombinant human protein expressed in Drosophila S2 cells: [PMID:23319596, "Disruption of N-glycosylation by site-directed mutagenesis or tunicamycin treatment completely inhibited secretion so that only small quantities of inclusion bodies were detected."] This expression-system dependence should be retained.
LOXL2 must not be described using the classic LOX precursor/propeptide model. LOX and LOXL1 have removable activation propeptides, whereas LOXL2 has four N-terminal SRCR domains. Full-length LOXL2 can be active, and its SRCR1/2 processing is not catalytic activation: [PMID:30676771, "Our data suggest that SRCR domains 1 and 2 are located away from the catalytic domain, supporting the notion that LOXL2 processing is not associated with enzyme activation, as recently proposed in López-Jiménez et al. (4)."]

Localization audit

The reliable core localization is the secretory pathway and extracellular matrix/basement membrane. Intracellular observations are real experimental contexts but require narrower interpretation.

Secreted recombinant human LOXL2 and ECM activity are supported by PMID:23319596 and PMID:21835952.
Nuclear/cytoplasmic LOXL2 was detected by tumor immunohistochemistry, but this does not demonstrate nuclear catalysis: [PMID:22204712, "The protein manifested decreased nuclear expression and increased cytoplasmic expression."]
Endoplasmic-reticulum accumulation was induced by LOXL2 overexpression in carcinoma cells: [PMID:28332555, "We demonstrate that overexpression of LOXL2 promotes its accumulation in the Endoplasmic Reticulum (ER), inducing ER stress and activating the IRE1-XBP1 signalling pathway of the ER-stress response."] It is a maturation/overexpression context rather than the mature extracellular enzyme's terminal site of action.
The UniProt chromosome/chromatin localization currently cites PMID:27735137, which belongs to the disputed H3K4me3 evidence chain described below. It should not be treated as secure catalytic localization.

Retraction and disputed H3K4me3 oxidation

PMID:22483618 is explicitly a retracted publication: [PMID:22483618, "1. RETRACTED ARTICLE"] The linked notice states: [PMID:27392148, "Retraction of Mol Cell. 2012 May 11;46(3):369-76. doi: 10.1016/j.molcel.2012.03.002."] Its LOXL2/H3K4me3 oxidation claim is invalid evidence and must not support chromosome localization or a nuclear histone-oxidase core function.

PMID:27735137 later reasserted that recombinant LOXL2 deaminates H3K4me3: [PMID:27735137, "Infrared spectroscopy and mass spectrometry analyses demonstrated that recombinant LOXL2 specifically deaminates trimethylated H3K4."] Because it is an abstract-only report from substantially the same author group after the earlier paper's retraction, it is classified here as DISPUTED, not as independent restoration of the claim. PMID:24239292 likewise depends mechanistically on an H3K4-deaminase premise and is not secure evidence for chromosome-associated catalysis.

The methylated-TAF10 claim is distinct from histone H3K4: [PMID:25959397, "Using an unbiased proteomic approach, we have identified methylated TAF10, a member of the TFIID complex, as a LOXL2 substrate."] It remains context-specific, abstract-only evidence and does not make LOXL2 a stable TFIID subunit.

Interaction and complex boundaries

The structural fragment studied in PMID:29581294 was monomeric in solution: [PMID:29581294, "Despite the observation of two molecules in a single ASU, hLOXL2 is revealed as being in a monomeric state in solution."] Therefore crystal packing must not be converted into a physiological LOXL2 homodimer annotation.

Reported partners include SNAI1, MARCKSL1, vimentin, collagen IV, fibronectin, and tropoelastin in different assays and disease/cell contexts. These establish pairwise association or context-dependent scaffolding, not one stable complex containing all partners. In particular, the PMID:27339457 cached abstract names binding of fibulin-4 to LOX and LOXL1, not LOXL2; because the cache is abstract-only, the curator's LOXL2 IPI is retained as unverified rather than declared a miscitation.

Human versus ortholog evidence

Human recombinant protein establishes catalytic activity, structural chemistry, and several interactions. Physiological angiogenesis evidence in PMID:21835952 combines endothelial-cell assays with zebrafish knockdown, while inhibitor phenotypes in PMID:20818376 use xenograft and fibrosis models. These ortholog/model results support conserved biology but do not by themselves demonstrate the identical tissue-specific mechanism in healthy humans.

📄 View Raw YAML

id: Q9Y4K0
gene_symbol: LOXL2
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  LOXL2 is a secreted copper- and lysine-tyrosylquinone-dependent protein-lysine
  oxidase with four N-terminal scavenger receptor cysteine-rich domains and a
  C-terminal catalytic domain. In the extracellular matrix and basement membrane,
  it oxidatively deaminates selected peptidyl lysines in collagen and elastin
  precursors, generating aldehydes that initiate covalent cross-link formation and
  stabilize matrix fibers. Its SRCR domains also bind extracellular-matrix proteins
  and can organize collagen IV and fibronectin deposition independently of catalytic
  activity. LOXL2 thereby contributes to connective-tissue matrix assembly and, in
  endothelial contexts, vascular basement-membrane organization and angiogenesis.
  Proteolytic removal of the first two SRCR domains can alter form and substrate
  presentation but is not required to activate the full-length enzyme. Intracellular
  pools and catalytic-independent effects have been reported in tumor and
  differentiation models, but they are context dependent and distinct from the core
  extracellular oxidase and matrix-scaffolding activities.
existing_annotations:
- term:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  supporting_entities:
  - FB:FBgn0034660
  - FB:FBgn0039848
  - MGI:MGI:106096
  - MGI:MGI:1337004
  - MGI:MGI:1914823
  - MGI:MGI:96817
  - PANTHER:PTN002550804
  - RGD:3015
  - UniProtKB:P28300
  - UniProtKB:P58215
  - UniProtKB:Q05063
  - UniProtKB:Q95L39
  - UniProtKB:Q96JB6
  - UniProtKB:Q9Y4K0
  review:
    summary: The IBA annotation assigns protein-lysine 6-oxidase activity to LOXL2.
    action: ACCEPT
    reason: >-
      The phylogenetic inference agrees with direct recombinant-human LOXL2 assays
      showing oxidation of collagen and elastin substrates and copper-dependent LTQ
      formation; protein-lysine 6-oxidase is the conserved core activity.
    supported_by:
    - reference_id: PMID:20306300
      supporting_text: >-
        All of the purified recombinant LOXL2 proteins, with or without the SRCR
        domains in the N-terminus, showed significant amine oxidase activity toward
        several different types of collagen and elastin in in vitro amine oxidase
        assays.
    propagation_review:
      root_cause: NO_FAILURE_CORE
      source_entities:
      - source_id: FB:FBgn0034660
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: FB:FBgn0039848
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: MGI:MGI:106096
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: MGI:MGI:1337004
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: MGI:MGI:1914823
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: MGI:MGI:96817
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: PANTHER:PTN002550804
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: RGD:3015
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:P28300
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:P58215
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:Q05063
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:Q95L39
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:Q96JB6
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:Q9Y4K0
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  supporting_entities:
  - MGI:MGI:106096
  - MGI:MGI:1337004
  - MGI:MGI:1914823
  - MGI:MGI:96817
  - PANTHER:PTN002550804
  - RGD:1308435
  - RGD:1308752
  - RGD:3015
  - UniProtKB:P28300
  - UniProtKB:P33072
  - UniProtKB:P58215
  - UniProtKB:Q08397
  - UniProtKB:Q9Y4K0
  review:
    summary: The IBA annotation assigns extracellular region to LOXL2.
    action: ACCEPT
    reason: >-
      Conserved extracellular activity is corroborated by secretion of recombinant
      human LOXL2 and its recovery with extracellular-matrix material. This is the
      physiological compartment for the core collagen/elastin oxidase activity.
    supported_by:
    - reference_id: PMID:23319596
      supporting_text: >-
        Disruption of N-glycosylation by site-directed mutagenesis or tunicamycin
        treatment completely inhibited secretion so that only small quantities of
        inclusion bodies were detected.
    propagation_review:
      root_cause: NO_FAILURE_CORE
      source_entities:
      - source_id: MGI:MGI:106096
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: MGI:MGI:1337004
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: MGI:MGI:1914823
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: MGI:MGI:96817
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: PANTHER:PTN002550804
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: RGD:1308435
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: RGD:1308752
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: RGD:3015
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:P28300
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:P33072
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:P58215
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:Q08397
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:Q9Y4K0
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  supporting_entities:
  - MGI:MGI:106096
  - MGI:MGI:96817
  - PANTHER:PTN008698711
  - RGD:1308435
  - RGD:1308752
  - RGD:3015
  review:
    summary: The IBA annotation assigns extracellular matrix to LOXL2.
    action: ACCEPT
    reason: >-
      The phylogenetic assignment is reinforced by direct human endothelial evidence
      for LOXL2-dependent matrix deposition and by recombinant-human-protein studies
      demonstrating secretion and extracellular matrix-substrate oxidation.
    supported_by:
    - reference_id: PMID:21835952
      supporting_text: >-
        Further investigation in vitro by loss and gain of function experiments
        confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and
        demonstrated that this enzyme was required for collagen IV assembly in the ECM.
    propagation_review:
      root_cause: NO_FAILURE_CORE
      source_entities:
      - source_id: MGI:MGI:106096
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: MGI:MGI:96817
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: PANTHER:PTN008698711
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: RGD:1308435
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: RGD:1308752
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: RGD:3015
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0002040
    label: sprouting angiogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - PANTHER:PTN002910812
  - UniProtKB:Q9Y4K0
  - ZFIN:ZDB-GENE-070818-1
  review:
    summary: The IBA annotation assigns sprouting angiogenesis to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: Sprouting angiogenesis is directly supported by PMID:21835952 but is a contextual tissue program rather than LOXL2 core catalysis.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      source_entities:
      - source_id: PANTHER:PTN002910812
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:Q9Y4K0
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: ZFIN:ZDB-GENE-070818-1
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0030199
    label: collagen fibril organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - MGI:MGI:96817
  - PANTHER:PTN008698711
  - RGD:3015
  - UniProtKB:Q9Y4K0
  review:
    summary: The IBA annotation assigns collagen fibril organization to LOXL2.
    action: ACCEPT
    reason: >-
      LOXL2 directly oxidizes collagen substrates, and loss/gain experiments show a
      requirement for LOXL2 in collagen-IV matrix assembly. These data support the
      conserved collagen-organization process represented by the IBA term.
    supported_by:
    - reference_id: PMID:21835952
      supporting_text: >-
        Further investigation in vitro by loss and gain of function experiments
        confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and
        demonstrated that this enzyme was required for collagen IV assembly in the ECM.
    propagation_review:
      root_cause: NO_FAILURE_CORE
      source_entities:
      - source_id: MGI:MGI:96817
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: PANTHER:PTN008698711
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: RGD:3015
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: UniProtKB:Q9Y4K0
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  supporting_entities:
  - ARBA:ARBA00088088
  - RHEA:24544
  - EC:1.4.3.13
  review:
    summary: The IEA annotation assigns protein-lysine 6-oxidase activity to LOXL2.
    action: ACCEPT
    reason: >-
      The Rhea/EC reaction mapping exactly matches LOXL2's experimentally established
      oxidative deamination of peptidyl lysines in collagen and elastin and is not
      merely a family-level prediction.
    supported_by:
    - reference_id: PMID:20306300
      supporting_text: >-
        All of the purified recombinant LOXL2 proteins, with or without the SRCR
        domains in the N-terminus, showed significant amine oxidase activity toward
        several different types of collagen and elastin in in vitro amine oxidase
        assays.
    propagation_review:
      root_cause: NO_FAILURE_CORE
      source_entities:
      - source_id: ARBA:ARBA00088088
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: RHEA:24544
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: EC:1.4.3.13
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  supporting_entities:
  - InterPro:IPR001695
  - InterPro:IPR019828
  review:
    summary: The IEA annotation assigns copper ion binding to LOXL2.
    action: ACCEPT
    reason: >-
      The InterPro copper-binding-domain mapping is corroborated by the human LOXL2
      structure and biochemical copper loading, which restores LTQ formation and
      catalytic activity.
    supported_by:
    - reference_id: PMID:29581294
      supporting_text: >-
        Biochemical analysis confirms that copper loading robustly activates hLOXL2
        and supports LTQ formation.
    propagation_review:
      root_cause: NO_FAILURE_CORE
      source_entities:
      - source_id: InterPro:IPR001695
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: InterPro:IPR019828
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0005604
    label: basement membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0025
  review:
    summary: The IEA annotation assigns basement membrane to LOXL2.
    action: ACCEPT
    reason: >-
      The UniProt subcellular-location mapping is supported by human endothelial
      studies placing LOXL2 in collagen-IV/fibronectin deposition and showing its
      role in vascular basement-membrane organization.
    supported_by:
    - reference_id: PMID:31759052
      supporting_text: >-
        Neither enzyme activity nor catalytic domain were necessary for collagen IV
        deposition and angiogenesis, whereas the SRCR domains were effective for these
        processes.
    propagation_review:
      root_cause: NO_FAILURE_CORE
      source_entities:
      - source_id: UniProtKB-SubCell:SL-0025
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0191
  review:
    summary: The IEA annotation assigns nucleus to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: >-
      UniProt's nuclear-location mapping is corroborated by tumor-cell and tissue
      studies that detect a nuclear LOXL2 pool. Those observations are
      disease/context dependent and do not displace the core extracellular activity.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      source_entities:
      - source_id: UniProtKB-SubCell:SL-0191
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0005694
    label: chromosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0468
  review:
    summary: The IEA annotation assigns chromosome to LOXL2.
    action: UNDECIDED
    reason: >-
      This electronic row faithfully maps UniProt's chromosome location, but the
      underlying H3K4me3 evidence chain is disputed. The localization therefore cannot
      be independently verified and should not be used to support chromatin catalysis.
    propagation_review:
      root_cause: UNRESOLVED
      failure_modes:
      - SOURCE_EVIDENCE_WEAK
      source_entities:
      - source_id: UniProtKB-SubCell:SL-0468
        source_status: SOURCE_WEAK_OR_INFERRED
        comment: The mapping is preserved, but its underlying chromosome evidence is disputed.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0095
  review:
    summary: The IEA annotation assigns endoplasmic reticulum to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secretory-pathway transit makes ER localization plausible, and overexpressed
      LOXL2 accumulates in the ER in carcinoma cells. The observed accumulation is a
      maturation/overexpression context, not the mature enzyme's core site of action.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      source_entities:
      - source_id: UniProtKB-SubCell:SL-0095
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  supporting_entities:
  - InterPro:IPR001190
  - InterPro:IPR036772
  review:
    summary: The IEA annotation assigns membrane to LOXL2.
    action: MARK_AS_OVER_ANNOTATED
    reason: LOXL2 is secreted and lacks a transmembrane segment; an SRCR-domain mapping does not establish membrane residence.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      source_entities:
      - source_id: InterPro:IPR001190
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: InterPro source is present but does not establish membrane localization.
      - source_id: InterPro:IPR036772
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: InterPro source is present but does not establish membrane localization.
- term:
    id: GO:0016641
    label: oxidoreductase activity, acting on the CH-NH2 group of donors, oxygen as
      acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  supporting_entities:
  - InterPro:IPR001695
  - InterPro:IPR019828
  review:
    summary: The IEA annotation assigns the broad oxygen-dependent CH-NH2 oxidoreductase activity to LOXL2.
    action: MODIFY
    reason: LOXL2 substrate specificity is known, so replace this broad parent activity with protein-lysine 6-oxidase activity.
    proposed_replacement_terms:
    - id: GO:0004720
      label: protein-lysine 6-oxidase activity
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: InterPro:IPR001695
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: InterPro:IPR019828
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0071953
    label: elastic fiber
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  supporting_entities:
  - ARBA:ARBA00084594
  review:
    summary: The IEA annotation assigns elastic fiber to LOXL2.
    action: ACCEPT
    reason: >-
      Although ARBA supplies this row, independent human-protein evidence shows direct
      tropoelastin binding, lysine oxidation, and cross-link formation, while vascular
      tissue places LOXL2 with elastin. Those data support elastic-fiber association.
    supported_by:
    - reference_id: PMID:30676771
      supporting_text: >-
        We detected direct interaction between LOXL2 and tropoelastin (TE) and also
        LOXL2-mediated deamination of TE. Using proteomics, we identified several
        allysines together with cross-linked TE peptides.
    propagation_review:
      root_cause: NO_FAILURE_CORE
      source_entities:
      - source_id: ARBA:ARBA00084594
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24863880
  qualifier: enables
  supporting_entities:
  - UniProtKB:P49006
  review:
    summary: The IPI annotation assigns protein binding to LOXL2.
    action: UNDECIDED
    reason: >-
      PMID:24863880 verifies an SRCR-region interaction with the actin-regulatory
      protein MARCKSL1, but MARCKSL1 is not itself a cytoskeletal structural component.
      The accessible evidence does not justify a more informative GO molecular-function
      term than generic protein binding, so no inaccurate replacement is proposed.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30676771
  qualifier: enables
  supporting_entities:
  - UniProtKB:P15502-2
  review:
    summary: The IPI annotation assigns protein binding to LOXL2.
    action: MODIFY
    reason: PMID:30676771 directly demonstrates tropoelastin binding and oxidation; extracellular matrix protein binding is the informative term.
    proposed_replacement_terms:
    - id: GO:1990430
      label: extracellular matrix protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31759052
  qualifier: enables
  supporting_entities:
  - UniProtKB:P02751
  review:
    summary: The IPI annotation assigns protein binding to LOXL2.
    action: MODIFY
    reason: PMID:31759052 directly demonstrates fibronectin binding through LOXL2 SRCR domains; use extracellular matrix protein binding.
    proposed_replacement_terms:
    - id: GO:1990430
      label: extracellular matrix protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31911079
  qualifier: enables
  supporting_entities:
  - UniProtKB:P08670
  - UniProtKB:P17655
  review:
    summary: The IPI annotation assigns protein binding to LOXL2.
    action: MODIFY
    reason: >-
      PMID:31911079 and the two IntAct partners identify vimentin and calpain-2.
      Intermediate-filament binding and protease binding describe those interactions
      more precisely than generic protein binding.
    proposed_replacement_terms:
    - id: GO:0019215
      label: intermediate filament binding
    - id: GO:0002020
      label: protease binding
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P58022
  - ensembl:ENSMUSP00000022660
  review:
    summary: The IEA annotation assigns response to hypoxia to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: Human LOXL2 is hypoxia inducible, but response to hypoxia is regulatory context rather than its core enzymatic function.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      source_entities:
      - source_id: UniProtKB:P58022
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: ensembl:ENSMUSP00000022660
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0032332
    label: positive regulation of chondrocyte differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P58022
  - ensembl:ENSMUSP00000022660
  review:
    summary: The IEA annotation assigns positive regulation of chondrocyte differentiation to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: Mouse orthology supports this developmental role, but chondrocyte differentiation is tissue-specific downstream biology.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      source_entities:
      - source_id: UniProtKB:P58022
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: ensembl:ENSMUSP00000022660
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:1902455
    label: negative regulation of stem cell population maintenance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P58022
  - ensembl:ENSMUSP00000022660
  review:
    summary: The IEA annotation assigns negative regulation of stem cell population maintenance to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: TAF10 oxidation links LOXL2 to loss of pluripotency, but stem-cell maintenance is a contextual downstream process.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      source_entities:
      - source_id: UniProtKB:P58022
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
      - source_id: ensembl:ENSMUSP00000022660
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0071953
    label: elastic fiber
  evidence_type: TAS
  original_reference_id: PMID:23962539
  qualifier: located_in
  review:
    summary: The TAS annotation assigns elastic fiber to LOXL2.
    action: ACCEPT
    reason: >-
      The broad review cited by this TAS row does not expose a LOXL2-specific statement
      in the cached abstract. Retain the biologically correct localization on
      independent PMID:30676771 evidence for direct tropoelastin binding/cross-linking
      and vascular codistribution, rather than treating PMID:23962539 as verification.
    additional_reference_ids:
    - PMID:30676771
    supported_by:
    - reference_id: PMID:30676771
      supporting_text: >-
        We detected direct interaction between LOXL2 and tropoelastin (TE) and also
        LOXL2-mediated deamination of TE. Using proteomics, we identified several
        allysines together with cross-linked TE peptides.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: The IDA annotation assigns nucleoplasm to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: >-
      This row comes from direct HPA immunofluorescence curation and therefore supports
      nucleoplasmic detection, but it does not establish a nuclear catalytic or
      transcriptional mechanism. The compartment is retained as non-core.
- term:
    id: GO:0005694
    label: chromosome
  evidence_type: EXP
  original_reference_id: PMID:27735137
  qualifier: located_in
  review:
    summary: The EXP annotation assigns chromosome to LOXL2.
    action: UNDECIDED
    reason: >-
      The cached PMID:27735137 record is abstract-only, and its H3K4me3 mechanism is
      disputed after retraction of the foundational same-group report. Chromosome
      localization cannot be independently verified from the accessible evidence, so
      curator deference requires an unresolved decision rather than a positive keep.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27339457
  qualifier: enables
  supporting_entities:
  - UniProtKB:O95967
  review:
    summary: The IPI annotation assigns protein binding to LOXL2.
    action: MODIFY
    reason: The reported partner is fibulin-4, so extracellular matrix protein binding is more informative than generic protein binding.
    proposed_replacement_terms:
    - id: GO:1990430
      label: extracellular matrix protein binding
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:28327460
  qualifier: colocalizes_with
  extensions:
  - predicate: BFO:0000050
    term:
      id: CL:0002540
      label: mesenchymal stem cell of the bone marrow
  - predicate: BFO:0000050
    term:
      id: CL:0002570
      label: mesenchymal stem cell of adipose tissue
  review:
    summary: The HDA annotation assigns extracellular matrix to LOXL2.
    action: ACCEPT
    reason: >-
      The mesenchymal-cell proteomics record is retained with curator deference, while
      its cached narrative does not expose the LOXL2 peptide-level result. Extracellular
      matrix localization is independently established by IBA and PMID:23319596 and
      PMID:21835952; this reason does not claim PMID:28327460 was independently verified.
    additional_reference_ids:
    - PMID:23319596
    - PMID:21835952
    supported_by:
    - reference_id: PMID:21835952
      supporting_text: >-
        Further investigation in vitro by loss and gain of function experiments
        confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and
        demonstrated that this enzyme was required for collagen IV assembly in the ECM.
- term:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:29581294
  qualifier: enables
  review:
    summary: The IDA annotation assigns protein-lysine 6-oxidase activity to LOXL2.
    action: ACCEPT
    reason: >-
      PMID:29581294 directly shows that copper loading activates recombinant human
      LOXL2 and supports LTQ formation. Together with direct collagen/elastin substrate
      assays, this establishes the specific protein-lysine oxidase activity.
    additional_reference_ids:
    - PMID:20306300
    supported_by:
    - reference_id: PMID:29581294
      supporting_text: >-
        Biochemical analysis confirms that copper loading robustly activates hLOXL2
        and supports LTQ formation.
    - reference_id: PMID:20306300
      supporting_text: >-
        All of the purified recombinant LOXL2 proteins, with or without the SRCR
        domains in the N-terminus, showed significant amine oxidase activity toward
        several different types of collagen and elastin in in vitro amine oxidase
        assays.
- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: IDA
  original_reference_id: PMID:29581294
  qualifier: enables
  review:
    summary: The IDA annotation assigns copper ion binding to LOXL2.
    action: ACCEPT
    reason: >-
      The human LOXL2 structure defines the metal-binding site, and biochemical copper
      loading restores LTQ formation and catalytic activity whereas zinc occupancy
      traps an inactive precursor state.
    supported_by:
    - reference_id: PMID:29581294
      supporting_text: >-
        Biochemical analysis confirms that copper loading robustly activates hLOXL2
        and supports LTQ formation.
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:29581294
  qualifier: enables
  review:
    summary: The IDA annotation assigns calcium ion binding to LOXL2.
    action: ACCEPT
    reason: >-
      PMID:29581294 directly resolves a coordinated calcium ion in the recombinant
      human LOXL2 structure. The truncated precursor-state construct bounds the
      structural inference but still supports ion binding.
    supported_by:
    - reference_id: PMID:29581294
      supporting_text: >-
        This octahedral coordination pattern is consistent with a bound calcium ion,
        which might play a role in local structure stabilization.
- term:
    id: GO:0018057
    label: peptidyl-lysine oxidation
  evidence_type: IDA
  original_reference_id: PMID:29581294
  qualifier: involved_in
  review:
    summary: The IDA annotation assigns peptidyl-lysine oxidation to LOXL2.
    action: ACCEPT
    reason: >-
      Copper-dependent LTQ formation in PMID:29581294 supplies the catalytic chemistry,
      and independent recombinant-human LOXL2 assays directly demonstrate oxidation of
      lysines in collagen and tropoelastin substrates.
    additional_reference_ids:
    - PMID:20306300
    - PMID:30676771
    supported_by:
    - reference_id: PMID:20306300
      supporting_text: >-
        All of the purified recombinant LOXL2 proteins, with or without the SRCR
        domains in the N-terminus, showed significant amine oxidase activity toward
        several different types of collagen and elastin in in vitro amine oxidase
        assays.
    - reference_id: PMID:30676771
      supporting_text: >-
        We detected direct interaction between LOXL2 and tropoelastin (TE) and also
        LOXL2-mediated deamination of TE. Using proteomics, we identified several
        allysines together with cross-linked TE peptides.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:23979707
  qualifier: located_in
  extensions:
  - predicate: BFO:0000050
    term:
      id: CL:0002543
      label: vein endothelial cell
  review:
    summary: The HDA annotation assigns extracellular matrix to LOXL2.
    action: ACCEPT
    reason: >-
      The endothelial proteomics record is retained with curator deference, while its
      cached narrative does not expose a LOXL2-specific result. Independent human
      endothelial loss/gain experiments and recombinant secretion establish ECM
      localization, so the action does not rely on claiming this dataset was verified.
    additional_reference_ids:
    - PMID:21835952
    - PMID:23319596
    supported_by:
    - reference_id: PMID:21835952
      supporting_text: >-
        Further investigation in vitro by loss and gain of function experiments
        confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and
        demonstrated that this enzyme was required for collagen IV assembly in the ECM.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:25959397
  qualifier: involved_in
  review:
    summary: The IDA annotation assigns negative regulation of transcription by RNA polymerase II to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: >-
      PMID:25959397 identifies methylated TAF10 as an intracellular LOXL2 substrate and
      reports altered TFIID-dependent transcription during neural differentiation.
      This is a specific developmental context, not the core extracellular function.
- term:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:25959397
  qualifier: enables
  review:
    summary: The IDA annotation assigns protein-lysine 6-oxidase activity to LOXL2.
    action: ACCEPT
    reason: >-
      PMID:25959397 reports oxidation of a methylated protein lysine in TAF10, directly
      supporting the broad protein-lysine oxidase activity. The TAF10 context is
      non-core, but the enzymatic activity is independently established extracellularly.
    supported_by:
    - reference_id: PMID:25959397
      supporting_text: >-
        Using an unbiased proteomic approach, we have identified methylated TAF10, a
        member of the TFIID complex, as a LOXL2 substrate.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:24414204
  qualifier: located_in
  review:
    summary: The IDA annotation assigns nucleus to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: >-
      PMID:24414204 studies intracellular LOXL2/SNAI1-dependent EMT and
      catalytic-independent signaling in carcinoma cells. Nuclear localization is
      retained as a context-specific pool rather than a core catalytic compartment.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:28332555
  qualifier: located_in
  review:
    summary: The IDA annotation assigns endoplasmic reticulum to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: >-
      PMID:28332555 directly shows that overexpressed LOXL2 accumulates in the ER and
      activates IRE1-XBP1 stress signaling in carcinoma cells. Because accumulation is
      overexpression-induced, it is retained as non-core maturation/disease context.
- term:
    id: GO:0010718
    label: positive regulation of epithelial to mesenchymal transition
  evidence_type: IMP
  original_reference_id: PMID:24239292
  qualifier: involved_in
  review:
    summary: The IMP annotation assigns positive regulation of epithelial to mesenchymal transition to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: >-
      PMID:24239292 directly reports LOXL2-dependent heterochromatin changes and
      mesenchymal-cell behavior during EMT, supporting this contextual phenotype as
      non-core. Its proposed H3K4-deaminase mechanism is disputed and is not accepted as
      the explanation for the observed EMT effect.
- term:
    id: GO:0018057
    label: peptidyl-lysine oxidation
  evidence_type: IDA
  original_reference_id: PMID:25959397
  qualifier: involved_in
  review:
    summary: The IDA annotation assigns peptidyl-lysine oxidation to LOXL2.
    action: ACCEPT
    reason: >-
      PMID:25959397 identifies methylated TAF10 as a protein substrate oxidized by
      LOXL2. The neural-differentiation context is non-core, but oxidation of a
      peptidyl lysine directly supports this general process term.
    supported_by:
    - reference_id: PMID:25959397
      supporting_text: >-
        Using an unbiased proteomic approach, we have identified methylated TAF10, a
        member of the TFIID complex, as a LOXL2 substrate.
- term:
    id: GO:0070828
    label: heterochromatin organization
  evidence_type: IMP
  original_reference_id: PMID:24239292
  qualifier: involved_in
  review:
    summary: The IMP annotation assigns heterochromatin organization to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: >-
      The abstract directly reports LOXL2-dependent HP1alpha release and major-satellite
      transcript downregulation during EMT, supporting a contextual heterochromatin
      phenotype. The proposed H3K4-deaminase mechanism is disputed and is not accepted
      as the biochemical basis of this non-core annotation.
- term:
    id: GO:1902455
    label: negative regulation of stem cell population maintenance
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P58022
  review:
    summary: The ISS annotation assigns negative regulation of stem cell population maintenance to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: Mouse transfer agrees with human TAF10/pluripotency evidence but represents a contextual cell-state outcome.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      source_entities:
      - source_id: UniProtKB:P58022
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IDA
  original_reference_id: PMID:27735137
  qualifier: located_in
  review:
    summary: The IDA annotation assigns chromatin to LOXL2.
    action: UNDECIDED
    reason: >-
      The cached PMID:27735137 record is abstract-only, and its H3K4me3 mechanism is
      disputed after retraction of the foundational same-group report. Chromatin
      localization cannot be independently verified from the accessible evidence, so
      curator deference requires an unresolved decision rather than a positive keep.
- term:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:27735137
  qualifier: enables
  review:
    summary: The IDA annotation assigns protein-lysine 6-oxidase activity to LOXL2.
    action: ACCEPT
    reason: >-
      Protein-lysine 6-oxidase activity is independently established by recombinant
      human LOXL2 biochemistry, including copper-dependent LTQ formation and oxidation
      of collagen substrates. The specific H3K4me3 substrate claim in PMID:27735137
      remains disputed and is not used to support this broader catalytic term.
    additional_reference_ids:
    - PMID:20306300
    - PMID:29581294
    supported_by:
    - reference_id: PMID:20306300
      supporting_text: >-
        All of the purified recombinant LOXL2 proteins, with or without the SRCR
        domains in the N-terminus, showed significant amine oxidase activity toward
        several different types of collagen and elastin in in vitro amine oxidase
        assays.
    - reference_id: PMID:29581294
      supporting_text: >-
        Biochemical analysis confirms that copper loading robustly activates hLOXL2
        and supports LTQ formation.
- term:
    id: GO:0018057
    label: peptidyl-lysine oxidation
  evidence_type: IDA
  original_reference_id: PMID:27735137
  qualifier: involved_in
  review:
    summary: The IDA annotation assigns peptidyl-lysine oxidation to LOXL2.
    action: ACCEPT
    reason: >-
      Peptidyl-lysine oxidation is independently established for recombinant human
      LOXL2 acting on extracellular protein substrates. The disputed H3K4me3 substrate
      claim in PMID:27735137 is not used to support this broader process term.
    additional_reference_ids:
    - PMID:20306300
    - PMID:30676771
    supported_by:
    - reference_id: PMID:20306300
      supporting_text: >-
        All of the purified recombinant LOXL2 proteins, with or without the SRCR
        domains in the N-terminus, showed significant amine oxidase activity toward
        several different types of collagen and elastin in in vitro amine oxidase
        assays.
    - reference_id: PMID:30676771
      supporting_text: >-
        We detected direct interaction between LOXL2 and tropoelastin (TE) and also
        LOXL2-mediated deamination of TE. Using proteomics, we identified several
        allysines together with cross-linked TE peptides.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:22204712
  qualifier: located_in
  review:
    summary: The IDA annotation assigns nucleus to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Human esophageal-carcinoma immunohistochemistry in PMID:22204712 directly detects
      nuclear and cytoplasmic LOXL2. This supports compartmental detection in tumors,
      not a normal nuclear catalytic core function.
- term:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:23319596
  qualifier: enables
  review:
    summary: The IDA annotation assigns protein-lysine 6-oxidase activity to LOXL2.
    action: ACCEPT
    reason: >-
      Recombinant human LOXL2 in PMID:23319596 contains the LTQ cross-link and directly
      oxidizes tropoelastin, establishing the specific protein-lysine oxidase activity
      despite the Drosophila S2 expression-system boundary.
    supported_by:
    - reference_id: PMID:23319596
      supporting_text: >-
        The recombinant proteins also show activity in tropoelastin oxidation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:23319596
  qualifier: located_in
  review:
    summary: The IDA annotation assigns extracellular region to LOXL2.
    action: ACCEPT
    reason: >-
      PMID:23319596 directly analyzes recombinant human LOXL2 recovered from S2-cell
      secretion medium and shows that N-glycosylation is required for efficient
      secretion. This supports extracellular localization with an explicit expression
      system boundary.
    supported_by:
    - reference_id: PMID:23319596
      supporting_text: >-
        Disruption of N-glycosylation by site-directed mutagenesis or tunicamycin
        treatment completely inhibited secretion so that only small quantities of
        inclusion bodies were detected.
- term:
    id: GO:0036211
    label: protein modification process
  evidence_type: IDA
  original_reference_id: PMID:23319596
  qualifier: involved_in
  review:
    summary: The IDA annotation assigns protein modification process to LOXL2.
    action: MODIFY
    reason: PMID:23319596 supports the specific process peptidyl-lysine oxidation, not merely generic protein modification.
    proposed_replacement_terms:
    - id: GO:0018057
      label: peptidyl-lysine oxidation
- term:
    id: GO:0046688
    label: response to copper ion
  evidence_type: IDA
  original_reference_id: PMID:23319596
  qualifier: involved_in
  review:
    summary: The IDA annotation assigns response to copper ion to LOXL2.
    action: UNDECIDED
    reason: >-
      The accessible PMID:23319596 record establishes LTQ formation, glycosylation, and
      secretion but does not expose a cellular response-to-copper assay. Copper binding
      and copper-dependent activation are independently secure, yet they do not justify
      replacing this biological-process row across GO aspects; defer to the curator.
- term:
    id: GO:0070492
    label: oligosaccharide binding
  evidence_type: IDA
  original_reference_id: PMID:23319596
  qualifier: enables
  review:
    summary: The IDA annotation assigns oligosaccharide binding to LOXL2.
    action: UNDECIDED
    reason: The accessible PMID:23319596 record demonstrates N-linked glycosylation of LOXL2, not clearly oligosaccharide binding. Full-text curator evidence is unavailable, so defer.
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P58022
  review:
    summary: The ISS annotation assigns response to hypoxia to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: Human LOXL2 is hypoxia inducible, but this response is non-core context.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      source_entities:
      - source_id: UniProtKB:P58022
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0001837
    label: epithelial to mesenchymal transition
  evidence_type: IDA
  original_reference_id: PMID:16096638
  qualifier: involved_in
  review:
    summary: The IDA annotation assigns epithelial to mesenchymal transition to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: PMID:16096638 directly supports LOXL2/SNAI1-dependent EMT, a contextual tumor/developmental program.
- term:
    id: GO:0001935
    label: endothelial cell proliferation
  evidence_type: IMP
  original_reference_id: PMID:21835952
  qualifier: involved_in
  review:
    summary: The IMP annotation assigns endothelial cell proliferation to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: PMID:21835952 supports the proliferation phenotype downstream of endothelial matrix organization.
- term:
    id: GO:0002040
    label: sprouting angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:21835952
  qualifier: involved_in
  review:
    summary: The IMP annotation assigns sprouting angiogenesis to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: PMID:21835952 supports angiogenesis through collagen IV scaffolding, but this is downstream context.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16096638
  qualifier: enables
  supporting_entities:
  - UniProtKB:O95863
  review:
    summary: The IPI annotation assigns protein binding to LOXL2.
    action: MODIFY
    reason: PMID:16096638 establishes functional interaction with SNAI1; transcription factor binding is more informative.
    proposed_replacement_terms:
    - id: GO:0008134
      label: transcription factor binding
- term:
    id: GO:0005604
    label: basement membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  supporting_entities:
  - UniProtKB:B5DF27
  review:
    summary: The ISS annotation assigns basement membrane to LOXL2.
    action: ACCEPT
    reason: >-
      The orthology transfer is independently supported in human endothelial cells:
      LOXL2 is required for collagen-IV deposition and its SRCR domains organize
      vascular basement-membrane matrix.
    supported_by:
    - reference_id: PMID:31759052
      supporting_text: >-
        Neither enzyme activity nor catalytic domain were necessary for collagen IV
        deposition and angiogenesis, whereas the SRCR domains were effective for these
        processes.
    propagation_review:
      root_cause: NO_FAILURE_CORE
      source_entities:
      - source_id: UniProtKB:B5DF27
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:16096638
  qualifier: located_in
  review:
    summary: The TAS annotation assigns nucleus to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: >-
      PMID:16096638 reports intracellular LOXL2 interaction with SNAI1 and repression
      of E-cadherin in carcinoma models, supporting a nuclear-context role. This is
      retained as non-core and does not establish the normal site of oxidase action.
- term:
    id: GO:0030199
    label: collagen fibril organization
  evidence_type: IMP
  original_reference_id: PMID:21835952
  qualifier: involved_in
  review:
    summary: The IMP annotation assigns collagen fibril organization to LOXL2.
    action: ACCEPT
    reason: >-
      Loss- and gain-of-function experiments in PMID:21835952 directly show that LOXL2
      is required for collagen-IV assembly in endothelial ECM. Together with direct
      collagen oxidation, this supports a collagen-organization role.
    supported_by:
    - reference_id: PMID:21835952
      supporting_text: >-
        Further investigation in vitro by loss and gain of function experiments
        confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and
        demonstrated that this enzyme was required for collagen IV assembly in the ECM.
- term:
    id: GO:0032332
    label: positive regulation of chondrocyte differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P58022
  review:
    summary: The ISS annotation assigns positive regulation of chondrocyte differentiation to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: Mouse orthology supports this plausible tissue-specific developmental role.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      source_entities:
      - source_id: UniProtKB:P58022
        source_status: SUPPORTS_TRANSFER
        comment: Identifier preserved exactly from live QuickGO WITH/FROM provenance.
- term:
    id: GO:0043542
    label: endothelial cell migration
  evidence_type: IMP
  original_reference_id: PMID:21835952
  qualifier: involved_in
  review:
    summary: The IMP annotation assigns endothelial cell migration to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: PMID:21835952 supports endothelial migration downstream of matrix organization.
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:16096638
  qualifier: involved_in
  review:
    summary: The IDA annotation assigns negative regulation of DNA-templated transcription to LOXL2.
    action: KEEP_AS_NON_CORE
    reason: >-
      PMID:16096638 directly reports LOXL2/SNAI1-dependent E-cadherin repression in
      carcinoma models. The transcriptional phenotype is experimentally supported but
      remains a context-specific intracellular role rather than core matrix catalysis.

- term:
    id: GO:0048251
    label: elastic fiber assembly
  evidence_type: IDA
  original_reference_id: PMID:30676771
  qualifier: involved_in
  review:
    summary: Recombinant full-length human LOXL2 binds, deaminates, and cross-links
      tropoelastin into an insoluble elastin-like material.
    action: NEW
    reason: Direct substrate binding, allysine formation, cross-linked tropoelastin
      peptides, and elastin-like material formation justify elastic fiber assembly as
      a specific process annotation. The demonstrated chemistry is in vitro, while
      vascular codistribution supports but does not by itself prove the in-vivo scope.
    supported_by:
    - reference_id: PMID:30676771
      supporting_text: >-
        We detected direct interaction between LOXL2 and tropoelastin (TE) and also
        LOXL2-mediated deamination of TE. Using proteomics, we identified several
        allysines together with cross-linked TE peptides.
- term:
    id: GO:0071711
    label: basement membrane organization
  evidence_type: IMP
  original_reference_id: PMID:31759052
  qualifier: involved_in
  review:
    summary: LOXL2 SRCR domains organize endothelial collagen IV and fibronectin
      deposition independently of the catalytic domain.
    action: NEW
    reason: Direct binding, loss-of-function, domain-deletion, and rescue evidence
      establish a non-catalytic LOXL2 scaffolding role in vascular basement-membrane
      organization. Angiogenesis is a downstream endothelial context and is not
      asserted as a separate molecular activity.
    supported_by:
    - reference_id: PMID:31759052
      supporting_text: >-
        Neither enzyme activity nor catalytic domain were necessary for collagen IV
        deposition and angiogenesis, whereas the SRCR domains were effective for these
        processes.

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16096638
  title: A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression.
  findings:
  - statement: LOXL2 interacts and cooperates with SNAI1 to repress E-cadherin and promote epithelial-to-mesenchymal transition in carcinoma models.
    supporting_text: Here we show that lysyl-oxidase-like 2 and 3 (LOXL2 and LOXL3), two members of the lysyl-oxidase gene family, interact and cooperate with Snail to downregulate E-cadherin expression.
    reference_section_type: ABSTRACT
    full_text_unavailable: false
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Direct interaction and functional perturbation in carcinoma cells; this is a context-dependent intracellular/non-matrix role and does not establish a stable obligate complex.
- id: PMID:21835952
  title: Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV
    collagen assembly in the endothelial basement membrane.
  findings:
  - statement: LOXL2 accumulates in endothelial extracellular matrix and is required for collagen-IV assembly and sprouting angiogenesis.
    supporting_text: Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct endothelial-cell, zebrafish, and matrix evidence; cache is abstract-only, so organism and assay boundaries in the finding are retained.
- id: PMID:22204712
  title: Reduced nuclear and ectopic cytoplasmic expression of lysyl oxidase-like
    2 is associated with lymph node metastasis and poor prognosis in esophageal squamous
    cell carcinoma.
  findings:
  - statement: LOXL2 protein was detected in nuclear and cytoplasmic compartments of human esophageal carcinoma samples, with altered distribution associated with progression.
    supporting_text: The protein manifested decreased nuclear expression and increased cytoplasmic expression.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Human tumor immunohistochemistry supports compartmental detection but does not establish catalytic action in the nucleus or chromosome.
- id: PMID:23319596
  title: Post-translational modifications of recombinant human lysyl oxidase-like
    2 (rhLOXL2) secreted from Drosophila S2 cells.
  findings:
  - statement: Recombinant human LOXL2 contains LTQ at Lys653/Tyr689, oxidizes tropoelastin, and requires N-glycosylation for efficient secretion from Drosophila S2 cells.
    supporting_text: The recombinant proteins also show activity in tropoelastin oxidation. After phenylhydrazine derivatization and trypsin digestion, we used mass spectrometry to identify peptides containing the derivatized lysine tyrosylquinone cross-link at Lys-653 and Tyr-689, as well as N-linked glycans at Asn-455 and Asn-644.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct recombinant-human-protein biochemistry with a Drosophila S2 expression-system boundary; glycosylation effects may be expression-system dependent.
- id: PMID:23962539
  title: Elastic fibres in health and disease.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Broad elastic-fibre review. The cached abstract does not mention LOXL2 specifically, so it is insufficient alone to establish LOXL2 localization to elastic fibres.
- id: PMID:23979707
  title: SILAC-based proteomics of human primary endothelial cell morphogenesis unveils
    tumor angiogenic markers.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Human endothelial morphogenesis proteomics dataset; visible narrative does not identify a LOXL2-specific result, so the underlying HDA provenance remains dataset-level.
- id: PMID:24239292
  title: Regulation of heterochromatin transcription by Snail1/LOXL2 during epithelial-to-mesenchymal transition.
  findings:
  - statement: The paper attributes repression of mouse pericentromeric transcription during EMT to a SNAI1/LOXL2 pathway, but its H3K4-deaminase mechanism is disputed.
    supporting_text: Here, we show that the Snail1 transcription factor represses mouse pericentromeric transcription, acting through the H3K4 deaminase LOXL2.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: DISPUTED
    review_notes: Abstract-only mouse mechanistic study whose H3K4-deaminase premise overlaps the subsequently retracted PMID:22483618 claim; do not use as secure evidence of chromosome-associated LOXL2 catalysis.
- id: PMID:24414204
  title: LOXL2 catalytically inactive mutants mediate epithelial-to-mesenchymal transition.
  findings:
  - statement: Catalytically inactive LOXL2 mutants can cooperate with SNAI1 and activate FAK/Src signaling to drive EMT.
    supporting_text: Here we show that LOXL2 catalytic inactive mutants collaborate with Snail1 in E-cadherin gene repression to trigger EMT and, in addition, promote FAK/Src pathway activation to support EMT.
    reference_section_type: ABSTRACT
    full_text_unavailable: false
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Direct cell-based evidence for a catalytic-independent, context-specific LOXL2 role; it should not be conflated with the core extracellular amine-oxidase activity.
- id: PMID:24863880
  title: Lysyl oxidase-like 2 (LOXL2) controls tumor-associated cell proliferation through the interaction with MARCKSL1.
  findings:
  - statement: The LOXL2 SRCR region interacts with MARCKSL1 in human breast carcinoma cells and modulates proliferation/apoptosis signaling.
    supporting_text: The scavenger-receptor domain of LOXL2 was shown to interact with the N-terminal domain of MARCKSL1.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Direct interaction mapping in a tumor-cell context; abstract-only cache and no evidence that this is a constitutive physiological LOXL2 complex.
- id: PMID:25959397
  title: LOXL2 Oxidizes Methylated TAF10 and Controls TFIID-Dependent Genes during
    Neural Progenitor Differentiation.
  findings:
  - statement: Methylated TAF10 was reported as an intracellular LOXL2 substrate whose oxidation changes TFIID-dependent transcription during neural differentiation.
    supporting_text: Using an unbiased proteomic approach, we have identified methylated TAF10, a member of the TFIID complex, as a LOXL2 substrate.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-verified substrate claim in embryonic stem-cell and zebrafish contexts; distinct from the disputed H3K4me3 claim and not evidence that LOXL2 is a stable TFIID subunit.
- id: PMID:27339457
  title: Functional consequence of fibulin-4 missense mutations associated with vascular
    and skeletal abnormalities and cutis laxa.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: The cached abstract explicitly reports fibulin-4 binding to LOX and LOXL1, not LOXL2. Because the cache is abstract-only and the curator may have used full text, the LOXL2 interaction remains unverified rather than declared miscited.
- id: PMID:27735137
  title: Lysyl oxidase-like 2 (LOXL2) oxidizes trimethylated lysine 4 in histone H3.
  findings:
  - statement: The authors report recombinant LOXL2 oxidation of H3K4me3, but this claim is disputed and unsuitable as secure annotation evidence.
    supporting_text: Infrared spectroscopy and mass spectrometry analyses demonstrated that recombinant LOXL2 specifically deaminates trimethylated H3K4.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: DISPUTED
    review_notes: Later abstract-only paper from substantially the same author group reasserting the H3K4me3 chemistry after PMID:22483618 was retracted. It does not erase the retraction or provide independently verified support suitable for confident GO curation.
- id: PMID:28327460
  title: Comprehensive proteomic characterization of stem cell-derived extracellular
    matrices.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Proteomic ECM dataset supports matrix colocalization at a high-throughput level, but the visible paper text discusses LOX-like family proteins collectively rather than a direct LOXL2 functional assay.
- id: PMID:28332555
  title: LOXL2 drives epithelial-mesenchymal transition via activation of IRE1-XBP1 signalling pathway.
  findings:
  - statement: Overexpressed LOXL2 accumulates in the endoplasmic reticulum and activates IRE1-XBP1 signaling in carcinoma-cell EMT models independently of catalytic activity.
    supporting_text: We demonstrate that overexpression of LOXL2 promotes its accumulation in the Endoplasmic Reticulum (ER), inducing ER stress and activating the IRE1-XBP1 signalling pathway of the ER-stress response.
    reference_section_type: ABSTRACT
    full_text_unavailable: false
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Direct human cell evidence, but ER accumulation occurs under overexpression and is a context/processing phenotype rather than proof that ER is the mature enzyme's extracellular site of action.
- id: PMID:29581294
  title: Crystal structure of human lysyl oxidase-like 2 (hLOXL2) in a precursor state.
  findings:
  - statement: Copper loading activates human LOXL2 and supports LTQ formation, whereas zinc occupancy traps an inactive precursor state.
    supporting_text: Unexpectedly, the copper-binding site of hLOXL2 is occupied by zinc, which blocks LTQ generation and the enzymatic activity of hLOXL2 in our in vitro assay. Biochemical analysis confirms that copper loading robustly activates hLOXL2 and supports LTQ formation.
    reference_section_type: ABSTRACT
    full_text_unavailable: false
  - statement: The crystallized human LOXL2 fragment is monomeric in solution and contains a structurally coordinated calcium ion.
    supporting_text: Despite the observation of two molecules in a single ASU, hLOXL2 is revealed as being in a monomeric state in solution.
    reference_section_type: RESULTS
    full_text_unavailable: false
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct structural and biochemical work on recombinant human LOXL2. The construct is a truncated N455Q precursor-state fragment, so it defines activation chemistry and architecture but not a native stable complex.
- id: PMID:30676771
  title: Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin.
  findings:
  - statement: Full-length recombinant human LOXL2 directly binds and deaminates tropoelastin and creates allysines and cross-linked tropoelastin peptides in vitro.
    supporting_text: We detected direct interaction between LOXL2 and tropoelastin (TE) and also LOXL2-mediated deamination of TE. Using proteomics, we identified several allysines together with cross-linked TE peptides.
    reference_section_type: ABSTRACT
    full_text_unavailable: false
  - statement: LOXL2 N-terminal processing is not required for catalytic activation, unlike propeptide cleavage of LOX and LOXL1.
    supporting_text: Our data suggest that SRCR domains 1 and 2 are located away from the catalytic domain, supporting the notion that LOXL2 processing is not associated with enzyme activation, as recently proposed in López-Jiménez et al. (4).
    reference_section_type: DISCUSSION
    full_text_unavailable: false
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct full-length recombinant-human-protein substrate and processing evidence. Elastogenesis in vivo is suggested by vascular codistribution but the demonstrated cross-link chemistry is in vitro.
- id: PMID:31759052
  title: Scavenger Receptor Cysteine-Rich domains of Lysyl Oxidase-Like2 regulate
    endothelial ECM and angiogenesis through non-catalytic scaffolding mechanisms.
  findings:
  - statement: LOXL2 SRCR domains directly bind collagen IV and support endothelial collagen-IV deposition and angiogenesis independently of the catalytic domain.
    supporting_text: Neither enzyme activity nor catalytic domain were necessary for collagen IV deposition and angiogenesis, whereas the SRCR domains were effective for these processes.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct endothelial-cell and recombinant-domain evidence for non-catalytic ECM scaffolding. The cache is abstract-only; interactions with collagen IV and fibronectin do not establish one stable multicomponent complex.
- id: PMID:31911079
  title: LOXL2 promotes oncogenic progression in alveolar rhabdomyosarcoma independently
    of its catalytic activity.
  findings:
  - statement: LOXL2 promotes rhabdomyosarcoma motility and metastasis independently of catalytic activity and was reported to interact with vimentin.
    supporting_text: The intermediated filament protein vimentin was validated as a LOXL2-interactor.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Direct tumor-cell interaction/phenotype evidence, but highly context-specific and not a core physiological LOXL2 function or stable-complex assignment.
- id: PMID:20026874
  title: 'The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1.'
  findings:
  - statement: LOXL2 is induced as a direct HIF-1 target and contributes to hypoxia-driven E-cadherin repression and EMT in cell models.
    supporting_text: In addition to the previously demonstrated LOX, we characterize LOXL2 as a direct transcriptional target of HIF-1.
    reference_section_type: ABSTRACT
    full_text_unavailable: false
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Direct human-cell hypoxia pathway evidence; this is regulated expression and downstream EMT context, not a distinct oxygen-sensing molecular activity.
- id: PMID:20306300
  title: The human lysyl oxidase-like 2 protein functions as an amine oxidase toward collagen and elastin.
  findings:
  - statement: Recombinant human LOXL2 oxidizes multiple collagen types and elastin in vitro, and its N-terminal SRCR domains are dispensable for this catalytic activity.
    supporting_text: All of the purified recombinant LOXL2 proteins, with or without the SRCR domains in the N-terminus, showed significant amine oxidase activity toward several different types of collagen and elastin in in vitro amine oxidase assays.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct human-protein substrate evidence from recombinant E. coli-expressed constructs; in vitro biochemical scope is explicit.
- id: PMID:20439985
  title: Modulation of lysyl oxidase-like 2 enzymatic activity by an allosteric antibody inhibitor.
  findings:
  - statement: LOXL2 oxidizes diamine substrates and fibrillar type-I collagen and is inhibited allosterically by an antibody binding SRCR4.
    supporting_text: In this report, we assessed the steady-state enzymatic activity of lysyl oxidase-like 2 (LOXL2) against the substrates 1,5-diaminopentane (DAP), spermine, and fibrillar type I collagen.
    reference_section_type: ABSTRACT
    full_text_unavailable: false
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct recombinant-human LOXL2 enzymology and inhibitor mapping. Small-diamine activity is an assay capability; fibrillar collagen is the more biologically relevant substrate.
- id: PMID:20818376
  title: Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment.
  findings:
  - statement: LOXL2 inhibition reduces fibrotic and tumor-associated stromal remodeling in animal models.
    supporting_text: Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) was efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Functional inhibitor evidence across mouse disease models with human biopsy context; it supports matrix-remodeling importance but not substrate identity by itself.
- id: PMID:22483618
  title: Lysyl oxidase-like 2 deaminates lysine 4 in histone H3.
  is_invalid: true
  findings:
  - statement: This paper's H3K4-deamination claim was retracted and must not support LOXL2 annotation.
    supporting_text: 1. RETRACTED ARTICLE
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: DISPUTED
    review_notes: PubMed classifies this record as a Retracted Publication and explicitly links retraction notice PMID:27392148. Exclude its H3K4me3 oxidation and chromosome-catalysis claims from accepted evidence.
- id: PMID:27392148
  title: 'Retraction Notice to: Lysyl Oxidase-like 2 Deaminates Lysine 4 in Histone H3.'
  findings:
  - statement: This notice retracts PMID:22483618.
    supporting_text: 'Retraction of Mol Cell. 2012 May 11;46(3):369-76. doi: 10.1016/j.molcel.2012.03.002.'
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified retraction notice; retained to make the invalidity of the original H3K4 paper explicit and machine-auditable.
- id: file:human/LOXL2/LOXL2-uniprot.txt
  title: UniProtKB record for human LOXL2 (Q9Y4K0)
  findings:
  - statement: UniProt curates LOXL2 as a precursor with extracellular matrix, basement-membrane, nuclear, chromosome, and endoplasmic-reticulum localizations.
    supporting_text: >-
      CC   -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
      CC       matrix, basement membrane {ECO:0000269|PubMed:23319596}. Nucleus
      CC       {ECO:0000269|PubMed:22204712, ECO:0000269|PubMed:24414204}. Chromosome
      CC       {ECO:0000269|PubMed:27735137}. Endoplasmic reticulum
      CC       {ECO:0000269|PubMed:28332555}.
    reference_section_type: OTHER
    full_text_unavailable: false
  reference_review:
    relevance: HIGH
    correctness: DISPUTED
    review_notes: The sequence, precursor status, extracellular localization, catalytic reaction, and cofactors are authoritative. However, the chromosome/chromatin statements depend on disputed PMID:27735137, and the record still mentions retracted PMID:22483618 in its intracellular-location note; those nuclear catalytic claims must be separated from the reliable extracellular enzyme record.
- id: file:human/LOXL2/LOXL2-deep-research-falcon.md
  title: Falcon deep-research report for human LOXL2
  findings:
  - statement: The provider report prioritizes LOXL2 extracellular protein-lysine oxidation and collagen/elastin cross-link initiation as the most defensible core function.
    supporting_text: The most defensible functional annotation of human LOXL2 is **a secreted copper/LTQ-dependent protein-lysine oxidase that initiates collagen and elastin cross-linking in the extracellular matrix**.
    reference_section_type: CONCLUSIONS
    full_text_unavailable: false
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Useful secondary lead source inspected after the primary literature audit. Its core framing is concordant with cached primary papers, but provider-generated claims are not treated as independent verification and its newer translational leads were not added without local primary caches.

core_functions:
- description: >-
    Secreted LOXL2 uses copper and its lysine-tyrosylquinone cofactor to oxidatively
    deaminate peptidyl lysine residues in extracellular collagen and elastin
    precursors. The resulting allysines initiate spontaneous covalent cross-links
    that stabilize collagen fibrils and elastic fibers. Recombinant human LOXL2
    directly oxidizes fibrillar type-I collagen and multiple collagen preparations,
    binds and deaminates tropoelastin, and generates cross-linked tropoelastin
    peptides. Copper loading activates LTQ formation; zinc-bound precursor-state
    protein is inactive. Full-length LOXL2 is catalytically competent, so cleavage
    between SRCR2 and SRCR3 is not treated as the activation step characteristic of
    LOX/LOXL1 propeptide removal. Nuclear, chromatin, hypoxia, EMT, and tumor-cell
    phenotypes are excluded from this core node, as are the retracted/disputed
    H3K4me3 claims. No stable protein-complex membership is asserted.
  molecular_function:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  directly_involved_in:
  - id: GO:0018057
    label: peptidyl-lysine oxidation
  - id: GO:0030199
    label: collagen fibril organization
  - id: GO:0048251
    label: elastic fiber assembly
  locations:
  - id: GO:0031012
    label: extracellular matrix
  - id: GO:0005604
    label: basement membrane
  - id: GO:0071953
    label: elastic fiber
  supported_by:
  - reference_id: PMID:20306300
    supporting_text: >-
      All of the purified recombinant LOXL2 proteins, with or without the SRCR
      domains in the N-terminus, showed significant amine oxidase activity toward
      several different types of collagen and elastin in in vitro amine oxidase
      assays.
  - reference_id: PMID:20439985
    supporting_text: >-
      In this report, we assessed the steady-state enzymatic activity of lysyl
      oxidase-like 2 (LOXL2) against the substrates 1,5-diaminopentane (DAP),
      spermine, and fibrillar type I collagen.
  - reference_id: PMID:29581294
    supporting_text: >-
      Biochemical analysis confirms that copper loading robustly activates hLOXL2
      and supports LTQ formation.
  - reference_id: PMID:30676771
    supporting_text: >-
      We detected direct interaction between LOXL2 and tropoelastin (TE) and also
      LOXL2-mediated deamination of TE. Using proteomics, we identified several
      allysines together with cross-linked TE peptides.
- description: >-
    LOXL2 also acts as a non-catalytic extracellular-matrix scaffold through its
    N-terminal SRCR domains. These domains directly bind collagen IV, while LOXL2
    associates with collagen IV and fibronectin before their exocytic deposition,
    supporting endothelial basement-membrane organization independently of the
    catalytic domain. This is modeled separately from lysine oxidation because
    catalytic-dead and catalytic-domain-deleted proteins retain the relevant
    deposition activity. Sprouting angiogenesis is a downstream endothelial context,
    not a second molecular activity. The observed pairwise matrix interactions do not
    establish a single stable LOXL2-containing complex.
  molecular_function:
    id: GO:1990430
    label: extracellular matrix protein binding
  directly_involved_in:
  - id: GO:0071711
    label: basement membrane organization
  locations:
  - id: GO:0005604
    label: basement membrane
  supported_by:
  - reference_id: PMID:31759052
    supporting_text: >-
      LOXL2 interacts intracellularly and directly with collagen IV and fibronectin
      before incorporation into ECM fibrillar structures upon exocytosis, as
      demonstrated by TIRF time-lapse microscopy.
  - reference_id: PMID:31759052
    supporting_text: >-
      Neither enzyme activity nor catalytic domain were necessary for collagen IV
      deposition and angiogenesis, whereas the SRCR domains were effective for these
      processes.

knowledge_gaps:
- gap_statement: >-
    The endogenous human collagen and elastin lysine/hydroxylysine sites modified
    specifically by LOXL2, rather than another LOX-family enzyme, and their
    tissue-specific partitioning are unresolved.
  boundary: >-
    Recombinant human LOXL2 oxidizes several collagen preparations, fibrillar type-I
    collagen, and tropoelastin, but these assays do not define enzyme-specific sites
    or quantify LOXL2's share of cross-link formation in native human tissues.
  gap_kind:
  - BIOLOGY
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  significance: >-
    Site- and enzyme-specific maps are needed to distinguish LOXL2 physiology from
    paralog redundancy and to interpret selective inhibition.
  resolution: >-
    Quantify site-resolved allysines, hydroxyallysines, and mature cross-links in
    primary human matrix-producing cells or organoids after selective endogenous
    LOXL2 degradation, with LOX/LOXL1/LOXL3/LOXL4 activity measured and controlled.
  provenance:
  - reference_id: PMID:29581294
    supporting_text: >-
      although their specific functions and substrate preferences in vivo remain to
      be elucidated.
- gap_statement: >-
    The physiological purpose and tissue regulation of LOXL2 cleavage between SRCR2
    and SRCR3 remain unknown, including whether processing changes substrate choice,
    extracellular retention, or SRCR-dependent scaffolding without activating
    catalysis.
  boundary: >-
    Full-length recombinant LOXL2 is active, and structural work places SRCR1/2 away
    from the catalytic domain. Cleavage therefore differs from activating propeptide
    removal in LOX and LOXL1, but its endogenous consequences are not defined.
  gap_kind:
  - BIOLOGY
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  significance: >-
    Conflating processing with activation obscures which LOXL2 form performs
    catalysis versus matrix targeting and may misdirect form-selective interventions.
  resolution: >-
    Introduce endogenous cleavage-resistant and cleavage-mimetic alleles in human
    endothelial cells and fibroblasts, then compare secretion, matrix retention,
    substrate binding, site-resolved oxidation, and basement-membrane deposition.
  provenance:
  - reference_id: PMID:30676771
    supporting_text: >-
      Our data suggest that SRCR domains 1 and 2 are located away from the catalytic
      domain, supporting the notion that LOXL2 processing is not associated with
      enzyme activation, as recently proposed in López-Jiménez et al. (4).
- gap_statement: >-
    The molecular architecture, stoichiometry, and dynamics by which LOXL2 SRCR
    domains organize collagen IV and fibronectin deposition are not known.
  boundary: >-
    Direct binding and domain-rescue experiments establish a catalytic-independent
    matrix-scaffolding role, but they do not show whether LOXL2 simultaneously bridges
    substrates, acts sequentially during secretion, or forms a persistent complex.
  gap_kind:
  - BIOLOGY
  dark_aspect: MF_DARK
  status: OPEN
  significance: >-
    Defining this mechanism is necessary to distinguish transient substrate handling
    from stable complex membership and to separate SRCR-targeted from catalytic
    interventions.
  resolution: >-
    Use endogenous split-proximity labeling, single-molecule stoichiometry, pulse-chase
    secretion imaging, and purified-domain reconstitution with collagen IV and
    fibronectin, including catalytic-dead and SRCR-deletion controls.
  provenance:
  - reference_id: PMID:31759052
    supporting_text: >-
      LOXL2 interacts intracellularly and directly with collagen IV and fibronectin
      before incorporation into ECM fibrillar structures upon exocytosis, as
      demonstrated by TIRF time-lapse microscopy.
- gap_statement: >-
    Whether endogenous LOXL2 has a reproducible normal intracellular catalytic
    substrate and how any intracellular pool bypasses or exits the secretory pathway
    remain unresolved.
  boundary: >-
    Tumor immunohistochemistry and overexpression experiments detect nuclear,
    cytoplasmic, and endoplasmic-reticulum pools, and methylated TAF10 was reported as
    a substrate. The H3K4me3 oxidation evidence is retracted or disputed and cannot
    establish normal chromatin catalysis.
  gap_kind:
  - BIOLOGY
  - CURATION
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  significance: >-
    Resolving this boundary would prevent extracellular catalytic function from being
    conflated with tumor-specific localization or invalid histone chemistry.
  resolution: >-
    Tag endogenous LOXL2 in normal and matched tumor-derived human cells, quantify
    secretory and intracellular forms, and test candidate intracellular substrates by
    activity-dependent proteomics and catalytic-dead rescue without relying on H3K4me3
    as a positive control.
  provenance:
  - reference_id: PMID:22204712
    supporting_text: >-
      The protein manifested decreased nuclear expression and increased cytoplasmic
      expression.
  - reference_id: PMID:22483618
    supporting_text: 1. RETRACTED ARTICLE

proposed_new_terms: []
suggested_questions:
- question: >-
    Which lysine and hydroxylysine sites in native human collagen and elastin are
    modified specifically by LOXL2 rather than another LOX-family enzyme?
- question: >-
    What controls endogenous SRCR1/2 cleavage, and does it alter LOXL2 substrate
    choice, matrix retention, or scaffolding without changing catalytic activation?
- question: >-
    Do LOXL2 SRCR domains bridge collagen IV and fibronectin simultaneously, or do
    they mediate sequential, transient interactions during basement-membrane
    secretion and assembly?
- question: >-
    Is there a normal endogenous intracellular LOXL2 catalytic substrate independent
    of the retracted/disputed H3K4me3 claim, and how is that LOXL2 pool generated?
suggested_experiments:
- hypothesis: >-
    LOXL2 oxidizes a defined subset of collagen and elastin sites in human matrix that
    is not redundantly modified by other LOX-family enzymes.
  description: >-
    Engineer an acute endogenous LOXL2 degron in primary human fibroblasts,
    endothelial cells, and matrix-producing organoids. Quantify site-resolved
    allysines, hydroxyallysines, and mature cross-links by targeted mass spectrometry,
    with wild-type and catalytic-dead rescue and parallel measurement or perturbation
    of LOX-family paralogs.
  experiment_type: endogenous protein degradation and matrix cross-link proteomics
- hypothesis: >-
    SRCR1/2 cleavage changes LOXL2 substrate presentation and extracellular retention
    but is not required for catalytic activation.
  description: >-
    Create endogenous cleavage-resistant and cleavage-mimetic LOXL2 alleles in human
    endothelial cells and fibroblasts. Compare secretion kinetics, full-length and
    processed forms, copper/LTQ-dependent activity, collagen/tropoelastin oxidation,
    collagen-IV/fibronectin binding, and matrix deposition.
  experiment_type: endogenous processing and substrate-targeting analysis
- hypothesis: >-
    LOXL2 SRCR domains transiently coordinate collagen IV and fibronectin during
    exocytosis rather than forming a stable extracellular complex.
  description: >-
    Combine endogenous pulse-chase imaging, split-proximity labeling, cross-linking
    mass spectrometry, and single-molecule stoichiometry with purified SRCR-domain
    reconstitution. Compare wild-type, SRCR-deleted, and catalytic-dead LOXL2 while
    separately measuring deposition and angiogenic phenotypes.
  experiment_type: matrix-scaffold interaction dynamics
- hypothesis: >-
    Reported nuclear and chromatin-associated LOXL2 catalysis is context dependent and
    absent from normal human cells at endogenous abundance.
  description: >-
    Endogenously tag LOXL2 on both sides of the signal peptide/processing boundaries
    in normal and matched tumor-derived cells, quantify intracellular forms by
    compartment-resolved proteomics, and test TAF10 and unbiased candidate substrates
    with wild-type versus catalytic-dead rescue. Treat H3K4me3 oxidation as a disputed
    claim requiring independent replication, not as an assay-positive control.
  experiment_type: endogenous localization and intracellular-substrate validation

LOXL2

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Knowledge Gaps

Deep Research

Falcon

Human LOXL2 (UniProt Q9Y4K0): Functional-Annotation Research Report

Executive summary

1. Identity, nomenclature and domain verification

2. Primary biochemical function

2.1 Catalyzed reaction

2.2 Cofactors and active site

2.3 Substrate specificity

3. Biosynthesis, processing and site of action

4. Biological pathways and processes

4.1 ECM assembly and mechanobiology

4.2 Fibrosis

4.3 Cancer and metastasis

5. Recent developments, emphasizing 2023–2024

5.1 Re-evaluation of anti-LOXL2 therapy in pulmonary fibrosis

5.2 Other 2023–2024 directions

6. Applications and real-world implementation

6.1 Drug development

6.2 Biomarkers

6.3 Biomaterials and tissue engineering

7. Evidence assessment and annotation recommendations

High-confidence annotation

Moderate-confidence/context-dependent annotation

Important unresolved questions

Conclusion

Artifacts

Citations

📚 Additional Documentation

Notes

LOXL2 literature and provenance notes

Provenance and evidence boundary

Core catalytic activity and substrates

Cofactors, precursor state, processing, and domain boundary

Localization audit

Retraction and disputed H3K4me3 oxidation

Interaction and complex boundaries

Human versus ortholog evidence

📄 View Raw YAML