{"gene":"LGALS3BP","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1994,"finding":"90K/LGALS3BP is a secreted glycoprotein carrying a scavenger receptor cysteine-rich (SRCR) domain, and stimulates natural killer cell and lymphokine-activated killer cell activity, with immunostimulatory effects potentially mediated through induction of interleukin-2.","method":"Monoclonal antibody-based protein purification, Northern blot, functional NK/LAK cell assays, cytokine induction assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assays with purified protein in multiple cell-based assays, single lab","pmids":["8034587"],"is_preprint":false},{"year":1995,"finding":"Engineered enhancement of 90K expression in tumor cell lines results in significant (>80%) tumor growth inhibition in athymic mice, not by direct action on tumor cells, but by stimulation of residual cell-mediated immune defense, and involves induction of ICAM-1 and VCAM-1 in tumor endothelium.","method":"Stable overexpression in mammary carcinoma and glioblastoma cell lines, xenograft tumor growth assays in nude mice, immunohistochemistry for ICAM-1/VCAM-1","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss/gain of function with defined cellular phenotype, single lab, multiple orthogonal readouts","pmids":["7542166"],"is_preprint":false},{"year":1988,"finding":"Recombinant interferon-alpha 2b stimulates de novo synthesis and secretion of 90K in human breast cancer cells in a dose-dependent manner, an effect blocked by cycloheximide, indicating transcriptional/translational regulation by IFN-alpha.","method":"Cell culture treatment with rIFN-alpha 2b, immunoassay of conditioned media, cycloheximide block experiment, in vivo patient serum measurement","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct pharmacological manipulation with protein-level readout, single lab, multiple orthogonal methods","pmids":["3403063"],"is_preprint":false},{"year":2001,"finding":"90K/LGALS3BP interacts with galectin-1 at a site distinct from the galectin-3 binding site (the two galectins do not compete), with a dissociation constant of ~10^-7 M, and galectin-1-induced aggregation of melanoma A375 cells is mediated at least in part by 90K, as shown by inhibition with anti-90K monoclonal antibody.","method":"Solid-phase binding assay with recombinant proteins, lactose-inhibition controls, competitive binding assay, cell aggregation assay with blocking antibody","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding reconstitution with Kd measurement, cell-based functional assay with antibody inhibition, single lab","pmids":["11146440"],"is_preprint":false},{"year":2008,"finding":"Endosialin (Tem1), expressed by tumor stromal fibroblasts, directly binds Mac-2 BP/90K; the C-terminal fragment of Mac-2 BP/90K (containing binding sites for galectin-3 and collagens) is responsible for endosialin binding. This interaction is repulsive: adhesion of Mac-2 BP/90K-expressing tumor cells on endosialin-expressing fibroblasts yields a repulsive outcome.","method":"Affinity chromatography, biochemical binding assays with domain deletion constructs, loss-of-function adhesion experiments, in vivo expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping biochemistry plus cell-based functional assay, single lab, multiple methods","pmids":["18490383"],"is_preprint":false},{"year":2010,"finding":"90K interacts with the CD9/CD82 tetraspanin complex and suppresses Wnt/beta-catenin signaling via a novel ISG15 (ISGylation)-dependent ubiquitination/proteasomal degradation of beta-catenin that is independent of GSK-3beta and Siah/APC. In a syngeneic mouse colon tumor model, 90K knockdown increased tumor growth and lung metastasis.","method":"Co-immunoprecipitation, cell invasion assays, ISGylation pathway manipulation, syngeneic mouse tumor model, immunohistochemistry of human CRC tissues","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo KD model with defined metastasis phenotype, mechanistic pathway delineation with multiple orthogonal methods, corroborated by human tissue data","pmids":["20581239"],"is_preprint":false},{"year":2013,"finding":"LGALS3BP is a centriole- and basal body-associated protein with a dual role: overexpression triggers centrosome hypertrophy, while knockdown causes accumulation of centriolar substructures (comprising CPAP, acetylated tubulin and centrin). Depletion of LGALS3BP in cells endogenously overexpressing it reverses centrosome hypertrophy.","method":"Protein-interaction network screen, siRNA knockdown, overexpression, immunofluorescence microscopy, analysis of cancer cell lines and seminoma tissue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional loss/gain-of-function with specific molecular phenotype, protein interaction network, validated in endogenous overexpression context and tissue samples","pmids":["23443559"],"is_preprint":false},{"year":2013,"finding":"LGALS3BP constitutes a novel integrin ligand for integrins alpha1beta1, alpha5beta1, alphavbeta1, and alpha6beta1, and LGALS3BP-mediated integrin activation transmits signals via Akt, JNK, Ras/Raf-ERK, while keeping p38 at baseline. Sustained LGALS3BP exposure supports cell viability, motility and migration, and anti-LGALS3BP antibody SP2 impedes these signaling events.","method":"Integrin-binding assays, phosphorylation/signaling assays (Akt, JNK, ERK, p38), cell adhesion, viability, migration assays, antibody blocking experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assays plus downstream signaling readouts, antibody rescue, single lab with multiple orthogonal methods","pmids":["24362527"],"is_preprint":false},{"year":2013,"finding":"90K/LGALS3BP is an interferon-stimulated gene product that dose-dependently decreases HIV-1 particle infectivity by impairing gp160 processing and reducing incorporation of mature gp120/gp41 into virions, without directly interacting with HIV-1 Env or entrapping Env in the ER. The two intermediate domains of 90K are sufficient for antiviral activity; the N-terminal SRCR and C-terminal domains are dispensable. siRNA knockdown of 90K in macrophages enhanced Env incorporation and HIV-1 spread.","method":"Overexpression/siRNA knockdown in producer cells, HIV-1 infectivity assays, Western blot for viral proteins, domain truncation mutants, IFN-alpha treatment of macrophages","journal":"Retrovirology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — domain mutagenesis, gain and loss of function, multiple cell types and orthogonal assays, mechanistic pathway defined","pmids":["24156545"],"is_preprint":false},{"year":2014,"finding":"LGALS3BP is identified as a sialic acid-dependent ligand for the immunomodulatory Siglec-9 (and Siglec-5 and Siglec-10) via affinity chromatography of tumor cell extracts; LGALS3BP inhibits neutrophil activation in a sialic acid- and Siglec-dependent manner. The mouse homolog binds murine Siglec-E with lower affinity.","method":"Affinity chromatography of tumor cell extracts, Siglec binding assays, sialic acid-dependency experiments, neutrophil activation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity-based identification of binding partner, functional inhibition assay, single lab with multiple orthogonal methods","pmids":["25320078"],"is_preprint":false},{"year":2012,"finding":"LGALS3BP knockdown in MDA-MB-231 breast cancer cells decreases adhesion to fibronectin, reduces transendothelial migration, and reduces VEGF expression; VEGF production was restored by exogenous recombinant LGALS3BP and requires intact PI3K/Akt signaling. Additionally, LGALS3BP directly stimulates HUVEC tubulogenesis in a VEGF-independent, galectin-3-dependent manner.","method":"siRNA knockdown, VEGF ELISA, PI3K inhibitor rescue, HUVEC tubulogenesis assay, anti-galectin-3 blocking, adhesion and migration assays","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with specific readouts, pharmacological rescue, galectin-3-dependence shown, single lab with multiple orthogonal methods","pmids":["22864925"],"is_preprint":false},{"year":2019,"finding":"LGALS3BP functions as a scaffold/adaptor protein that interacts with TRAF6, TRAF3, TAK1, and TBK1; it enhances TRAF6 and TRAF3 ubiquitination, is itself a ubiquitination substrate of TRAF6, and promotes NF-κB, IRF3, and IRF7 nuclear translocation, leading to IFN and pro-inflammatory cytokine production upon viral infection.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, overexpression, reporter assays for NF-κB/IRF3/IRF7 activity, viral infection models","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with multiple partners, ubiquitination substrate assays, bidirectional functional experiments, multiple orthogonal methods in single rigorous study","pmids":["31404116"],"is_preprint":false},{"year":2016,"finding":"M2BP/90K inhibits HIV-1 virion production by trapping HIV-1 Gag to vimentin filaments to inhibit Gag trafficking to the plasma membrane. M2BP interacts with both HIV-1 Gag and vimentin. Collapsing vimentin filaments (by acrylamide or dominant-negative vimentin) relieves M2BP-mediated inhibition of virion production.","method":"Co-immunoprecipitation (M2BP with Gag and vimentin), vimentin disruption experiments, HIV-1 virion production assays, dominant-negative vimentin overexpression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of three-way interaction, pharmacological and genetic rescue of the phenotype, single lab","pmids":["27604950"],"is_preprint":false},{"year":2018,"finding":"The antiviral activity of 90K/LGALS3BP against HIV-1 is conserved across most primate orthologs but absent in rhesus macaque 90K. A single amino acid exchange in the BTB/POZ domain restores antiviral activity in a shortened rhesus macaque 90K. Structural analysis of BTB/POZ domains from rhesus macaque and human 90K reveals a slightly larger hydrophobic patch in rhesus macaque that may modulate protein-protein interactions. Reduction of virion-associated gp120, not merely reduced cell-surface gp120, correlates with antiviral activity.","method":"Comparative ortholog expression assays, HIV-1 infectivity assays, domain mutagenesis, X-ray crystallography of BTB/POZ domains","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus functional assay, mechanistic model validated across multiple primate orthologs","pmids":["29743357"],"is_preprint":false},{"year":2006,"finding":"TAA90K/Mac-2-binding protein purified from colon cancer cells binds fibronectin, collagen IV, laminins-1/-5/-10, and galectin-3 in solid-phase assays; binding to galectin-3 is carbohydrate-dependent (inhibited by lactose and asialo-fetuin) and requires proper N-glycosylation. At low concentrations, TAA90K enhances galectin-3-mediated HT-29 cell adhesion; at high concentrations it inhibits adhesion.","method":"Protein purification from vaccinia-virus-expressed TAA90K, solid-phase binding assays, glycosylation inhibitor (1-deoxymannojirimycin), lactose inhibition, cell adhesion assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct in vitro binding assays with purified recombinant protein, glycan-dependency demonstrated, single lab","pmids":["16518858"],"is_preprint":false},{"year":2009,"finding":"TAA90K/Mac-2-binding protein is a novel substrate for matrix metalloproteinases MMP-2, MMP-7, and MMP-9; MMP-7-mediated cleavage of TAA90K reduces its interaction with fibronectin and laminin-10 but not with laminin-1, collagen IV, or galectin-3. TAA90K also enhances extracellular levels of proMMP-7 in HT-29 colon cancer cells.","method":"SDS-PAGE and protein sequencing of cleavage products, solid-phase binding assays before and after cleavage, ELISA for proMMP-7 levels","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct in vitro enzymatic cleavage with protein sequencing and binding consequence assays, single lab","pmids":["19665518"],"is_preprint":false},{"year":2017,"finding":"90K promotes E-cadherin degradation via ubiquitination-mediated proteasomal degradation. 90K interacts with the E-cadherin-p120-catenin complex, induces its dissociation, and alters the phosphorylation status of p120-catenin, but does not associate with beta-catenin. This effect is cell-density-dependent and is diminished in p120-catenin knockdown cells.","method":"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor treatment, p120-catenin siRNA knockdown, cell adhesion and invasion assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, siRNA rescue, biochemical mechanism delineated, single lab with multiple methods","pmids":["29207493"],"is_preprint":false},{"year":2016,"finding":"90K-mediated beta-catenin degradation via ISGylation requires the N-terminal 86 amino acids of beta-catenin. 90K induces Herc5 and ISG15 expression; the N-terminus of beta-catenin is not essential for interaction with Herc5, but is required for 90K-induced degradation. 90K can degrade mutant beta-catenin lacking GSK-3beta phosphorylation sites, indicating a phosphorylation-independent degradation pathway.","method":"Beta-catenin deletion and point mutants, Western blot, co-immunoprecipitation, overexpression in HeLa and CSC221 cells","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function mutagenesis with biochemical readouts, single lab, mechanistic extension of prior work","pmids":["27668402"],"is_preprint":false},{"year":2021,"finding":"LGALS3BP suppresses colon inflammation and tumorigenesis by downregulating the TAK1-NF-κB signaling axis in colon epithelial cells. Lgals3bp-/- mice show hyperactivated NF-κB, excessive pro-inflammatory cytokines (IL-6, TNFα, IL-1β), elevated GM-CSF, and accumulation of myeloid-derived suppressor cells during tumorigenesis.","method":"Lgals3bp-/- knockout mice, colitis and colon tumor models, NF-κB reporter/activation assays, cytokine measurement, MDSC quantification","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse model with defined molecular pathway (TAK1-NF-κB), multiple disease models, multiple orthogonal readouts","pmids":["33824294"],"is_preprint":false},{"year":2023,"finding":"LGALS3BP suppresses TNF-alpha-mediated MMP9 gene expression in triple-negative breast cancer by inhibiting activation of TAK1 kinase, the key signaling node linking TNF-α and MMP9 expression. Nanoparticle-delivered LGALS3BP inhibits TAK1 phosphorylation and MMP9 expression in tumors and suppresses lung metastasis in vivo.","method":"LGALS3BP overexpression/knockdown, TNF-alpha stimulation, TAK1 phosphorylation assays, MMP9 reporter/ELISA, nanoparticle delivery in vivo, xenograft metastasis model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with specific kinase readout (TAK1 phosphorylation), in vivo validation, single lab with multiple methods","pmids":["37041137"],"is_preprint":false},{"year":2024,"finding":"LGALS3BP directly binds integrin αV and promotes assembly of integrin αV complexes, enabling release of active TGF-β1 from the extracellular latent complex with rearrangement of F-actin cytoskeleton. Released TGF-β1 activates JunB transcription factor, creating a positive feedback loop for TGF-β1 production. Hepatocyte-specific LGALS3BP knockin mice show aggravated liver fibrosis with increased TGF-β1; LGALS3BP knockout reduces TGF-β1 signaling and CCl4-induced fibrosis.","method":"Co-immunoprecipitation (LGALS3BP with integrin αV), LC-MS/MS proteomics, RNA-seq, ATAC-seq, conditional knockin/knockout mice, CCl4 fibrosis model, F-actin cytoskeleton analysis","journal":"Cancer communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding assay, multi-omics, bidirectional genetic mouse models, mechanistic pathway fully delineated with multiple orthogonal methods","pmids":["39073023"],"is_preprint":false},{"year":2021,"finding":"LGALS3BP is a secreted protein enriched in human neural progenitor cells (NPCs) that regulates the position of NPCs; LGALS3BP-mediated mechanisms involve the extracellular matrix in NPC anchoring and migration. Its temporal expression influences NPC delamination, corticogenesis, and gyrification, demonstrated in cerebral organoids, human fetal tissue, and mouse models.","method":"Cerebral organoids, human fetal tissue analysis, mouse in utero experiments, single-cell RNA-sequencing, proteomics, analysis of individuals with de novo LGALS3BP variants","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple complementary model systems (organoids, fetal tissue, mice, human genetics), proteomics plus scRNA-seq, mechanistic link to ECM established","pmids":["34728600"],"is_preprint":false},{"year":2017,"finding":"WFA+-M2BP (glycosylated LGALS3BP) is secreted by hepatic stellate cells (HSCs). Exogenous WFA+-M2BP stimulation enhances Mac-2/galectin-3 expression in Kupffer cells; Mac-2-depleted Kupffer cells (siRNA) show reduced alpha-smooth muscle actin expression when co-cultured with HSCs, establishing a paracrine circuit: HSC-secreted LGALS3BP→Kupffer cell Mac-2 expression→Kupffer cell activation→HSC fibrogenic activation.","method":"Subpopulation cell culture with sandwich immunoassay, siRNA knockdown of Mac-2 in Kupffer cells, co-culture experiments, immunoblot, liver tissue immunohistochemistry","journal":"Journal of gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific source identified, siRNA rescue in co-culture, paracrine mechanism delineated, single lab","pmids":["28008658"],"is_preprint":false},{"year":1997,"finding":"The 90K protein domain structure was mapped: an N-terminal SRCR-like domain (D1), a heavily glycosylated mucin-like domain (D2), and a ~27 kDa C-terminal domain (D3). Monoclonal antibodies SP2 and L3 both recognize D2. Point mutations at residues 189, 223, and 259 and a truncated form (aa 1-383) are defective in secretion, identifying specific residues required for normal processing and secretion.","method":"Ig fusion protein construction with domain deletions, monoclonal antibody epitope mapping, COS-1 cell expression, secretion assays with point mutants","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — domain mapping with deletion constructs and point mutagenesis, functional secretion readout, single lab","pmids":["9125183"],"is_preprint":false},{"year":1999,"finding":"The human 90K promoter is TATA-less, lacks GC-richness and SP1 dependence, has a minimal promoter of 51 bp, and contains an interferon regulatory factor element (IRF-E) required for induction by poly(I:C) (viral mimic) and interferon-gamma. Two regions mediating poly(I:C) induction were identified by deletion analysis.","method":"Promoter deletion analysis, RNase protection assay for transcription start sites, point mutations in the IRF-E, poly(I:C) stimulation, reporter gene assays","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — systematic deletion and point-mutation analysis of promoter elements, functional reporter assays, single lab","pmids":["10198166"],"is_preprint":false},{"year":2007,"finding":"Constitutive expression of 90K/LGALS3BP depends on upstream stimulatory factor (USF) binding to an E-box in the minimal promoter. Hormonal suppression (TSH/cAMP plus insulin/IGF-I) of constitutive and IFN-gamma-induced 90K expression occurs via decreased USF binding to this E-box. Transfection with USF1/USF2 cDNAs increases constitutive promoter activity and attenuates hormonal suppression.","method":"Promoter cloning, EMSA (electrophoretic mobility shift assay) for USF binding, transfection with USF1/USF2 expression plasmids, reporter gene assays, TSH/cAMP/insulin treatments","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — EMSA plus gain-of-function transfection rescue, pharmacological manipulation, single lab","pmids":["17446190"],"is_preprint":false},{"year":1996,"finding":"Exposure of the human breast cancer cell line EVSA-T to purified 90K protein causes approximately sixfold increase in MHC class I expression as measured by flow cytometry, demonstrating a direct effect of secreted 90K on immune recognition molecules.","method":"Purified 90K protein treatment of cancer cells, flow cytometry for MHC class I expression","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single functional assay with purified protein, no mechanism further defined, single lab","pmids":["8753808"],"is_preprint":false},{"year":2019,"finding":"GALNT6 O-glycosylates LGALS3BP at three sites (T556, T571, S582), and this O-glycosylation is required for LGALS3BP secretion and autocrine growth promotion in breast cancer cells. Triple Ala substitution (T556A/T571A/S582A) drastically reduces GALNT6-dependent LGALS3BP O-glycosylation and secretion, suppressing autocrine growth.","method":"GALNT6 siRNA knockdown, O-glycosylation site mutagenesis (T→A substitutions), LGALS3BP secretion assay, cell growth assay","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — site-specific mutagenesis of glycosylation sites with functional secretion and growth readout, single lab","pmids":["31894262"],"is_preprint":false},{"year":2016,"finding":"Mac-2 binding protein (M2BP) is identified as a novel serum adiponectin-binding protein by immunoprecipitation with anti-adiponectin antibody followed by mass spectrometry; the M2BP-APN association was confirmed with reconstituted proteins in vitro. M2BP abrogates the suppressive effect of adiponectin on TNF-alpha-induced inflammation in vascular endothelial cells.","method":"Immunoprecipitation with anti-adiponectin antibody, mass spectrometry, in vitro reconstitution with purified proteins, endothelial cell inflammation assay","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — immunoprecipitation plus in vitro reconstitution of binding, functional consequence shown, single lab","pmids":["27588936"],"is_preprint":false},{"year":2023,"finding":"In platelets from SLE patients, interferon-alpha induces LGALS3BP transcription and translation in megakaryoblastic cells in a dose-dependent manner. Platelet-released LGALS3BP and recombinant LGALS3BP enhance proinflammatory cytokine production by macrophages, establishing a platelet-to-macrophage proinflammatory signaling role for LGALS3BP.","method":"RNA sequencing of SLE patient platelets, IFN-alpha treatment of MEG-01 cells, ELISA for platelet releasate LGALS3BP, macrophage cytokine production assays with recombinant LGALS3BP","journal":"Arthritis & rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic in vitro experiments with recombinant protein and cell-based assays, IFN-alpha dose-response, single lab","pmids":["36245285"],"is_preprint":false},{"year":2024,"finding":"LGALS3BP is broadly expressed in the CNS and upregulated during WNV infection and aging; Lgals3bp-deficient mice exhibit reduced neuroinflammation, increased homeostatic microglial numbers, and altered T cell populations after WNV encephalitis recovery, without differences in virologic control or survival, indicating a role in regulating microglial activation and neuroinflammation.","method":"Spatial transcriptomics, RNA sequencing, flow cytometry, Lgals3bp-knockout mouse model, WNV infection model","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO model with defined cellular phenotypes (microglial numbers, T cell populations), multiple transcriptomic methods, single lab","pmids":["39062523"],"is_preprint":false},{"year":2025,"finding":"LGALS3BP expression in tamoxifen-resistant breast cancer is suppressed by estrogen signaling through direct ERα binding to the LGALS3BP promoter. Secreted LGALS3BP promotes adhesion to the extracellular matrix and HUVEC tube formation. LGALS3BP knockdown in tamoxifen-resistant cells completely abrogated increased pulmonary metastasis in xenograft experiments.","method":"Chromatin immunoprecipitation (ERα to LGALS3BP promoter), TurboID secretome labeling, shRNA knockdown, HUVEC tube formation assay, xenograft metastasis model","journal":"Breast cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for transcriptional regulation, in vivo KD with defined metastasis phenotype, single lab with multiple orthogonal methods","pmids":["39789641"],"is_preprint":false}],"current_model":"LGALS3BP (90K/Mac-2 BP) is a secreted, heavily glycosylated SRCR-domain glycoprotein whose O-glycosylation by GALNT6 at defined sites is required for its secretion; it functions extracellularly as a ligand for galectin-1, galectin-3, multiple beta1-integrins (alpha1beta1, alpha5beta1, alphavbeta1, alpha6beta1), integrin αV, endosialin (Tem1), sialic acid-dependent Siglecs (Siglec-5/-9/-10), and adiponectin, and binds ECM proteins (fibronectin, collagens, laminins); intracellularly it acts as a scaffold/adaptor for the TRAF6-TRAF3-TAK1-TBK1 innate immune complex to promote NF-κB and IRF3/IRF7 activation, suppresses Wnt/β-catenin signaling via ISGylation-dependent proteasomal degradation of β-catenin through the CD9/CD82 tetraspanin complex, suppresses TAK1-NF-κB-dependent inflammation and colon tumorigenesis, inhibits HIV-1 particle infectivity by impairing gp160 processing and Env incorporation into virions (function requiring the BTB/POZ intermediate domain), traps HIV-1 Gag to vimentin filaments to reduce virion production, regulates centriole biogenesis and centrosome morphology, activates TGF-β1 release via integrin αV engagement and F-actin remodeling in liver fibrosis, promotes E-cadherin degradation via p120-catenin dissociation, and influences neural progenitor cell positioning and cortical development through extracellular matrix interactions; its expression is transcriptionally induced by interferons and viral dsRNA through an IRF-E and USF-binding E-box in its TATA-less promoter, and is suppressed by estrogen receptor signaling."},"narrative":{"mechanistic_narrative":"LGALS3BP (90K/Mac-2 binding protein) is a secreted, heavily glycosylated SRCR-domain glycoprotein that operates at the interface of innate immunity, cell adhesion, and tumor progression [PMID:8034587, PMID:16518858]. Its three-domain architecture (N-terminal SRCR domain, glycosylated mucin-like domain, C-terminal domain) was mapped early, with specific residues required for proper secretion [PMID:9125183]; secretion depends on GALNT6-mediated O-glycosylation at T556/T571/S582, which is in turn required for its autocrine growth-promoting activity [PMID:31894262]. Extracellularly, LGALS3BP is a multivalent ligand: it binds galectin-1 and galectin-3 [PMID:11146440, PMID:16518858], ECM proteins including fibronectin, collagen IV, and laminins [PMID:16518858], beta1-integrins and integrin alphaV [PMID:24362527, PMID:39073023], endosialin/Tem1 [PMID:18490383], sialic acid-dependent Siglecs to inhibit neutrophil activation [PMID:25320078], and adiponectin, blocking its anti-inflammatory effect [PMID:27588936]; it is also a substrate of MMP-2/-7/-9, whose cleavage modulates its ECM binding [PMID:19665518]. Through integrin engagement it transmits Akt, JNK, and Ras/Raf-ERK signals supporting cell viability and migration [PMID:24362527], and via direct integrin alphaV binding it drives F-actin remodeling and release of active TGF-beta1, establishing a JunB-dependent feedback loop that aggravates liver fibrosis [PMID:39073023]. As an interferon- and viral-dsRNA-inducible gene controlled by an IRF-E and USF/E-box in its TATA-less promoter [PMID:10198166, PMID:17446190], LGALS3BP acts intracellularly as a scaffold/adaptor for the TRAF6-TRAF3-TAK1-TBK1 complex, promoting NF-kB and IRF3/IRF7 activation and antiviral/proinflammatory cytokine production [PMID:31404116], yet it conversely restrains the TAK1-NF-kB axis to suppress colon inflammation and tumorigenesis [PMID:33824294, PMID:37041137]. It restricts HIV-1 by impairing gp160 processing and Env incorporation into virions through its intermediate/BTB-POZ domains [PMID:24156545, PMID:29743357] and by trapping Gag on vimentin filaments to limit virion production [PMID:27604950]. LGALS3BP additionally suppresses Wnt/beta-catenin signaling via ISGylation-dependent proteasomal degradation of beta-catenin through the CD9/CD82 tetraspanin complex [PMID:20581239, PMID:27668402], promotes E-cadherin degradation via p120-catenin dissociation [PMID:29207493], regulates centriole biogenesis and centrosome morphology [PMID:23443559], and controls neural progenitor positioning and corticogenesis through ECM interactions [PMID:34728600].","teleology":[{"year":1988,"claim":"Established that 90K is not constitutive but an inducible secreted product, placing it downstream of interferon signaling — a regulatory anchor for all later innate-immunity work.","evidence":"rIFN-alpha 2b treatment of breast cancer cells with conditioned-media immunoassay and cycloheximide block","pmids":["3403063"],"confidence":"Medium","gaps":["Promoter elements mediating induction not yet defined","Did not address function of the secreted protein"]},{"year":1994,"claim":"Defined 90K as a secreted SRCR-domain glycoprotein with immunostimulatory activity, framing it as an effector of host immune defense rather than a passive serum marker.","evidence":"Antibody-based purification, Northern blot, and NK/LAK functional and cytokine-induction assays","pmids":["8034587"],"confidence":"Medium","gaps":["Molecular receptors mediating NK/LAK stimulation unknown","Direct vs indirect immune effect unresolved"]},{"year":1997,"claim":"Resolved the three-domain architecture and identified residues required for secretion, providing the structural framework for later domain-mapping of ligand binding and antiviral activity.","evidence":"Domain-deletion Ig fusion constructs, mAb epitope mapping, and point-mutant secretion assays in COS-1 cells","pmids":["9125183"],"confidence":"Medium","gaps":["Functional assignment of each domain not established here","Glycosylation requirement for secretion not yet linked to specific enzymes"]},{"year":1999,"claim":"Mapped the TATA-less promoter and the IRF-E required for poly(I:C)/IFN-gamma induction, mechanistically explaining the interferon-stimulated-gene behavior of LGALS3BP.","evidence":"Promoter deletion, RNase protection, and IRF-E point-mutation reporter assays under poly(I:C) stimulation","pmids":["10198166"],"confidence":"Medium","gaps":["Transcription factors binding the IRF-E not identified","Constitutive expression control not addressed"]},{"year":2001,"claim":"Showed galectin-1 binds 90K at a site distinct from galectin-3 with measured affinity, establishing 90K as a bivalent galectin ligand mediating cell aggregation.","evidence":"Solid-phase binding with Kd determination, non-competition assay, and antibody-blocked melanoma aggregation","pmids":["11146440"],"confidence":"Medium","gaps":["Glycan dependence of galectin-1 binding not dissected","Downstream signaling of aggregation unknown"]},{"year":2006,"claim":"Defined the ECM/galectin-3 ligand repertoire and its glycan dependence, and revealed concentration-dependent biphasic effects on cell adhesion.","evidence":"Solid-phase binding with purified recombinant 90K, glycosylation-inhibitor and lactose controls, adhesion assays","pmids":["16518858"],"confidence":"Medium","gaps":["Physiological relevance of biphasic adhesion in vivo unclear","Receptors for ECM-bridging not all defined"]},{"year":2008,"claim":"Identified endosialin as a C-terminal-domain binding partner producing repulsive tumor-cell/stromal interactions, extending the ligand map to the stromal compartment.","evidence":"Affinity chromatography, domain-deletion binding, and loss-of-function adhesion assays","pmids":["18490383"],"confidence":"Medium","gaps":["Signaling basis of repulsion not defined","In vivo consequence for metastasis untested"]},{"year":2010,"claim":"Revealed an intracellular tumor-suppressive function: LGALS3BP drives ISGylation-dependent, GSK-3beta-independent beta-catenin degradation via the CD9/CD82 complex, with knockdown promoting tumor growth and metastasis.","evidence":"Reciprocal Co-IP, ISGylation manipulation, invasion assays, and a syngeneic colon tumor model","pmids":["20581239"],"confidence":"High","gaps":["E3 ligase/ISGylation machinery details not fully defined here","How a secreted glycoprotein acts intracellularly unresolved"]},{"year":2012,"claim":"Linked LGALS3BP to angiogenesis and breast cancer dissemination via fibronectin adhesion, PI3K/Akt-dependent VEGF induction, and galectin-3-dependent endothelial tubulogenesis.","evidence":"siRNA knockdown, VEGF ELISA, PI3K inhibitor rescue, HUVEC tubulogenesis, and galectin-3 blocking","pmids":["22864925"],"confidence":"Medium","gaps":["Receptor coupling LGALS3BP to PI3K/Akt not defined","VEGF-independent tubulogenesis mechanism incomplete"]},{"year":2013,"claim":"Established LGALS3BP as a direct multi-integrin ligand transmitting pro-survival/pro-migratory signals, and as a centriole/basal-body protein controlling centrosome number — two distinct cell-autonomous roles.","evidence":"Integrin-binding and phospho-signaling assays with antibody blocking; siRNA/overexpression with immunofluorescence of centriolar markers","pmids":["24362527","23443559"],"confidence":"High","gaps":["Connection between extracellular integrin role and centriolar role unknown","Centriolar interactors beyond CPAP/centrin not enumerated"]},{"year":2013,"claim":"Defined LGALS3BP as an interferon-induced HIV-1 restriction factor acting by impairing gp160 processing and Env incorporation, localizing the activity to its two intermediate domains.","evidence":"Gain/loss-of-function in producer cells, infectivity assays, viral protein blotting, and domain truncation mutants","pmids":["24156545"],"confidence":"High","gaps":["Direct molecular target in the Env processing pathway not identified","Whether restriction operates in vivo untested"]},{"year":2014,"claim":"Identified LGALS3BP as a sialic acid-dependent Siglec ligand that dampens neutrophil activation, adding an immunosuppressive arm to its extracellular function.","evidence":"Affinity chromatography of tumor-cell extracts, Siglec binding, and sialic-acid-dependent neutrophil activation assays","pmids":["25320078"],"confidence":"Medium","gaps":["In vivo relevance of Siglec engagement untested","Which sialoglycans on LGALS3BP mediate binding not mapped"]},{"year":2016,"claim":"Refined the beta-catenin degradation mechanism to the N-terminal 86 residues of beta-catenin via Herc5/ISG15 induction, confirming a phosphorylation-independent route; separately defined a second HIV restriction mechanism (Gag trapping on vimentin) and identified adiponectin as a binding partner whose anti-inflammatory action LGALS3BP blocks.","evidence":"beta-catenin deletion/point mutants and Co-IP; three-way Co-IP with Gag/vimentin plus vimentin-disruption rescue; anti-adiponectin IP/MS with reconstitution and endothelial inflammation assay","pmids":["27668402","27604950","27588936"],"confidence":"Medium","gaps":["Coordination between the two distinct HIV-restriction mechanisms unclear","Stoichiometry of adiponectin sequestration in vivo unknown"]},{"year":2017,"claim":"Showed LGALS3BP promotes proteasomal E-cadherin degradation by dissociating the E-cadherin/p120-catenin complex in a density- and p120-dependent manner, distinguishing this from its beta-catenin pathway; and identified hepatic stellate cells as a source feeding a paracrine Kupffer-cell activation circuit.","evidence":"Co-IP, ubiquitination and proteasome-inhibitor assays, p120-catenin knockdown; subpopulation co-culture with Mac-2 knockdown in Kupffer cells","pmids":["29207493","28008658"],"confidence":"Medium","gaps":["E3 ligase for E-cadherin degradation not identified","Receptor mediating Kupffer-cell Mac-2 induction unknown"]},{"year":2018,"claim":"Provided crystallographic and cross-ortholog evidence that the BTB/POZ domain governs HIV-1 restriction, with a single residue change restoring activity in rhesus 90K, tying structure to antiviral function.","evidence":"Comparative ortholog infectivity assays, domain mutagenesis, and X-ray crystallography of BTB/POZ domains","pmids":["29743357"],"confidence":"High","gaps":["Direct protein-protein interaction the hydrophobic patch mediates not identified","Full-length structure unavailable"]},{"year":2019,"claim":"Defined the intracellular innate-immune scaffolding function: LGALS3BP nucleates the TRAF6-TRAF3-TAK1-TBK1 complex, enhancing TRAF ubiquitination and driving NF-kB/IRF3/IRF7 activation, and it is itself a TRAF6 ubiquitination substrate; separately GALNT6 O-glycosylation was shown necessary for secretion and autocrine growth.","evidence":"Reciprocal Co-IP, ubiquitination assays, reporter assays and viral infection models; GALNT6 knockdown and O-glycosite mutagenesis with secretion/growth readouts","pmids":["31404116","31894262"],"confidence":"High","gaps":["Reconciling positive (TRAF complex) versus negative (TAK1-NF-kB suppression) effects on inflammation unresolved","Spatial topology of intracellular scaffolding for a secreted protein not explained"]},{"year":2021,"claim":"Genetic KO established LGALS3BP as a suppressor of the TAK1-NF-kB axis restraining colon inflammation and tumorigenesis, and human-genetics-coupled organoid/mouse work defined an ECM-dependent role in neural progenitor positioning and corticogenesis.","evidence":"Lgals3bp-/- colitis/tumor models with cytokine and MDSC quantification; cerebral organoids, fetal tissue, in utero mouse experiments, scRNA-seq, and de novo variant analysis","pmids":["33824294","34728600"],"confidence":"High","gaps":["Mechanism by which a secreted protein both promotes and suppresses NF-kB context-dependently unresolved","ECM partners mediating NPC anchoring not fully defined"]},{"year":2023,"claim":"Extended the TAK1-suppressive function to TNF-alpha-driven MMP9 expression in breast cancer and showed therapeutic nanoparticle delivery suppresses metastasis; separately defined an IFN-alpha-driven platelet-to-macrophage proinflammatory axis in lupus.","evidence":"Gain/loss-of-function with TAK1 phosphorylation and MMP9 readouts plus nanoparticle xenograft model; platelet RNA-seq, MEG-01 IFN-alpha dose-response, and macrophage cytokine assays","pmids":["37041137","36245285"],"confidence":"Medium","gaps":["Direct LGALS3BP-TAK1 contact vs upstream effect not distinguished","Macrophage receptor for platelet-released LGALS3BP unknown"]},{"year":2024,"claim":"Mechanistically linked LGALS3BP to fibrosis: direct integrin alphaV binding assembles integrin complexes that release active TGF-beta1 via F-actin remodeling, creating a JunB feedback loop, validated bidirectionally in mouse liver; and a CNS KO study defined a role in regulating microglial activation and neuroinflammation.","evidence":"Co-IP/LC-MS/MS, RNA-seq, ATAC-seq, conditional knockin/knockout mice and CCl4 fibrosis; spatial transcriptomics, flow cytometry, and Lgals3bp-KO WNV encephalitis model","pmids":["39073023","39062523"],"confidence":"High","gaps":["Whether integrin-alphaV/TGF-beta1 axis operates outside liver untested","Microglial mechanism downstream of LGALS3BP not defined"]},{"year":2025,"claim":"Defined transcriptional repression of LGALS3BP by ERalpha and showed its de-repression in tamoxifen-resistant breast cancer drives ECM adhesion, angiogenesis, and metastasis.","evidence":"ChIP of ERalpha at the LGALS3BP promoter, TurboID secretome labeling, shRNA knockdown, HUVEC tube formation, and xenograft metastasis model","pmids":["39789641"],"confidence":"Medium","gaps":["Direct receptor mediating pro-metastatic adhesion not defined","Interaction with prior USF/IFN regulation not integrated"]},{"year":null,"claim":"How a single secreted glycoprotein reconciles its opposing roles — pro- versus anti-inflammatory NF-kB modulation, tumor suppression versus pro-metastatic signaling — and how it accesses intracellular scaffolding and centriolar compartments despite being secreted remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model for context-dependent NF-kB outcomes","Mechanism of intracellular vs extracellular partitioning unknown","Receptor identity for several extracellular activities undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,18,20]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[14,7]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[7,14]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,23,27]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[14,21]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,18,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,20,5]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[14,15,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,13,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[21]}],"complexes":["TRAF6-TRAF3-TAK1-TBK1 innate immune complex","CD9/CD82 tetraspanin complex"],"partners":["LGALS3","LGALS1","TRAF6","TRAF3","ITGAV","CD248","VIM","ADIPOQ"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q08380","full_name":"Galectin-3-binding protein","aliases":["Basement membrane autoantigen p105","Lectin galactoside-binding soluble 3-binding protein","Mac-2-binding protein","MAC2BP","Mac-2 BP","Tumor-associated antigen 90K"],"length_aa":585,"mass_kda":65.3,"function":"Promotes integrin-mediated cell adhesion. May stimulate host defense against viruses and tumor cells","subcellular_location":"Secreted; Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q08380/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LGALS3BP","classification":"Not Classified","n_dependent_lines":66,"n_total_lines":1208,"dependency_fraction":0.054635761589403975},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LGALS3BP","total_profiled":1310},"omim":[{"mim_id":"600626","title":"LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 3 BINDING PROTEIN; LGALS3BP","url":"https://www.omim.org/entry/600626"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LGALS3BP"},"hgnc":{"alias_symbol":["MAC-2-BP","90K","BTBD17B","TANGO10B","M2BP","gp90","CyCAP"],"prev_symbol":[]},"alphafold":{"accession":"Q08380","domains":[{"cath_id":"3.10.250.10","chopping":"22-122","consensus_level":"high","plddt":92.6588,"start":22,"end":122},{"cath_id":"3.30.710.10","chopping":"130-251","consensus_level":"high","plddt":87.3892,"start":130,"end":251},{"cath_id":"1.25.40.420","chopping":"268-390","consensus_level":"high","plddt":92.7085,"start":268,"end":390},{"cath_id":"-","chopping":"412-424_455-576","consensus_level":"high","plddt":77.1184,"start":412,"end":576}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08380","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q08380-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q08380-F1-predicted_aligned_error_v6.png","plddt_mean":82.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LGALS3BP","jax_strain_url":"https://www.jax.org/strain/search?query=LGALS3BP"},"sequence":{"accession":"Q08380","fasta_url":"https://rest.uniprot.org/uniprotkb/Q08380.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q08380/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08380"}},"corpus_meta":[{"pmid":"6191218","id":"PMC_6191218","title":"Evidence 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This interaction is repulsive: adhesion of Mac-2 BP/90K-expressing tumor cells on endosialin-expressing fibroblasts yields a repulsive outcome.\",\n      \"method\": \"Affinity chromatography, biochemical binding assays with domain deletion constructs, loss-of-function adhesion experiments, in vivo expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping biochemistry plus cell-based functional assay, single lab, multiple methods\",\n      \"pmids\": [\"18490383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"90K interacts with the CD9/CD82 tetraspanin complex and suppresses Wnt/beta-catenin signaling via a novel ISG15 (ISGylation)-dependent ubiquitination/proteasomal degradation of beta-catenin that is independent of GSK-3beta and Siah/APC. In a syngeneic mouse colon tumor model, 90K knockdown increased tumor growth and lung metastasis.\",\n      \"method\": \"Co-immunoprecipitation, cell invasion assays, ISGylation pathway manipulation, syngeneic mouse tumor model, immunohistochemistry of human CRC tissues\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo KD model with defined metastasis phenotype, mechanistic pathway delineation with multiple orthogonal methods, corroborated by human tissue data\",\n      \"pmids\": [\"20581239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LGALS3BP is a centriole- and basal body-associated protein with a dual role: overexpression triggers centrosome hypertrophy, while knockdown causes accumulation of centriolar substructures (comprising CPAP, acetylated tubulin and centrin). Depletion of LGALS3BP in cells endogenously overexpressing it reverses centrosome hypertrophy.\",\n      \"method\": \"Protein-interaction network screen, siRNA knockdown, overexpression, immunofluorescence microscopy, analysis of cancer cell lines and seminoma tissue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional loss/gain-of-function with specific molecular phenotype, protein interaction network, validated in endogenous overexpression context and tissue samples\",\n      \"pmids\": [\"23443559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LGALS3BP constitutes a novel integrin ligand for integrins alpha1beta1, alpha5beta1, alphavbeta1, and alpha6beta1, and LGALS3BP-mediated integrin activation transmits signals via Akt, JNK, Ras/Raf-ERK, while keeping p38 at baseline. Sustained LGALS3BP exposure supports cell viability, motility and migration, and anti-LGALS3BP antibody SP2 impedes these signaling events.\",\n      \"method\": \"Integrin-binding assays, phosphorylation/signaling assays (Akt, JNK, ERK, p38), cell adhesion, viability, migration assays, antibody blocking experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assays plus downstream signaling readouts, antibody rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24362527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"90K/LGALS3BP is an interferon-stimulated gene product that dose-dependently decreases HIV-1 particle infectivity by impairing gp160 processing and reducing incorporation of mature gp120/gp41 into virions, without directly interacting with HIV-1 Env or entrapping Env in the ER. The two intermediate domains of 90K are sufficient for antiviral activity; the N-terminal SRCR and C-terminal domains are dispensable. siRNA knockdown of 90K in macrophages enhanced Env incorporation and HIV-1 spread.\",\n      \"method\": \"Overexpression/siRNA knockdown in producer cells, HIV-1 infectivity assays, Western blot for viral proteins, domain truncation mutants, IFN-alpha treatment of macrophages\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — domain mutagenesis, gain and loss of function, multiple cell types and orthogonal assays, mechanistic pathway defined\",\n      \"pmids\": [\"24156545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LGALS3BP is identified as a sialic acid-dependent ligand for the immunomodulatory Siglec-9 (and Siglec-5 and Siglec-10) via affinity chromatography of tumor cell extracts; LGALS3BP inhibits neutrophil activation in a sialic acid- and Siglec-dependent manner. The mouse homolog binds murine Siglec-E with lower affinity.\",\n      \"method\": \"Affinity chromatography of tumor cell extracts, Siglec binding assays, sialic acid-dependency experiments, neutrophil activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity-based identification of binding partner, functional inhibition assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25320078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LGALS3BP knockdown in MDA-MB-231 breast cancer cells decreases adhesion to fibronectin, reduces transendothelial migration, and reduces VEGF expression; VEGF production was restored by exogenous recombinant LGALS3BP and requires intact PI3K/Akt signaling. Additionally, LGALS3BP directly stimulates HUVEC tubulogenesis in a VEGF-independent, galectin-3-dependent manner.\",\n      \"method\": \"siRNA knockdown, VEGF ELISA, PI3K inhibitor rescue, HUVEC tubulogenesis assay, anti-galectin-3 blocking, adhesion and migration assays\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with specific readouts, pharmacological rescue, galectin-3-dependence shown, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22864925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LGALS3BP functions as a scaffold/adaptor protein that interacts with TRAF6, TRAF3, TAK1, and TBK1; it enhances TRAF6 and TRAF3 ubiquitination, is itself a ubiquitination substrate of TRAF6, and promotes NF-κB, IRF3, and IRF7 nuclear translocation, leading to IFN and pro-inflammatory cytokine production upon viral infection.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, overexpression, reporter assays for NF-κB/IRF3/IRF7 activity, viral infection models\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with multiple partners, ubiquitination substrate assays, bidirectional functional experiments, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"31404116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"M2BP/90K inhibits HIV-1 virion production by trapping HIV-1 Gag to vimentin filaments to inhibit Gag trafficking to the plasma membrane. M2BP interacts with both HIV-1 Gag and vimentin. Collapsing vimentin filaments (by acrylamide or dominant-negative vimentin) relieves M2BP-mediated inhibition of virion production.\",\n      \"method\": \"Co-immunoprecipitation (M2BP with Gag and vimentin), vimentin disruption experiments, HIV-1 virion production assays, dominant-negative vimentin overexpression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of three-way interaction, pharmacological and genetic rescue of the phenotype, single lab\",\n      \"pmids\": [\"27604950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The antiviral activity of 90K/LGALS3BP against HIV-1 is conserved across most primate orthologs but absent in rhesus macaque 90K. A single amino acid exchange in the BTB/POZ domain restores antiviral activity in a shortened rhesus macaque 90K. Structural analysis of BTB/POZ domains from rhesus macaque and human 90K reveals a slightly larger hydrophobic patch in rhesus macaque that may modulate protein-protein interactions. Reduction of virion-associated gp120, not merely reduced cell-surface gp120, correlates with antiviral activity.\",\n      \"method\": \"Comparative ortholog expression assays, HIV-1 infectivity assays, domain mutagenesis, X-ray crystallography of BTB/POZ domains\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus functional assay, mechanistic model validated across multiple primate orthologs\",\n      \"pmids\": [\"29743357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TAA90K/Mac-2-binding protein purified from colon cancer cells binds fibronectin, collagen IV, laminins-1/-5/-10, and galectin-3 in solid-phase assays; binding to galectin-3 is carbohydrate-dependent (inhibited by lactose and asialo-fetuin) and requires proper N-glycosylation. At low concentrations, TAA90K enhances galectin-3-mediated HT-29 cell adhesion; at high concentrations it inhibits adhesion.\",\n      \"method\": \"Protein purification from vaccinia-virus-expressed TAA90K, solid-phase binding assays, glycosylation inhibitor (1-deoxymannojirimycin), lactose inhibition, cell adhesion assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct in vitro binding assays with purified recombinant protein, glycan-dependency demonstrated, single lab\",\n      \"pmids\": [\"16518858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TAA90K/Mac-2-binding protein is a novel substrate for matrix metalloproteinases MMP-2, MMP-7, and MMP-9; MMP-7-mediated cleavage of TAA90K reduces its interaction with fibronectin and laminin-10 but not with laminin-1, collagen IV, or galectin-3. TAA90K also enhances extracellular levels of proMMP-7 in HT-29 colon cancer cells.\",\n      \"method\": \"SDS-PAGE and protein sequencing of cleavage products, solid-phase binding assays before and after cleavage, ELISA for proMMP-7 levels\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct in vitro enzymatic cleavage with protein sequencing and binding consequence assays, single lab\",\n      \"pmids\": [\"19665518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"90K promotes E-cadherin degradation via ubiquitination-mediated proteasomal degradation. 90K interacts with the E-cadherin-p120-catenin complex, induces its dissociation, and alters the phosphorylation status of p120-catenin, but does not associate with beta-catenin. This effect is cell-density-dependent and is diminished in p120-catenin knockdown cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor treatment, p120-catenin siRNA knockdown, cell adhesion and invasion assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, siRNA rescue, biochemical mechanism delineated, single lab with multiple methods\",\n      \"pmids\": [\"29207493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"90K-mediated beta-catenin degradation via ISGylation requires the N-terminal 86 amino acids of beta-catenin. 90K induces Herc5 and ISG15 expression; the N-terminus of beta-catenin is not essential for interaction with Herc5, but is required for 90K-induced degradation. 90K can degrade mutant beta-catenin lacking GSK-3beta phosphorylation sites, indicating a phosphorylation-independent degradation pathway.\",\n      \"method\": \"Beta-catenin deletion and point mutants, Western blot, co-immunoprecipitation, overexpression in HeLa and CSC221 cells\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function mutagenesis with biochemical readouts, single lab, mechanistic extension of prior work\",\n      \"pmids\": [\"27668402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LGALS3BP suppresses colon inflammation and tumorigenesis by downregulating the TAK1-NF-κB signaling axis in colon epithelial cells. Lgals3bp-/- mice show hyperactivated NF-κB, excessive pro-inflammatory cytokines (IL-6, TNFα, IL-1β), elevated GM-CSF, and accumulation of myeloid-derived suppressor cells during tumorigenesis.\",\n      \"method\": \"Lgals3bp-/- knockout mice, colitis and colon tumor models, NF-κB reporter/activation assays, cytokine measurement, MDSC quantification\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse model with defined molecular pathway (TAK1-NF-κB), multiple disease models, multiple orthogonal readouts\",\n      \"pmids\": [\"33824294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LGALS3BP suppresses TNF-alpha-mediated MMP9 gene expression in triple-negative breast cancer by inhibiting activation of TAK1 kinase, the key signaling node linking TNF-α and MMP9 expression. Nanoparticle-delivered LGALS3BP inhibits TAK1 phosphorylation and MMP9 expression in tumors and suppresses lung metastasis in vivo.\",\n      \"method\": \"LGALS3BP overexpression/knockdown, TNF-alpha stimulation, TAK1 phosphorylation assays, MMP9 reporter/ELISA, nanoparticle delivery in vivo, xenograft metastasis model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with specific kinase readout (TAK1 phosphorylation), in vivo validation, single lab with multiple methods\",\n      \"pmids\": [\"37041137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS3BP directly binds integrin αV and promotes assembly of integrin αV complexes, enabling release of active TGF-β1 from the extracellular latent complex with rearrangement of F-actin cytoskeleton. Released TGF-β1 activates JunB transcription factor, creating a positive feedback loop for TGF-β1 production. Hepatocyte-specific LGALS3BP knockin mice show aggravated liver fibrosis with increased TGF-β1; LGALS3BP knockout reduces TGF-β1 signaling and CCl4-induced fibrosis.\",\n      \"method\": \"Co-immunoprecipitation (LGALS3BP with integrin αV), LC-MS/MS proteomics, RNA-seq, ATAC-seq, conditional knockin/knockout mice, CCl4 fibrosis model, F-actin cytoskeleton analysis\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding assay, multi-omics, bidirectional genetic mouse models, mechanistic pathway fully delineated with multiple orthogonal methods\",\n      \"pmids\": [\"39073023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LGALS3BP is a secreted protein enriched in human neural progenitor cells (NPCs) that regulates the position of NPCs; LGALS3BP-mediated mechanisms involve the extracellular matrix in NPC anchoring and migration. Its temporal expression influences NPC delamination, corticogenesis, and gyrification, demonstrated in cerebral organoids, human fetal tissue, and mouse models.\",\n      \"method\": \"Cerebral organoids, human fetal tissue analysis, mouse in utero experiments, single-cell RNA-sequencing, proteomics, analysis of individuals with de novo LGALS3BP variants\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple complementary model systems (organoids, fetal tissue, mice, human genetics), proteomics plus scRNA-seq, mechanistic link to ECM established\",\n      \"pmids\": [\"34728600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WFA+-M2BP (glycosylated LGALS3BP) is secreted by hepatic stellate cells (HSCs). Exogenous WFA+-M2BP stimulation enhances Mac-2/galectin-3 expression in Kupffer cells; Mac-2-depleted Kupffer cells (siRNA) show reduced alpha-smooth muscle actin expression when co-cultured with HSCs, establishing a paracrine circuit: HSC-secreted LGALS3BP→Kupffer cell Mac-2 expression→Kupffer cell activation→HSC fibrogenic activation.\",\n      \"method\": \"Subpopulation cell culture with sandwich immunoassay, siRNA knockdown of Mac-2 in Kupffer cells, co-culture experiments, immunoblot, liver tissue immunohistochemistry\",\n      \"journal\": \"Journal of gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific source identified, siRNA rescue in co-culture, paracrine mechanism delineated, single lab\",\n      \"pmids\": [\"28008658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The 90K protein domain structure was mapped: an N-terminal SRCR-like domain (D1), a heavily glycosylated mucin-like domain (D2), and a ~27 kDa C-terminal domain (D3). Monoclonal antibodies SP2 and L3 both recognize D2. Point mutations at residues 189, 223, and 259 and a truncated form (aa 1-383) are defective in secretion, identifying specific residues required for normal processing and secretion.\",\n      \"method\": \"Ig fusion protein construction with domain deletions, monoclonal antibody epitope mapping, COS-1 cell expression, secretion assays with point mutants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — domain mapping with deletion constructs and point mutagenesis, functional secretion readout, single lab\",\n      \"pmids\": [\"9125183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The human 90K promoter is TATA-less, lacks GC-richness and SP1 dependence, has a minimal promoter of 51 bp, and contains an interferon regulatory factor element (IRF-E) required for induction by poly(I:C) (viral mimic) and interferon-gamma. Two regions mediating poly(I:C) induction were identified by deletion analysis.\",\n      \"method\": \"Promoter deletion analysis, RNase protection assay for transcription start sites, point mutations in the IRF-E, poly(I:C) stimulation, reporter gene assays\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — systematic deletion and point-mutation analysis of promoter elements, functional reporter assays, single lab\",\n      \"pmids\": [\"10198166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Constitutive expression of 90K/LGALS3BP depends on upstream stimulatory factor (USF) binding to an E-box in the minimal promoter. Hormonal suppression (TSH/cAMP plus insulin/IGF-I) of constitutive and IFN-gamma-induced 90K expression occurs via decreased USF binding to this E-box. Transfection with USF1/USF2 cDNAs increases constitutive promoter activity and attenuates hormonal suppression.\",\n      \"method\": \"Promoter cloning, EMSA (electrophoretic mobility shift assay) for USF binding, transfection with USF1/USF2 expression plasmids, reporter gene assays, TSH/cAMP/insulin treatments\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — EMSA plus gain-of-function transfection rescue, pharmacological manipulation, single lab\",\n      \"pmids\": [\"17446190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Exposure of the human breast cancer cell line EVSA-T to purified 90K protein causes approximately sixfold increase in MHC class I expression as measured by flow cytometry, demonstrating a direct effect of secreted 90K on immune recognition molecules.\",\n      \"method\": \"Purified 90K protein treatment of cancer cells, flow cytometry for MHC class I expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional assay with purified protein, no mechanism further defined, single lab\",\n      \"pmids\": [\"8753808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GALNT6 O-glycosylates LGALS3BP at three sites (T556, T571, S582), and this O-glycosylation is required for LGALS3BP secretion and autocrine growth promotion in breast cancer cells. Triple Ala substitution (T556A/T571A/S582A) drastically reduces GALNT6-dependent LGALS3BP O-glycosylation and secretion, suppressing autocrine growth.\",\n      \"method\": \"GALNT6 siRNA knockdown, O-glycosylation site mutagenesis (T→A substitutions), LGALS3BP secretion assay, cell growth assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-specific mutagenesis of glycosylation sites with functional secretion and growth readout, single lab\",\n      \"pmids\": [\"31894262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mac-2 binding protein (M2BP) is identified as a novel serum adiponectin-binding protein by immunoprecipitation with anti-adiponectin antibody followed by mass spectrometry; the M2BP-APN association was confirmed with reconstituted proteins in vitro. M2BP abrogates the suppressive effect of adiponectin on TNF-alpha-induced inflammation in vascular endothelial cells.\",\n      \"method\": \"Immunoprecipitation with anti-adiponectin antibody, mass spectrometry, in vitro reconstitution with purified proteins, endothelial cell inflammation assay\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — immunoprecipitation plus in vitro reconstitution of binding, functional consequence shown, single lab\",\n      \"pmids\": [\"27588936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In platelets from SLE patients, interferon-alpha induces LGALS3BP transcription and translation in megakaryoblastic cells in a dose-dependent manner. Platelet-released LGALS3BP and recombinant LGALS3BP enhance proinflammatory cytokine production by macrophages, establishing a platelet-to-macrophage proinflammatory signaling role for LGALS3BP.\",\n      \"method\": \"RNA sequencing of SLE patient platelets, IFN-alpha treatment of MEG-01 cells, ELISA for platelet releasate LGALS3BP, macrophage cytokine production assays with recombinant LGALS3BP\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic in vitro experiments with recombinant protein and cell-based assays, IFN-alpha dose-response, single lab\",\n      \"pmids\": [\"36245285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS3BP is broadly expressed in the CNS and upregulated during WNV infection and aging; Lgals3bp-deficient mice exhibit reduced neuroinflammation, increased homeostatic microglial numbers, and altered T cell populations after WNV encephalitis recovery, without differences in virologic control or survival, indicating a role in regulating microglial activation and neuroinflammation.\",\n      \"method\": \"Spatial transcriptomics, RNA sequencing, flow cytometry, Lgals3bp-knockout mouse model, WNV infection model\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO model with defined cellular phenotypes (microglial numbers, T cell populations), multiple transcriptomic methods, single lab\",\n      \"pmids\": [\"39062523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LGALS3BP expression in tamoxifen-resistant breast cancer is suppressed by estrogen signaling through direct ERα binding to the LGALS3BP promoter. Secreted LGALS3BP promotes adhesion to the extracellular matrix and HUVEC tube formation. LGALS3BP knockdown in tamoxifen-resistant cells completely abrogated increased pulmonary metastasis in xenograft experiments.\",\n      \"method\": \"Chromatin immunoprecipitation (ERα to LGALS3BP promoter), TurboID secretome labeling, shRNA knockdown, HUVEC tube formation assay, xenograft metastasis model\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for transcriptional regulation, in vivo KD with defined metastasis phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39789641\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGALS3BP (90K/Mac-2 BP) is a secreted, heavily glycosylated SRCR-domain glycoprotein whose O-glycosylation by GALNT6 at defined sites is required for its secretion; it functions extracellularly as a ligand for galectin-1, galectin-3, multiple beta1-integrins (alpha1beta1, alpha5beta1, alphavbeta1, alpha6beta1), integrin αV, endosialin (Tem1), sialic acid-dependent Siglecs (Siglec-5/-9/-10), and adiponectin, and binds ECM proteins (fibronectin, collagens, laminins); intracellularly it acts as a scaffold/adaptor for the TRAF6-TRAF3-TAK1-TBK1 innate immune complex to promote NF-κB and IRF3/IRF7 activation, suppresses Wnt/β-catenin signaling via ISGylation-dependent proteasomal degradation of β-catenin through the CD9/CD82 tetraspanin complex, suppresses TAK1-NF-κB-dependent inflammation and colon tumorigenesis, inhibits HIV-1 particle infectivity by impairing gp160 processing and Env incorporation into virions (function requiring the BTB/POZ intermediate domain), traps HIV-1 Gag to vimentin filaments to reduce virion production, regulates centriole biogenesis and centrosome morphology, activates TGF-β1 release via integrin αV engagement and F-actin remodeling in liver fibrosis, promotes E-cadherin degradation via p120-catenin dissociation, and influences neural progenitor cell positioning and cortical development through extracellular matrix interactions; its expression is transcriptionally induced by interferons and viral dsRNA through an IRF-E and USF-binding E-box in its TATA-less promoter, and is suppressed by estrogen receptor signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LGALS3BP (90K/Mac-2 binding protein) is a secreted, heavily glycosylated SRCR-domain glycoprotein that operates at the interface of innate immunity, cell adhesion, and tumor progression [#0, #14]. Its three-domain architecture (N-terminal SRCR domain, glycosylated mucin-like domain, C-terminal domain) was mapped early, with specific residues required for proper secretion [#23]; secretion depends on GALNT6-mediated O-glycosylation at T556/T571/S582, which is in turn required for its autocrine growth-promoting activity [#27]. Extracellularly, LGALS3BP is a multivalent ligand: it binds galectin-1 and galectin-3 [#3, #14], ECM proteins including fibronectin, collagen IV, and laminins [#14], beta1-integrins and integrin alphaV [#7, #20], endosialin/Tem1 [#4], sialic acid-dependent Siglecs to inhibit neutrophil activation [#9], and adiponectin, blocking its anti-inflammatory effect [#28]; it is also a substrate of MMP-2/-7/-9, whose cleavage modulates its ECM binding [#15]. Through integrin engagement it transmits Akt, JNK, and Ras/Raf-ERK signals supporting cell viability and migration [#7], and via direct integrin alphaV binding it drives F-actin remodeling and release of active TGF-beta1, establishing a JunB-dependent feedback loop that aggravates liver fibrosis [#20]. As an interferon- and viral-dsRNA-inducible gene controlled by an IRF-E and USF/E-box in its TATA-less promoter [#24, #25], LGALS3BP acts intracellularly as a scaffold/adaptor for the TRAF6-TRAF3-TAK1-TBK1 complex, promoting NF-kB and IRF3/IRF7 activation and antiviral/proinflammatory cytokine production [#11], yet it conversely restrains the TAK1-NF-kB axis to suppress colon inflammation and tumorigenesis [#18, #19]. It restricts HIV-1 by impairing gp160 processing and Env incorporation into virions through its intermediate/BTB-POZ domains [#8, #13] and by trapping Gag on vimentin filaments to limit virion production [#12]. LGALS3BP additionally suppresses Wnt/beta-catenin signaling via ISGylation-dependent proteasomal degradation of beta-catenin through the CD9/CD82 tetraspanin complex [#5, #17], promotes E-cadherin degradation via p120-catenin dissociation [#16], regulates centriole biogenesis and centrosome morphology [#6], and controls neural progenitor positioning and corticogenesis through ECM interactions [#21].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Established that 90K is not constitutive but an inducible secreted product, placing it downstream of interferon signaling — a regulatory anchor for all later innate-immunity work.\",\n      \"evidence\": \"rIFN-alpha 2b treatment of breast cancer cells with conditioned-media immunoassay and cycloheximide block\",\n      \"pmids\": [\"3403063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Promoter elements mediating induction not yet defined\", \"Did not address function of the secreted protein\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defined 90K as a secreted SRCR-domain glycoprotein with immunostimulatory activity, framing it as an effector of host immune defense rather than a passive serum marker.\",\n      \"evidence\": \"Antibody-based purification, Northern blot, and NK/LAK functional and cytokine-induction assays\",\n      \"pmids\": [\"8034587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular receptors mediating NK/LAK stimulation unknown\", \"Direct vs indirect immune effect unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Resolved the three-domain architecture and identified residues required for secretion, providing the structural framework for later domain-mapping of ligand binding and antiviral activity.\",\n      \"evidence\": \"Domain-deletion Ig fusion constructs, mAb epitope mapping, and point-mutant secretion assays in COS-1 cells\",\n      \"pmids\": [\"9125183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional assignment of each domain not established here\", \"Glycosylation requirement for secretion not yet linked to specific enzymes\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapped the TATA-less promoter and the IRF-E required for poly(I:C)/IFN-gamma induction, mechanistically explaining the interferon-stimulated-gene behavior of LGALS3BP.\",\n      \"evidence\": \"Promoter deletion, RNase protection, and IRF-E point-mutation reporter assays under poly(I:C) stimulation\",\n      \"pmids\": [\"10198166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors binding the IRF-E not identified\", \"Constitutive expression control not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed galectin-1 binds 90K at a site distinct from galectin-3 with measured affinity, establishing 90K as a bivalent galectin ligand mediating cell aggregation.\",\n      \"evidence\": \"Solid-phase binding with Kd determination, non-competition assay, and antibody-blocked melanoma aggregation\",\n      \"pmids\": [\"11146440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Glycan dependence of galectin-1 binding not dissected\", \"Downstream signaling of aggregation unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the ECM/galectin-3 ligand repertoire and its glycan dependence, and revealed concentration-dependent biphasic effects on cell adhesion.\",\n      \"evidence\": \"Solid-phase binding with purified recombinant 90K, glycosylation-inhibitor and lactose controls, adhesion assays\",\n      \"pmids\": [\"16518858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of biphasic adhesion in vivo unclear\", \"Receptors for ECM-bridging not all defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified endosialin as a C-terminal-domain binding partner producing repulsive tumor-cell/stromal interactions, extending the ligand map to the stromal compartment.\",\n      \"evidence\": \"Affinity chromatography, domain-deletion binding, and loss-of-function adhesion assays\",\n      \"pmids\": [\"18490383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling basis of repulsion not defined\", \"In vivo consequence for metastasis untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed an intracellular tumor-suppressive function: LGALS3BP drives ISGylation-dependent, GSK-3beta-independent beta-catenin degradation via the CD9/CD82 complex, with knockdown promoting tumor growth and metastasis.\",\n      \"evidence\": \"Reciprocal Co-IP, ISGylation manipulation, invasion assays, and a syngeneic colon tumor model\",\n      \"pmids\": [\"20581239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase/ISGylation machinery details not fully defined here\", \"How a secreted glycoprotein acts intracellularly unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked LGALS3BP to angiogenesis and breast cancer dissemination via fibronectin adhesion, PI3K/Akt-dependent VEGF induction, and galectin-3-dependent endothelial tubulogenesis.\",\n      \"evidence\": \"siRNA knockdown, VEGF ELISA, PI3K inhibitor rescue, HUVEC tubulogenesis, and galectin-3 blocking\",\n      \"pmids\": [\"22864925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor coupling LGALS3BP to PI3K/Akt not defined\", \"VEGF-independent tubulogenesis mechanism incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established LGALS3BP as a direct multi-integrin ligand transmitting pro-survival/pro-migratory signals, and as a centriole/basal-body protein controlling centrosome number — two distinct cell-autonomous roles.\",\n      \"evidence\": \"Integrin-binding and phospho-signaling assays with antibody blocking; siRNA/overexpression with immunofluorescence of centriolar markers\",\n      \"pmids\": [\"24362527\", \"23443559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Connection between extracellular integrin role and centriolar role unknown\", \"Centriolar interactors beyond CPAP/centrin not enumerated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined LGALS3BP as an interferon-induced HIV-1 restriction factor acting by impairing gp160 processing and Env incorporation, localizing the activity to its two intermediate domains.\",\n      \"evidence\": \"Gain/loss-of-function in producer cells, infectivity assays, viral protein blotting, and domain truncation mutants\",\n      \"pmids\": [\"24156545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target in the Env processing pathway not identified\", \"Whether restriction operates in vivo untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified LGALS3BP as a sialic acid-dependent Siglec ligand that dampens neutrophil activation, adding an immunosuppressive arm to its extracellular function.\",\n      \"evidence\": \"Affinity chromatography of tumor-cell extracts, Siglec binding, and sialic-acid-dependent neutrophil activation assays\",\n      \"pmids\": [\"25320078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of Siglec engagement untested\", \"Which sialoglycans on LGALS3BP mediate binding not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Refined the beta-catenin degradation mechanism to the N-terminal 86 residues of beta-catenin via Herc5/ISG15 induction, confirming a phosphorylation-independent route; separately defined a second HIV restriction mechanism (Gag trapping on vimentin) and identified adiponectin as a binding partner whose anti-inflammatory action LGALS3BP blocks.\",\n      \"evidence\": \"beta-catenin deletion/point mutants and Co-IP; three-way Co-IP with Gag/vimentin plus vimentin-disruption rescue; anti-adiponectin IP/MS with reconstitution and endothelial inflammation assay\",\n      \"pmids\": [\"27668402\", \"27604950\", \"27588936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Coordination between the two distinct HIV-restriction mechanisms unclear\", \"Stoichiometry of adiponectin sequestration in vivo unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed LGALS3BP promotes proteasomal E-cadherin degradation by dissociating the E-cadherin/p120-catenin complex in a density- and p120-dependent manner, distinguishing this from its beta-catenin pathway; and identified hepatic stellate cells as a source feeding a paracrine Kupffer-cell activation circuit.\",\n      \"evidence\": \"Co-IP, ubiquitination and proteasome-inhibitor assays, p120-catenin knockdown; subpopulation co-culture with Mac-2 knockdown in Kupffer cells\",\n      \"pmids\": [\"29207493\", \"28008658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase for E-cadherin degradation not identified\", \"Receptor mediating Kupffer-cell Mac-2 induction unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided crystallographic and cross-ortholog evidence that the BTB/POZ domain governs HIV-1 restriction, with a single residue change restoring activity in rhesus 90K, tying structure to antiviral function.\",\n      \"evidence\": \"Comparative ortholog infectivity assays, domain mutagenesis, and X-ray crystallography of BTB/POZ domains\",\n      \"pmids\": [\"29743357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct protein-protein interaction the hydrophobic patch mediates not identified\", \"Full-length structure unavailable\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the intracellular innate-immune scaffolding function: LGALS3BP nucleates the TRAF6-TRAF3-TAK1-TBK1 complex, enhancing TRAF ubiquitination and driving NF-kB/IRF3/IRF7 activation, and it is itself a TRAF6 ubiquitination substrate; separately GALNT6 O-glycosylation was shown necessary for secretion and autocrine growth.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, reporter assays and viral infection models; GALNT6 knockdown and O-glycosite mutagenesis with secretion/growth readouts\",\n      \"pmids\": [\"31404116\", \"31894262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling positive (TRAF complex) versus negative (TAK1-NF-kB suppression) effects on inflammation unresolved\", \"Spatial topology of intracellular scaffolding for a secreted protein not explained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic KO established LGALS3BP as a suppressor of the TAK1-NF-kB axis restraining colon inflammation and tumorigenesis, and human-genetics-coupled organoid/mouse work defined an ECM-dependent role in neural progenitor positioning and corticogenesis.\",\n      \"evidence\": \"Lgals3bp-/- colitis/tumor models with cytokine and MDSC quantification; cerebral organoids, fetal tissue, in utero mouse experiments, scRNA-seq, and de novo variant analysis\",\n      \"pmids\": [\"33824294\", \"34728600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which a secreted protein both promotes and suppresses NF-kB context-dependently unresolved\", \"ECM partners mediating NPC anchoring not fully defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the TAK1-suppressive function to TNF-alpha-driven MMP9 expression in breast cancer and showed therapeutic nanoparticle delivery suppresses metastasis; separately defined an IFN-alpha-driven platelet-to-macrophage proinflammatory axis in lupus.\",\n      \"evidence\": \"Gain/loss-of-function with TAK1 phosphorylation and MMP9 readouts plus nanoparticle xenograft model; platelet RNA-seq, MEG-01 IFN-alpha dose-response, and macrophage cytokine assays\",\n      \"pmids\": [\"37041137\", \"36245285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LGALS3BP-TAK1 contact vs upstream effect not distinguished\", \"Macrophage receptor for platelet-released LGALS3BP unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mechanistically linked LGALS3BP to fibrosis: direct integrin alphaV binding assembles integrin complexes that release active TGF-beta1 via F-actin remodeling, creating a JunB feedback loop, validated bidirectionally in mouse liver; and a CNS KO study defined a role in regulating microglial activation and neuroinflammation.\",\n      \"evidence\": \"Co-IP/LC-MS/MS, RNA-seq, ATAC-seq, conditional knockin/knockout mice and CCl4 fibrosis; spatial transcriptomics, flow cytometry, and Lgals3bp-KO WNV encephalitis model\",\n      \"pmids\": [\"39073023\", \"39062523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether integrin-alphaV/TGF-beta1 axis operates outside liver untested\", \"Microglial mechanism downstream of LGALS3BP not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined transcriptional repression of LGALS3BP by ERalpha and showed its de-repression in tamoxifen-resistant breast cancer drives ECM adhesion, angiogenesis, and metastasis.\",\n      \"evidence\": \"ChIP of ERalpha at the LGALS3BP promoter, TurboID secretome labeling, shRNA knockdown, HUVEC tube formation, and xenograft metastasis model\",\n      \"pmids\": [\"39789641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor mediating pro-metastatic adhesion not defined\", \"Interaction with prior USF/IFN regulation not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single secreted glycoprotein reconciles its opposing roles — pro- versus anti-inflammatory NF-kB modulation, tumor suppression versus pro-metastatic signaling — and how it accesses intracellular scaffolding and centriolar compartments despite being secreted remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model for context-dependent NF-kB outcomes\", \"Mechanism of intracellular vs extracellular partitioning unknown\", \"Receptor identity for several extracellular activities undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 18, 20]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [14, 7]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [7, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 23, 27]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [14, 21]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 18, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 20, 5]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [14, 15, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 13, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"complexes\": [\n      \"TRAF6-TRAF3-TAK1-TBK1 innate immune complex\",\n      \"CD9/CD82 tetraspanin complex\"\n    ],\n    \"partners\": [\n      \"LGALS3\",\n      \"LGALS1\",\n      \"TRAF6\",\n      \"TRAF3\",\n      \"ITGAV\",\n      \"CD248\",\n      \"VIM\",\n      \"ADIPOQ\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}