Galectin-3 (Mac-2, CBP35, IgE-binding protein) is the only chimera-type member of the galectin family of beta-galactoside-binding lectins. It comprises a single C-terminal carbohydrate-recognition domain (CRD), which binds beta-galactosides such as lactose and N-acetyllactosamine (LacNAc), joined to an intrinsically disordered, proline/glycine-rich N-terminal tail. Although the protein is monomeric, the N-terminal tail mediates concentration-dependent self-association and liquid-liquid phase separation, giving galectin-3 functional multivalency so that it cross-links glycoconjugates into ordered lattices and agglutinates glycosylated cells and particles. Galectin-3 acts both intracellularly and extracellularly. Inside the cell it is found in the cytoplasm and nucleus (where it has been implicated as a pre-mRNA splicing factor and RNA-binding protein) and, together with TRIM16, it senses ruptured endo/lysosomal membranes by recognizing newly exposed luminal glycans and helps mobilize the autophagy machinery. It reaches the cell surface and extracellular space through a non-classical, TMED10-facilitated secretory route. Extracellularly it modulates cell adhesion, cross-links cell-surface glycoproteins (including branched N-glycans generated by GnT-V), acts as a chemoattractant for monocytes and macrophages, regulates T-cell, NK-cell and innate-lymphoid-cell activation and apoptosis, and contributes to inflammation, fibrosis and tumor biology. Its high-resolution CRD structure and beta-galactoside specificity make it a prominent drug target.
Definition: The process of cross-linking multivalent glycoconjugates (glycoproteins and glycolipids) on a cell surface or in the extracellular matrix into an ordered, higher-order lattice by a galectin, regulating the residence time, clustering, and signaling of the cross-linked glycoproteins.
Justification: Galectin-3 (and other galectins) form 'galectin-glycan lattices' that retain receptors at the cell surface and modulate their endocytosis and signaling. Current GO terms (carbohydrate binding, molecular condensate scaffold activity, negative regulation of endocytosis, positive regulation of protein localization to plasma membrane) only capture facets of this distinctive, well-described mechanism, with no single term for the lattice assembly process itself.
Supporting Evidence:
Definition: Binding to luminal glycans that become exposed on the cytosolic face of ruptured endosomal or lysosomal membranes, marking the damaged compartment for autophagic clearance.
Justification: Galectin-3 (with TRIM16) senses ruptured endo/lysosomal membranes by recognizing newly exposed luminal glycans and mobilizes the autophagy machinery (lysophagy). This glycan-damage-sensing role is mechanistically distinct from generic carbohydrate binding and is increasingly central to galectin-3 biology, but is not represented by a dedicated MF term.
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Galectin-3 is secreted and functions extracellularly, cross-linking ECM glycoproteins (e.g. laminin) into lattices. Extracellular matrix as a site of action is consistent with the lectin/lattice function, though it is a downstream/extracellular role rather than the gene's primary intracellular biology. Reason: Well-supported extracellular site of action via phylogenetic inference, but a pleiotropic extracellular localization rather than a core defining feature. |
| GO:0048030 disaccharide binding | IBA GO_REF:0000033 | ACCEPT | Summary: Galectin-3 binds beta-galactoside disaccharides such as lactose and LacNAc through its CRD. This is a more specific child of carbohydrate binding and accurately captures the core lectin activity. Reason: Disaccharide (beta-galactoside) binding is phylogenetically conserved and central to galectin-3 function; well supported experimentally. Supporting Evidence: PMID:11434930 Recognized by its specificity for galactose, a detailed characterization of its sugar binding ability has been investigated by isothermal titration calorimetry. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Galectin-3 is present and active in the nucleus (implicated as a pre-mRNA splicing factor and RNA-binding protein). Nuclear localization is well established experimentally and by phylogenetic inference. Reason: Nuclear localization is a conserved, experimentally corroborated feature of galectin-3. Supporting Evidence: PMID:12070075 galectin-3 was identified as a component of a nuclear and cytoplasmic complex, the survival of motor neuron complex, through its interaction with Gemin4. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Galectin-3 is predominantly cytoplasmic in many cell types, with roles in endomembrane-damage sensing and anti-apoptotic signaling. Cytoplasmic localization is well supported. Reason: Cytoplasmic localization is conserved and experimentally corroborated. Supporting Evidence: PMID:12070075 Shuttling of galectin-3 between the nucleus and cytoplasm. |
| GO:0050918 positive chemotaxis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Galectin-3 acts as a chemoattractant for monocytes/macrophages, a downstream immune-modulatory consequence of its extracellular lectin activity. Real but pleiotropic. Reason: Phylogenetically inferred chemoattractant role corroborated experimentally (PMID:10925302), but a downstream process rather than the core molecular function. Supporting Evidence: PMID:10925302 Human galectin-3 is a novel chemoattractant for monocytes and macrophages. |
| GO:0001772 immunological synapse | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Galectin-3 localizes to the immunological synapse where it negatively regulates TCR signaling. A specialized site of action, downstream of the lattice function. Reason: Specialized cell-type-specific site of action; supported but not core to the gene's general function. Supporting Evidence: PMID:19706535 Galectin-3 was recruited to the cytoplasmic side of the immunological synapse (IS) in activated T cells. |
| GO:0002548 monocyte chemotaxis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Monocyte chemotaxis is a documented downstream immune activity (PMID:10925302). Pleiotropic, not core. Reason: Real but downstream immune process; redundant with the experimental IDA annotation. Supporting Evidence: PMID:10925302 galectin-3 induced human monocyte migration in vitro in a dose-dependent manner, and it was chemotactic at high concentrations (1.0 microM) but chemokinetic at low concentrations (10-100 nM). |
| GO:0019863 IgE binding | IBA GO_REF:0000033 | ACCEPT | Summary: Galectin-3 was originally identified and named as the "IgE-binding protein"; IgE binding is the historical defining activity and a specific glycan-mediated manifestation of the core carbohydrate-binding function. Accepted as core, consistent with the IDA IgE-binding annotation and the accepted disaccharide-binding (GO:0048030) core function. Reason: Historical defining activity ("IgE-binding protein"); a specific manifestation of the core CRD glycan-binding function, kept consistent with the IDA annotation. Supporting Evidence: PMID:8347574 IgE-binding protein (epsilon BP) was originally identified in rat basophilic leukemia (RBL) cells by virtue of its affinity for IgE. |
| GO:0030593 neutrophil chemotaxis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Galectin-3 promotes neutrophil chemotaxis/adhesion in inflammation. Downstream immune role. Reason: Pleiotropic downstream immune process. Supporting Evidence: PMID:11823514 Role of galectin-3 as an adhesion molecule for neutrophil extravasation during streptococcal pneumonia. |
| GO:0043236 laminin binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Galectin-3 binds laminin (a heavily glycosylated ECM glycoprotein) via its CRD; historically named laminin-binding protein. A specific glycan-dependent binding event. Reason: A specific glycoprotein-binding facet of the core lectin function. Supporting Evidence: PMID:2332426 The major non-integrin laminin binding protein of macrophages is identical to carbohydrate binding protein 35 (Mac-2). |
| GO:0045806 negative regulation of endocytosis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Galectin-3 lattices retain glycoproteins at the cell surface and reduce their endocytosis (e.g. at the immunological synapse, PMID:19706535). Downstream consequence of lattice formation. Reason: Downstream regulatory effect of surface-lattice formation; not a core function. |
| GO:0048245 eosinophil chemotaxis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Galectin-3 promotes eosinophil chemotaxis in allergic inflammation. Downstream immune role. Reason: Pleiotropic downstream immune process. Supporting Evidence: PMID:23576987 allergen-challenged mice deficient in Gal-3 (Gal-3(-/-)) exhibit decreased airway recruitment of eosinophils (Eos) |
| GO:0048246 macrophage chemotaxis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Galectin-3 chemoattracts macrophages (PMID:10925302). Downstream immune role. Reason: Pleiotropic downstream immune process; redundant with experimental IDA. Supporting Evidence: PMID:10925302 Human galectin-3 is a novel chemoattractant for monocytes and macrophages. |
| GO:0090280 positive regulation of calcium ion import | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Galectin-3 triggers a Ca2+ influx in monocytes at high concentrations (PMID:10925302), a signaling consequence of receptor cross-linking. Downstream effect. Reason: Downstream signaling consequence of lattice/receptor cross-linking; not core. Supporting Evidence: PMID:10925302 Galectin-3 caused a Ca2+ influx in monocytes at high, but not low, concentrations, and both lactose and PTX inhibited this response. |
| GO:2001237 negative regulation of extrinsic apoptotic signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Galectin-3 has anti-apoptotic activity (Bcl-2-like, NWGR motif; PMID:8692888, PMID:22761016). A pleiotropic, context-dependent process. Reason: Real but pleiotropic apoptosis-regulatory role; not the core molecular function. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Galectin-3 is secreted via a non-classical route and is abundant extracellularly. Localization is correct but downstream of intracellular biology. Reason: Correct secreted localization (SubCell mapping), pleiotropic extracellular site. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization, consistent with the experimental IDA and IBA annotations. Reason: Correct nuclear localization corroborated by multiple experimental annotations. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic localization, consistent with experimental IDA/IBA annotations. Reason: Correct cytoplasmic localization corroborated by multiple experimental annotations. |
| GO:0007165 signal transduction | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: This is an extremely general term auto-inferred from the receptor-ligand-activity annotation. It conveys little about galectin-3's actual function and is far less informative than the specific immune-modulatory and lectin activities. Reason: Uninformative high-level BP term derived by inter-ontology inference; better captured by specific processes. |
| GO:0030246 carbohydrate binding | IEA GO_REF:0000120 | ACCEPT | Summary: Carbohydrate binding is the core molecular function of galectin-3. The IEA annotation is fully consistent with extensive experimental and structural data. Reason: Correct core molecular function; redundant with experimental EXP/TAS annotations. |
| GO:0042129 regulation of T cell proliferation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA-predicted; galectin-3 does modulate T-cell growth (PMID:8692888). Real but pleiotropic and also captured by the experimental IMP annotation. Reason: Pleiotropic immune process; redundant with experimental annotation. |
| GO:0046636 negative regulation of alpha-beta T cell activation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA-predicted; consistent with negative regulation of TCR signaling at the synapse (PMID:19706535). Pleiotropic immune process. Reason: Pleiotropic downstream immune regulation; supported but not core. |
| GO:0048018 receptor ligand activity | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA-predicted generic receptor ligand activity. For galectin-3 the experimentally supported activity is specifically an inhibitory ligand of NKp30 (GO:0141069, IDA); generic receptor ligand activity is less precise and partly conflicts with the inhibitory role. Reason: Less precise than the experimentally supported receptor ligand inhibitor activity; generic prediction. |
| GO:0070232 regulation of T cell apoptotic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA-predicted; consistent with the experimental IDA annotation (PMID:8692888). Pleiotropic immune process. Reason: Pleiotropic immune process; redundant with experimental annotation. |
| GO:0071677 positive regulation of mononuclear cell migration | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA-predicted; consistent with the experimental chemotaxis annotation (PMID:10925302). Downstream immune process. Reason: Pleiotropic downstream immune process; redundant with experimental annotation. |
| GO:0005515 protein binding | IPI PMID:19706535 Galectin-3 negatively regulates TCR-mediated CD4+ T-cell act... | MARK AS OVER ANNOTATED | Summary: A generic protein-binding (IPI) record recording a physical interaction from PMID:19706535. Generic protein binding is uninformative per curation guidelines and conveys no specific functional information about galectin-3. The informative molecular function is its carbohydrate/galactoside binding, with most partner contacts being glycan-mediated; this generic protein-binding term does not capture an annotated function and the specific physical-interaction details are better recorded elsewhere. Reason: Generic protein binding conveys no specific functional information; the informative MF is carbohydrate binding. |
| GO:0005515 protein binding | IPI PMID:20812334 Matrilysin-1 (MMP7) cleaves galectin-3 and inhibits wound he... | MARK AS OVER ANNOTATED | Summary: Interaction with MMP7 (which cleaves galectin-3). Generic protein binding is uninformative. Reason: Generic protein binding; not an informative molecular function. |
| GO:0005515 protein binding | IPI PMID:21712812 A novel strategy for evasion of NK cell immunity by tumours ... | MARK AS OVER ANNOTATED | Summary: Interaction with MICA in the context of NK-cell evasion. Generic protein binding is uninformative. Reason: Generic protein binding; not an informative molecular function. |
| GO:0005515 protein binding | IPI PMID:2402511 Molecular cloning of a human macrophage lectin specific for ... | MARK AS OVER ANNOTATED | Summary: From the original cloning paper (here the AHSG/fetuin-A interaction). Generic protein binding is uninformative; the paper's value is establishing the galactose-specific lectin identity. Reason: Generic protein binding; not an informative molecular function. |
| GO:0005515 protein binding | IPI PMID:24945728 Modulation of CD6 function through interaction with Galectin... | MARK AS OVER ANNOTATED | Summary: Interaction with CD6 (PMID:24945728). Generic protein binding is uninformative. Reason: Generic protein binding; not an informative molecular function. |
| GO:0005515 protein binding | IPI PMID:25315772 Tumor-released Galectin-3, a soluble inhibitory ligand of hu... | MARK AS OVER ANNOTATED | Summary: Interaction with NKp30/NCR3 as a soluble inhibitory ligand. The informative MF is receptor ligand inhibitor activity (GO:0141069), not generic protein binding. Reason: Generic protein binding; better captured by receptor ligand inhibitor activity. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: High-throughput interactome screen. Generic protein binding is uninformative. Reason: Generic protein binding from a high-throughput screen; not informative. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome screen. Generic protein binding is uninformative. Reason: Generic protein binding from a high-throughput screen; not informative. |
| GO:0005515 protein binding | IPI PMID:29427412 Galectin-3 Interacts with the CHI3L1 Axis and Contributes to... | MARK AS OVER ANNOTATED | Summary: Interaction with the CHI3L1/IL13RA2 axis. Generic protein binding is uninformative. Reason: Generic protein binding; not an informative molecular function. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: Interaction-disruption-by-variant screen. Generic protein binding is uninformative. Reason: Generic protein binding from a high-throughput screen; not informative. |
| GO:0005515 protein binding | IPI PMID:31540324 Endoglin Protein Interactome Profiling Identifies TRIM21 and... | MARK AS OVER ANNOTATED | Summary: Interaction with endoglin (ENG). Generic protein binding is uninformative. Reason: Generic protein binding; not an informative molecular function. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: High-throughput binary interactome screen. Generic protein binding is uninformative. Reason: Generic protein binding from a high-throughput screen; not informative. |
| GO:0005515 protein binding | IPI PMID:32915505 Structural Characterization of N-Linked Glycans in the Recep... | MARK AS OVER ANNOTATED | Summary: Interaction with SARS-CoV-2 spike glycoprotein, a glycan-mediated lectin contact. Generic protein binding is uninformative; the activity is carbohydrate (glycan) binding. Reason: Generic protein binding; the underlying activity is glycan recognition. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome screen. Generic protein binding is uninformative. Reason: Generic protein binding from a high-throughput screen; not informative. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: High-throughput cell-map interactome study (ALCAM interaction). Generic protein binding is uninformative. Reason: Generic protein binding from a high-throughput screen; not informative. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence places galectin-3 in the nucleoplasm, consistent with its established nuclear localization. Reason: Specific, experimentally supported nuclear sub-localization. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence places galectin-3 in the cytosol, consistent with its established cytoplasmic localization. Reason: Specific, experimentally supported cytosolic localization. |
| GO:0005576 extracellular region | EXP PMID:32272059 A Translocation Pathway for Vesicle-Mediated Unconventional ... | KEEP AS NON CORE | Summary: Galectin-3 is secreted via the TMED10-facilitated non-classical pathway into the extracellular region. Experimentally supported but downstream localization. Reason: Correct secreted localization; pleiotropic extracellular site of action. |
| GO:0005737 cytoplasm | EXP PMID:32272059 A Translocation Pathway for Vesicle-Mediated Unconventional ... | ACCEPT | Summary: Cytoplasmic pool of galectin-3 is the substrate for non-classical secretion via TMED10 (PMID:32272059). Consistent with established cytoplasmic localization. Reason: Experimentally supported cytoplasmic localization. |
| GO:0004864 protein phosphatase inhibitor activity | IDA PMID:24846175 Ξ²1,6 GlcNAc branches-modified PTPRT attenuates its activity ... | MARK AS OVER ANNOTATED | Summary: In PMID:24846175 galectin-3 binds branched N-glycans on the phosphatase PTPRT and promotes its dimerization, which indirectly reduces PTPRT catalytic activity. This is a glycan-lattice effect on receptor clustering, not a direct allosteric/competitive phosphatase-inhibitor molecular function. Reason: The effect on phosphatase activity is indirect (via glycan-mediated dimerization), not a direct enzyme-inhibitor molecular function. Supporting Evidence: PMID:24846175 GnT-V overexpression enhances galectin-3's cell-surface retention and promotes PTPRT's dimerization mediated by galectin-3. Increased dimerization subsequently reduces PTPRT's catalytic activity |
| GO:0005576 extracellular region | IDA PMID:26582946 Group 2 Innate Lymphoid Cells Express Functional NKp30 Recep... | KEEP AS NON CORE | Summary: Secreted galectin-3 acts extracellularly as an inhibitory ligand of NKp30 on ILC2 (PMID:26582946). Experimentally supported extracellular site of action. Reason: Correct extracellular site of action; pleiotropic immune context. |
| GO:0051134 negative regulation of NK T cell activation | IDA PMID:26582946 Group 2 Innate Lymphoid Cells Express Functional NKp30 Recep... | KEEP AS NON CORE | Summary: Galectin-3 blocks NKp30-B7-H6 activation (PMID:26582946), inhibiting NK/ILC2 activation. Downstream immune-modulatory process. Reason: Real but pleiotropic downstream immune process. Supporting Evidence: PMID:26582946 This interaction can be blocked by NKp30 blocking Ab and an inhibitory ligand, galectin-3. |
| GO:0141069 receptor ligand inhibitor activity | IDA PMID:26582946 Group 2 Innate Lymphoid Cells Express Functional NKp30 Recep... | ACCEPT | Summary: Galectin-3 acts as a soluble inhibitory ligand of the NKp30 (NCR3) receptor, blocking its activation by B7-H6 (PMID:26582946, PMID:25315772). This is a specific, experimentally supported molecular function. Reason: Specific, experimentally supported molecular function (inhibitory NKp30 ligand). Supporting Evidence: PMID:26582946 This interaction can be blocked by NKp30 blocking Ab and an inhibitory ligand, galectin-3. |
| GO:0030246 carbohydrate binding | EXP PMID:28973299 Novel polysaccharide binding to the N-terminal tail of galec... | ACCEPT | Summary: NMR mapping (PMID:28973299) demonstrates carbohydrate binding at two CRD sites and a novel N-terminal-tail site. This is the core molecular function of galectin-3. Reason: Direct experimental evidence for the core carbohydrate-binding molecular function. Supporting Evidence: PMID:28973299 epitopes for binding to three sites on 15N-labeled Gal-3, two within its carbohydrate recognition domain (CRD) and one at a novel site within the NT |
| GO:0140693 molecular condensate scaffold activity | IDA PMID:28893908 The intrinsically disordered N-terminal domain of galectin-3... | ACCEPT | Summary: The disordered N-terminal domain drives multisite self-association and liquid-liquid phase separation (PMID:28893908), the molecular basis of galectin-3's multivalency and lattice/condensate formation. A core, distinctive molecular function. Reason: Experimentally supported; underpins galectin-3's distinctive lattice/condensate behavior. Supporting Evidence: PMID:28893908 galectin-3 can also undergo liquid-liquid phase separation |
| GO:0140693 molecular condensate scaffold activity | IDA PMID:32144274 Liquid-liquid phase separation and extracellular multivalent... | ACCEPT | Summary: Galectin-3's N-terminal domain undergoes LLPS and bridges/aggregates glycosylated molecules (PMID:32144274), explaining its extracellular agglutination function. Supports the condensate-scaffold/lattice activity. Reason: Experimentally supported condensate-scaffold/lattice activity. Supporting Evidence: PMID:32144274 its N-terminal domain (NTD) undergoes LLPS driven by interactions between its aromatic residues |
| GO:0031334 positive regulation of protein-containing complex assembly | IDA PMID:24846175 Ξ²1,6 GlcNAc branches-modified PTPRT attenuates its activity ... | KEEP AS NON CORE | Summary: Galectin-3 promotes glycan-dependent dimerization of PTPRT (PMID:24846175), an instance of promoting receptor complex assembly via lattice formation. A downstream consequence of the lattice function. Reason: Downstream consequence of glycan-lattice formation; not a core function in itself. Supporting Evidence: PMID:24846175 promotes PTPRT's dimerization mediated by galectin-3 |
| GO:0031012 extracellular matrix | HDA PMID:28327460 Comprehensive proteomic characterization of stem cell-derive... | KEEP AS NON CORE | Summary: High-throughput proteomic detection of galectin-3 in stem-cell-derived ECM. Localization-by-detection, consistent with secretion. Reason: Proteomics colocalization; consistent with secreted galectin-3 but not a functional or core annotation. |
| GO:0019903 protein phosphatase binding | IPI PMID:24846175 Ξ²1,6 GlcNAc branches-modified PTPRT attenuates its activity ... | KEEP AS NON CORE | Summary: Galectin-3 binds the phosphatase PTPRT (PMID:24846175). This is a glycan-mediated contact; more informatively captured by carbohydrate binding, but a specific documented partner. Reason: Specific documented interaction; glycan-mediated and downstream of lectin activity. |
| GO:1903078 positive regulation of protein localization to plasma membrane | IDA PMID:24846175 Ξ²1,6 GlcNAc branches-modified PTPRT attenuates its activity ... | KEEP AS NON CORE | Summary: Galectin-3 lattices retain glycoproteins (e.g. PTPRT) at the cell surface, prolonging plasma-membrane residence (PMID:24846175). Downstream consequence of lattice formation. Reason: Downstream consequence of surface-lattice formation; not a core function. Supporting Evidence: PMID:24846175 addition of Ξ²1,6 GlcNAc branches on PTPRT prolongs PTPRT's cell-surface retention time |
| GO:0009986 cell surface | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Galectin-3 associates with the cell surface after non-classical secretion, where it forms glycan lattices. Cell-surface localization is consistent with its extracellular lattice function. Reason: Correct extracellular/cell-surface site of action; pleiotropic. |
| GO:0031012 extracellular matrix | HDA PMID:28675934 Characterization of the Extracellular Matrix of Normal and D... | KEEP AS NON CORE | Summary: Proteomic detection of galectin-3 in tissue ECM. Localization-by-detection. Reason: Proteomics localization consistent with secretion; not core. |
| GO:0031012 extracellular matrix | HDA PMID:25037231 Extracellular matrix signatures of human primary metastatic ... | KEEP AS NON CORE | Summary: Proteomic detection of galectin-3 in colon cancer ECM. Localization-by-detection. Reason: Proteomics localization consistent with secretion; not core. |
| GO:0005576 extracellular region | HDA PMID:27068509 Extracellular matrix remodelling in response to venous hyper... | KEEP AS NON CORE | Summary: Proteomic detection of galectin-3 in varicose-vein ECM. Localization-by-detection. Reason: Proteomics localization consistent with secretion; not core. |
| GO:0031012 extracellular matrix | HDA PMID:27559042 Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin... | KEEP AS NON CORE | Summary: Glycoproteomic detection of galectin-3 in atrial-fibrillation tissue ECM. Localization-by-detection. Reason: Proteomics localization consistent with secretion; not core. |
| GO:0031012 extracellular matrix | HDA PMID:20551380 Proteomics characterization of extracellular space component... | KEEP AS NON CORE | Summary: Proteomic characterization of aortic extracellular space detected galectin-3. Localization-by-detection. Reason: Proteomics localization consistent with secretion; not core. |
| GO:0030667 secretory granule membrane | TAS Reactome:R-HSA-6798743 | KEEP AS NON CORE | Summary: Reactome places galectin-3 at the secretory (specific) granule membrane in the context of neutrophil degranulation. Consistent with packaging for secretion in neutrophils; specialized cell-type context. Reason: Cell-type-specific granule localization from pathway annotation; not core. |
| GO:0101003 ficolin-1-rich granule membrane | TAS Reactome:R-HSA-6800426 | KEEP AS NON CORE | Summary: Reactome places galectin-3 at the ficolin-1-rich granule membrane in neutrophil degranulation. Specialized cell-type context. Reason: Cell-type-specific granule localization from pathway annotation; not core. |
| GO:2001200 positive regulation of dendritic cell differentiation | IDA NOT PMID:16116184 Galectin-9 induces maturation of human monocyte-derived dend... | ACCEPT | Summary: This is a NOT annotation. PMID:16116184 shows galectin-9 (not galectin-3) induces dendritic-cell maturation; galectin-3 lacks this activity. The negated annotation correctly records the absence of this function for galectin-3. Reason: Correctly recorded negative (NOT) annotation distinguishing galectin-3 from galectin-9. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Proteomic detection of galectin-3 in urinary/prostatic-secretion exosomes. Localization-by-detection, consistent with secretion. Reason: Proteomics localization; consistent with secretion but not core or functional. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: NK-cell membrane proteome detection. Very general localization-by-detection term. Reason: Extremely general localization from a proteomics screen; uninformative. |
| GO:0005634 nucleus | IDA PMID:7682704 Decreased expression of Mac-2 (carbohydrate binding protein ... | ACCEPT | Summary: Direct experimental evidence of nuclear localization of galectin-3 (Mac-2/CBP35) in colonic epithelium (PMID:7682704). Core localization. Reason: Direct experimental evidence for nuclear localization. |
| GO:0050860 negative regulation of T cell receptor signaling pathway | ISS PMID:19706535 Galectin-3 negatively regulates TCR-mediated CD4+ T-cell act... | KEEP AS NON CORE | Summary: Transferred from mouse ortholog (P16110); galectin-3 negatively regulates TCR signaling at the synapse. Pleiotropic downstream immune regulation. Reason: Pleiotropic downstream immune-regulatory process (ortholog transfer). |
| GO:2000521 negative regulation of immunological synapse formation | ISS PMID:19706535 Galectin-3 negatively regulates TCR-mediated CD4+ T-cell act... | KEEP AS NON CORE | Summary: Transferred from mouse ortholog; galectin-3 limits TCR clustering at the synapse. Pleiotropic downstream immune process. Reason: Pleiotropic downstream immune process (ortholog transfer). |
| GO:2001189 negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell | ISS PMID:19706535 Galectin-3 negatively regulates TCR-mediated CD4+ T-cell act... | KEEP AS NON CORE | Summary: Transferred from mouse ortholog; a highly specific child term of the negative TCR regulation role. Pleiotropic downstream immune process. Reason: Pleiotropic, highly specific downstream immune process (ortholog transfer). |
| GO:0042129 regulation of T cell proliferation | IMP PMID:8692888 Expression of galectin-3 modulates T-cell growth and apoptos... | KEEP AS NON CORE | Summary: Galectin-3 overexpression increases T-cell growth rates (PMID:8692888), an experimentally supported but pleiotropic immune process. Reason: Pleiotropic immune process supported by experimental evidence. Supporting Evidence: PMID:8692888 Transfectants expressing galectin-3 displayed higher growth rates than control transfectants |
| GO:0005737 cytoplasm | IDA PMID:9447709 Detection and distribution of the carbohydrate binding prote... | ACCEPT | Summary: Direct detection of cytoplasmic galectin-3 in notochord/intervertebral disc tissue (PMID:9447709). Core localization. Reason: Direct experimental evidence for cytoplasmic localization. |
| GO:0001772 immunological synapse | IDA PMID:19706535 Galectin-3 negatively regulates TCR-mediated CD4+ T-cell act... | KEEP AS NON CORE | Summary: Galectin-3 localizes to the immunological synapse where it down-regulates TCR signaling (PMID:19706535). Specialized site of action. Reason: Specialized cell-type-specific site of action; not core. |
| GO:0002548 monocyte chemotaxis | IDA PMID:10925302 Human galectin-3 is a novel chemoattractant for monocytes an... | KEEP AS NON CORE | Summary: Galectin-3 chemoattracts monocytes (PMID:10925302), blocked by lactose and a CRD fragment, via a PTX-sensitive pathway. Downstream immune process. Reason: Real but pleiotropic downstream immune process. Supporting Evidence: PMID:10925302 galectin-3 is a novel chemoattractant for monocytes and macrophages |
| GO:0005634 nucleus | IDA PMID:22761016 Downregulation of galectin-3 by EGF mediates the apoptosis o... | ACCEPT | Summary: Galectin-3 detected in the nucleus (PMID:22761016). Consistent with established nuclear localization. Reason: Experimentally supported nuclear localization. |
| GO:0005737 cytoplasm | IDA PMID:22761016 Downregulation of galectin-3 by EGF mediates the apoptosis o... | ACCEPT | Summary: Cytoplasmic galectin-3 mediates anti-apoptotic activity; EGF suppresses cytoplasmic galectin-3 to permit apoptosis (PMID:22761016). Consistent with cytoplasmic localization. Reason: Experimentally supported cytoplasmic localization. Supporting Evidence: PMID:22761016 High concentrations of EGF suppressed cytoplasmic expression of galectin-3 |
| GO:0019863 IgE binding | IDA PMID:2261464 Human IgE-binding protein: a soluble lectin exhibiting a hig... | ACCEPT | Summary: Galectin-3 was originally identified and named as the "IgE-binding protein," so IgE binding is the historical defining activity of this gene product. It is a direct manifestation of the CRD's beta-galactoside / glycan-binding activity (the core molecular function), recognizing IgE glycoforms via its lectin domain. Because it is a specific, directly demonstrated (IDA) instance of the core carbohydrate-binding activity, it is accepted as core, consistent with the IBA disaccharide-binding (GO:0048030) annotation being accepted as core. Reason: Historical defining activity of galectin-3 ("IgE-binding protein"); a specific, experimentally demonstrated manifestation of the core CRD glycan-binding function, consistent with treating the underlying beta-galactoside/glycan recognition as core. |
| GO:0030593 neutrophil chemotaxis | IDA PMID:10925302 Human galectin-3 is a novel chemoattractant for monocytes an... | KEEP AS NON CORE | Summary: Galectin-3 promotes neutrophil chemotaxis (PMID:10925302). Downstream immune process. Reason: Real but pleiotropic downstream immune process. |
| GO:0042056 chemoattractant activity | IDA PMID:10925302 Human galectin-3 is a novel chemoattractant for monocytes an... | KEEP AS NON CORE | Summary: Galectin-3 functions as a chemoattractant for monocytes/macrophages (PMID:10925302). This is an experimentally supported molecular function, mediated by its lectin/lattice activity at the cell surface. Real but a specialized immune-context activity. Reason: Experimentally supported but specialized immune-context molecular function, downstream of the core lectin activity. Supporting Evidence: PMID:10925302 galectin-3 induced human monocyte migration in vitro in a dose-dependent manner |
| GO:0045806 negative regulation of endocytosis | IDA PMID:19706535 Galectin-3 negatively regulates TCR-mediated CD4+ T-cell act... | KEEP AS NON CORE | Summary: Galectin-3 lattices reduce receptor endocytosis at the immunological synapse (PMID:19706535). Downstream consequence of surface-lattice formation. Reason: Downstream consequence of lattice formation; not core. |
| GO:0048245 eosinophil chemotaxis | IDA PMID:10925302 Human galectin-3 is a novel chemoattractant for monocytes an... | KEEP AS NON CORE | Summary: Galectin-3 promotes eosinophil chemotaxis (PMID:10925302). Downstream immune process. Reason: Real but pleiotropic downstream immune process. |
| GO:0048246 macrophage chemotaxis | IDA PMID:10925302 Human galectin-3 is a novel chemoattractant for monocytes an... | KEEP AS NON CORE | Summary: Galectin-3 chemoattracts macrophages (PMID:10925302). Downstream immune process. Reason: Real but pleiotropic downstream immune process. Supporting Evidence: PMID:10925302 Cultured human macrophages and alveolar macrophages also migrated toward galectin-3 |
| GO:0050918 positive chemotaxis | IDA PMID:10925302 Human galectin-3 is a novel chemoattractant for monocytes an... | KEEP AS NON CORE | Summary: Galectin-3 drives positive chemotaxis of myeloid cells (PMID:10925302). Downstream immune process; redundant parent of the specific chemotaxis terms. Reason: Pleiotropic downstream immune process. |
| GO:0070232 regulation of T cell apoptotic process | IDA PMID:8692888 Expression of galectin-3 modulates T-cell growth and apoptos... | KEEP AS NON CORE | Summary: Galectin-3 expression confers resistance to apoptosis in T cells (PMID:8692888). Pleiotropic immune/apoptosis process. Reason: Pleiotropic downstream immune/apoptosis process. Supporting Evidence: PMID:8692888 galectin-3 expression in these cells confers resistance to apoptosis induced by anti-Fas antibody and staurosporine |
| GO:0071674 mononuclear cell migration | IDA PMID:10925302 Human galectin-3 is a novel chemoattractant for monocytes an... | KEEP AS NON CORE | Summary: Galectin-3 induces mononuclear cell (monocyte) migration (PMID:10925302). Downstream immune process. Reason: Pleiotropic downstream immune process. |
| GO:0071677 positive regulation of mononuclear cell migration | IDA PMID:10925302 Human galectin-3 is a novel chemoattractant for monocytes an... | KEEP AS NON CORE | Summary: Galectin-3 positively regulates mononuclear cell migration (PMID:10925302). Downstream immune process. Reason: Pleiotropic downstream immune process. |
| GO:0090280 positive regulation of calcium ion import | IDA PMID:10925302 Human galectin-3 is a novel chemoattractant for monocytes an... | KEEP AS NON CORE | Summary: Galectin-3 induces Ca2+ influx in monocytes at high concentrations (PMID:10925302). Downstream signaling consequence of receptor cross-linking. Reason: Downstream signaling consequence; not core. Supporting Evidence: PMID:10925302 Galectin-3 caused a Ca2+ influx in monocytes at high, but not low, concentrations |
| GO:1902041 regulation of extrinsic apoptotic signaling pathway via death domain receptors | IMP PMID:8692888 Expression of galectin-3 modulates T-cell growth and apoptos... | KEEP AS NON CORE | Summary: Galectin-3 confers resistance to Fas (death-receptor)-induced apoptosis in T cells (PMID:8692888). Pleiotropic apoptosis-regulatory process. Reason: Pleiotropic downstream apoptosis-regulatory process. Supporting Evidence: PMID:8692888 confers resistance to apoptosis induced by anti-Fas antibody and staurosporine |
| GO:2001237 negative regulation of extrinsic apoptotic signaling pathway | IDA PMID:22761016 Downregulation of galectin-3 by EGF mediates the apoptosis o... | KEEP AS NON CORE | Summary: Cytoplasmic galectin-3 has anti-apoptotic activity; its downregulation by EGF permits apoptosis (PMID:22761016). Pleiotropic apoptosis-regulatory process. Reason: Pleiotropic downstream apoptosis-regulatory process. Supporting Evidence: PMID:22761016 overexpression of galectin-3 could reduce EGF-induced apoptosis in HepG2 cells |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | KEEP AS NON CORE | Summary: Galectin-3 was captured in a high-throughput mRNA-interactome screen (PMID:22658674) and has a proposed nuclear pre-mRNA splicing role. RNA binding is plausible but rests on a proteome-wide capture rather than a dedicated functional assay. Reason: Plausible nuclear RNA-associated role from a high-throughput screen; not a core, directly demonstrated molecular function. |
| GO:0043236 laminin binding | IDA PMID:2402511 Molecular cloning of a human macrophage lectin specific for ... | KEEP AS NON CORE | Summary: Galectin-3 binds laminin (PMID:2402511); historically named laminin-binding protein. A specific glycoprotein-binding facet of the core lectin function. Reason: Specific glycoprotein-binding facet of the core lectin function. |
| GO:0030855 epithelial cell differentiation | IEP PMID:21492153 Analysis of proteomic changes induced upon cellular differen... | KEEP AS NON CORE | Summary: Galectin-3 expression changes during Caco-2 enterocyte differentiation (PMID:21492153), an IEP (expression-pattern) correlation rather than a direct functional assay. Pleiotropic, correlative. Reason: Correlative expression-pattern (IEP) evidence; pleiotropic developmental process. |
| GO:0005576 extracellular region | HDA PMID:22664934 Comparison of tear protein levels in breast cancer patients ... | KEEP AS NON CORE | Summary: Proteomic detection of galectin-3 in tears. Localization-by-detection. Reason: Proteomics localization consistent with secretion; not core. |
| GO:0005576 extracellular region | HDA PMID:23580065 Shotgun proteomics reveals specific modulated protein patter... | KEEP AS NON CORE | Summary: Proteomic detection of galectin-3 in tears (glaucoma study). Localization-by-detection. Reason: Proteomics localization consistent with secretion; not core. |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: Proteomic detection of galectin-3 in parotid-gland exosomes. Localization-by-detection. Reason: Proteomics localization consistent with secretion; not core. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Proteomic detection of galectin-3 in urinary exosomes. Localization-by-detection. Reason: Proteomics localization consistent with secretion; not core. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6798743 | KEEP AS NON CORE | Summary: Reactome places galectin-3 at the plasma membrane in the neutrophil-degranulation pathway. Consistent with cell-surface association after secretion. Reason: Cell-surface association from pathway annotation; not core. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6800426 | KEEP AS NON CORE | Summary: Reactome plasma-membrane annotation (ficolin-rich granule pathway). Consistent with cell-surface association. Reason: Cell-surface association from pathway annotation; not core. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8938382 | KEEP AS NON CORE | Summary: Reactome plasma-membrane annotation (RUNX-regulated expression pathway). Consistent with cell-surface association after secretion. Reason: Cell-surface association from pathway annotation; not core. |
| GO:0005515 protein binding | IPI PMID:19016746 Identification of mitochondrial F(1)F(0)-ATP synthase intera... | MARK AS OVER ANNOTATED | Summary: Interaction with mitochondrial F1F0-ATP synthase in colon cancer cells. Generic protein binding is uninformative. Reason: Generic protein binding; not an informative molecular function. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:19016746 Identification of mitochondrial F(1)F(0)-ATP synthase intera... | KEEP AS NON CORE | Summary: A single study (PMID:19016746) reports galectin-3 at the mitochondrial inner membrane via interaction with F1F0-ATP synthase in colon cancer cells. This is an unusual, context-specific localization not corroborated by the broader literature (cytoplasm/nucleus/secreted), so it is treated as non-core. Reason: Single-study, context-specific localization not corroborated by the broader literature; retained but non-core. |
| GO:0005634 nucleus | IDA PMID:14961764 Nucling mediates apoptosis by inhibiting expression of galec... | ACCEPT | Summary: Galectin-3 detected in the nucleus (PMID:14961764). Consistent with established nuclear localization. Reason: Experimentally supported nuclear localization. |
| GO:0005737 cytoplasm | IDA PMID:14961764 Nucling mediates apoptosis by inhibiting expression of galec... | ACCEPT | Summary: Galectin-3 detected in the cytoplasm (PMID:14961764). Consistent with established cytoplasmic localization. Reason: Experimentally supported cytoplasmic localization. |
| GO:0030246 carbohydrate binding | TAS PMID:9162064 Strikingly different localization of galectin-3 and galectin... | ACCEPT | Summary: Carbohydrate binding, the core molecular function, asserted by a primary study (PMID:9162064). Redundant with the EXP/IEA carbohydrate-binding annotations. Reason: Core molecular function; well supported. |
| GO:0005886 plasma membrane | TAS PMID:9162064 Strikingly different localization of galectin-3 and galectin... | KEEP AS NON CORE | Summary: Galectin-3 associates with the plasma membrane / cell surface (PMID:9162064), consistent with its extracellular lattice function after secretion. Reason: Cell-surface association; consistent with secreted lattice function but not core. |
| GO:0062093 lysophagy | IDA PMID:32521192 MERIT, a cellular system coordinating lysosomal repair, remo... | NEW | Summary: Cytosolic galectin-3 detects lysosomal membrane rupture by binding luminal glycans newly exposed to the cytosol, recruits and organizes ESCRT components (PDCD6IP/ALIX, CHMP4A, CHMPB) for membrane repair, and at later stages cooperates with TRIM16 to engage the autophagy machinery (ATG16L1, ATG13, LC3) in selective autophagic removal of severely damaged lysosomes (PMID:32521192, PMID:27693506). This glycan-damage-sensing lysophagy role is among the strongest intracellular functions of galectin-3 and is not currently represented in GOA; it is added here as a NEW annotation. The same machinery also mediates galectin-3-dependent secretory autophagy of alpha-synuclein after vesicular damage (PMID:34612142). Reason: Strongly supported intracellular function (damaged-endomembrane glycan sensing leading to ESCRT repair and TRIM16-dependent lysophagy) that is absent from the existing GOA annotations; added as a core glycan-sensing process. Supporting Evidence: PMID:32521192 LGALS3 (galectin 3) detects membrane damage by detecting exposed lumenal glycosyl groups, recruits and organizes ESCRT components PDCD6IP/ALIX, CHMP4A, and CHMPB at damaged sites on the lysosomes, and facilitates ESCRT-driven repair of lysosomal membrane. At later stages, LGALS3 cooperates with TRIM16, an autophagy receptor-regulator, to engage autophagy machinery in removal of excessively damaged lysosomes. PMID:32521192 The capacity of LGALS3 to recognize glycans is required to initiate autophagy in response to lysosomal damage. |
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Download this section (compressed HTML)Q: Is the nuclear pre-mRNA splicing / RNA-binding role of galectin-3 a direct, sequence- or structure-specific RNA-binding activity, or an indirect association via glycosylated/RNP partners captured in proteome-wide screens?
Q: To what extent does liquid-liquid phase separation of the N-terminal domain operate intracellularly (e.g. in endomembrane-damage sensing) versus only in the extracellular agglutination context?
Experiment: Compare wild-type galectin-3 with a CRD point mutant (e.g. R186S, which abolishes beta-galactoside binding) for recruitment to ruptured lysosomes (induced by LLOMe or silica) and for co-recruitment of TRIM16/ATG16L1/BECN1, by live-cell imaging and co-IP.
Hypothesis: The carbohydrate-recognition activity of the CRD is required for galectin-3-mediated sensing of damaged endomembranes and recruitment of the autophagy machinery.
Type: structure-function / mutagenesis with damage-induced autophagy assay
Experiment: Compare full-length galectin-3 with N-terminal-tail deletion and aromatic-residue mutants (tryptophan/tyrosine substitutions that impair LLPS) for surface-receptor residence time (e.g. of GnT-V-modified receptors), lattice formation, and endocytosis rates.
Hypothesis: N-terminal-domain-driven self-association/LLPS is necessary for galectin-3 lattice formation and the consequent retention of branched-N-glycan receptors at the cell surface.
Type: domain-deletion / point-mutation with quantitative cell-surface imaging
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