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.
| 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. |
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Download this section (compressed HTML)Q: Which lysine and hydroxylysine sites in native human collagen and elastin are modified specifically by LOXL2 rather than another LOX-family enzyme?
Q: What controls endogenous SRCR1/2 cleavage, and does it alter LOXL2 substrate choice, matrix retention, or scaffolding without changing catalytic activation?
Q: Do LOXL2 SRCR domains bridge collagen IV and fibronectin simultaneously, or do they mediate sequential, transient interactions during basement-membrane secretion and assembly?
Q: Is there a normal endogenous intracellular LOXL2 catalytic substrate independent of the retracted/disputed H3K4me3 claim, and how is that LOXL2 pool generated?
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
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):
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):
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):
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):
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