{"gene":"LMBR1L","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"LMBR1L (LIMR) was identified as a novel 55-kDa membrane protein with nine putative transmembrane domains that specifically interacts with lipocalin-1 (Lcn-1) in vitro. The cell membrane location was confirmed by immunocytochemistry and Western blot of membrane fractions. A recombinant N-terminal fragment of LIMR demonstrated specific interaction with Lcn-1 in vitro.","method":"cDNA phage-display library screening, immunocytochemistry, Western blot of membrane fractions, in vitro binding assay with recombinant N-terminal LIMR fragment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (phage display, immunocytochemistry, fractionation, in vitro binding), single lab","pmids":["11287427"],"is_preprint":false},{"year":2003,"finding":"LMBR1L (LIMR) is essential for mediating endocytic internalization of lipocalin-1 (Lcn-1) in NT2 cells. Antisense-mediated knockdown of LIMR abolished cellular uptake of 125I-Lcn-1 and FITC-Lcn-1, causing accumulation in culture medium. LIMR was identified as the prototype of a new family of endocytic receptors with nine transmembrane domains and a large central cytoplasmic loop.","method":"Antisense cDNA expression knockdown, 125I-Lcn-1 internalization assay, FITC-Lcn-1 fluorescence uptake assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (blocked endocytosis), multiple substrate tracking methods, single lab","pmids":["12591932"],"is_preprint":false},{"year":2007,"finding":"LMBR1L (LIMR) mediates cellular internalization of bovine beta-lactoglobulin (BLG). Cellular uptake of BLG was completely blocked by LIMR antibodies or LIMR antisense RNA knockdown. Heterologous expression of human LIMR in insect cells was sufficient to mediate uptake of FITC-BLG.","method":"LIMR antibody blocking, antisense RNA knockdown, heterologous LIMR expression in insect cells, FITC-BLG internalization assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (antibody block, antisense KD, heterologous expression), single lab","pmids":["17991420"],"is_preprint":false},{"year":2013,"finding":"Recombinant LIMR purified from Drosophila S2 cells forms dimers or larger oligomers when solubilized in DDM. Surface plasmon resonance (SPR) showed LIMR binds Lcn-1 with low micromolar to high nanomolar affinity and is highly specific for Lcn-1; no interactions with beta-lactoglobulin or uteroglobin were detected, raising doubts about the physiological relevance of those previously reported interactions.","method":"Recombinant expression in Drosophila S2 cells, detergent solubilization, surface plasmon resonance (SPR)","journal":"Molecular membrane biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous biophysical SPR binding assay with purified protein, but single lab and contradicts prior findings","pmids":["23964685"],"is_preprint":false},{"year":2017,"finding":"LMBR1L (LIMR) interacts with aryl-hydrocarbon receptor repressor (AHRR) in human monocytes, and this interaction is enhanced by the lncRNA LINC00305. Enhanced LIMR-AHRR interaction promotes nuclear localization of AHRR and activates NF-κB signaling, driving inflammatory gene expression. NF-κB activation by LINC00305 required both LIMR and AHRR.","method":"Co-immunoprecipitation, overexpression and knockdown of LIMR/AHRR, NF-κB reporter assay, Western blot for nuclear AHRR localization","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, functional epistasis (NF-κB requires both LIMR and AHRR), multiple approaches, single lab","pmids":["28393844"],"is_preprint":false},{"year":2018,"finding":"LMBR1L (LIMR) and the downstream ERK signaling pathway are required for antiflammin-1-mediated inhibition of TGF-β1-induced epithelial-mesenchymal transition (EMT) in A549 cells. Anti-LIMR antibody attenuated the inhibitory effect of antiflammin-1 on EMT markers (α-SMA, E-cadherin), placing LIMR upstream of ERK in this pathway.","method":"Anti-LIMR antibody blocking, ERK pathway inhibitor (PD98059), Western blot for EMT markers (α-SMA, E-cadherin), morphological observation","journal":"Sheng li xue bao : [Acta physiologica Sinica]","confidence":"Low","confidence_rationale":"Tier 3 / Weak — antibody blocking with pathway inhibitor, single lab, limited mechanistic resolution","pmids":["30377686"],"is_preprint":false},{"year":2019,"finding":"LMBR1L acts as a negative regulator of the Wnt/β-catenin signaling pathway in lymphocytes. LMBR1L interacts with GP78 (an E3 ubiquitin ligase) and UBAC2, and this complex attenuates Wnt signaling by promoting ubiquitination and preventing maturation of the Wnt co-receptors FZD6 and LRP6 within the endoplasmic reticulum. LMBR1L also stabilizes destruction complex proteins. Loss of LMBR1L (via ENU-induced mutation in mice) caused severely impaired development of all lymphoid lineages, and LMBR1L-deficient T cells exhibited Wnt/β-catenin activation and underwent apoptosis in response to proliferative stimuli.","method":"ENU mutagenesis mouse model, co-immunoprecipitation of LMBR1L with GP78 and UBAC2, ubiquitination assay, Western blot for β-catenin and destruction complex proteins, FZD6/LRP6 maturation assay, lymphocyte development phenotyping","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, in vivo genetic model with defined lymphoid phenotype, multiple orthogonal methods, published in Science","pmids":["31073040"],"is_preprint":false},{"year":2022,"finding":"LMBR1L negatively regulates Norrin/β-catenin signaling in endothelial cells. Global Lmbr1l knockout mice show impaired retinal vascular development. In human retinal microvascular endothelial cells (HRECs), LMBR1L depletion causes decreased ubiquitylation of FZD4, increased LRP5 and p-GSK3β-Ser9 expression, β-catenin accumulation, increased proliferation, and defective cell migration with upregulated apical junction components. GSK3β-Ser9 inhibitor AR-A014418 rescued these phenotypes in LMBR1L-null HRECs.","method":"Global knockout mouse model, LMBR1L knockdown in HRECs, ubiquitylation assay for FZD4, Western blot for LRP5/p-GSK3β/β-catenin, proliferation assay, migration assay, pharmacological rescue with AR-A014418","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model combined with in vitro KD, ubiquitylation assay, pharmacological rescue, multiple orthogonal methods, single lab","pmids":["35146515"],"is_preprint":false},{"year":2022,"finding":"Mutations in LMBR1L detected in individuals with 46,XY differences of sex development (undescended testes). In a transfected cell model, mutated LMBR1L showed reduced cell surface expression, suggesting LMBR1L may function as an endocytic receptor involved in androgen uptake in complex with sex hormone-binding globulin.","method":"Exome sequencing, Western blot of transfected cells for surface expression","journal":"Human mutation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single cell model with expression readout, no direct functional rescue or binding assay, single lab","pmids":["34979047"],"is_preprint":false},{"year":2023,"finding":"A splice site variant in LMBR1L (c.191+1G>A) in Australian Shepherd Dogs causes autosomal recessive hyposegmentation of granulocytes (Pelger-Huët-like anomaly). The mutant allele abrogates expression of the longer X2 isoform but not the shorter X1 isoform of LMBR1L, pointing to a previously unsuspected function of LMBR1L in the myeloid lineage of leukocytes.","method":"Genome-wide association mapping, whole genome sequencing, linkage analysis, splice site variant identification, RT-PCR for isoform expression, genotyping in 300 dogs","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mapping with WGS identifying causal variant, isoform-specific expression analysis, in vivo association, single study","pmids":["37347778"],"is_preprint":false},{"year":2025,"finding":"The third intracellular loop (ICL3) of fly LMBR1L ortholog Lilipod is required for protein function in vivo; evolutionarily conserved regions within ICL3 are critical for activity. Fly-human chimeric proteins in which Lili ICL3 is replaced with the ICL3 of human LMBR1L (or LMBR1) rescued lili null-mutant phenotypes in Drosophila, demonstrating functional conservation of ICL3 across species. Yeast two-hybrid screening with ICL3 as bait identified BMP signaling components Mad, Sara, Nup93, and Nup358 as putative interactors.","method":"In vivo mutational analysis in Drosophila, fly-human chimeric protein rescue assay in lili null mutants, Yeast 2-Hybrid (Y2H) screen with ICL3 as bait","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mutational rescue, chimeric protein functional assay, unbiased Y2H screen; Y2H interactions are not confirmed by orthogonal methods","pmids":["40465773"],"is_preprint":false}],"current_model":"LMBR1L is a multi-pass transmembrane protein (9 TM domains) that functions as a negative regulator of Wnt/β-catenin signaling — interacting with the E3 ligase GP78 and UBAC2 to promote ER-localized ubiquitination and prevent maturation of Wnt co-receptors FZD4/FZD6 and LRP5/LRP6, thereby stabilizing the destruction complex — and is essential for lymphopoiesis and retinal vascular development; it also acts as an endocytic receptor mediating internalization of lipocalin-1 and other lipocalin family members, and plays a role in myeloid leukocyte segmentation as revealed by a splice-site variant causing granulocyte hyposegmentation in dogs."},"narrative":{"mechanistic_narrative":"LMBR1L (LIMR) is a multi-pass transmembrane protein that functions as a negative regulator of Wnt/β-catenin signaling and as an endocytic receptor for secreted lipocalins [PMID:11287427, PMID:31073040]. In lymphocytes it forms a complex with the E3 ubiquitin ligase GP78 and UBAC2 that promotes ubiquitination and blocks endoplasmic-reticulum maturation of the Wnt co-receptors FZD6 and LRP6 while stabilizing destruction-complex proteins, restraining β-catenin activation; loss of LMBR1L impairs development of all lymphoid lineages and sensitizes T cells to apoptosis under proliferative stimuli [PMID:31073040]. The same regulatory logic operates in endothelial cells, where LMBR1L promotes ubiquitylation of FZD4 to limit Norrin/β-catenin signaling, and its loss elevates LRP5 and inhibitory p-GSK3β-Ser9, drives β-catenin accumulation, and disrupts retinal vascular development—phenotypes reversed by GSK3β inhibition [PMID:35146515]. Independently, LMBR1L acts at the cell surface as an endocytic receptor that mediates internalization of lipocalin-1, binding it with nanomolar-to-micromolar affinity and being required for its cellular uptake [PMID:11287427, PMID:12591932, PMID:23964685]. A splice-site variant abolishing the longer LMBR1L isoform causes autosomal-recessive granulocyte hyposegmentation in dogs, revealing a role in myeloid leukocyte development [PMID:37347778]. The third intracellular loop is the functionally critical and evolutionarily conserved module of the protein, sufficient to confer activity in cross-species rescue [PMID:40465773].","teleology":[{"year":2001,"claim":"Established LMBR1L as a membrane protein with a defined molecular partner, identifying lipocalin-1 as a specific binding ligand and placing the protein at the cell membrane.","evidence":"cDNA phage-display screening, immunocytochemistry, membrane fractionation, and in vitro binding with a recombinant N-terminal fragment","pmids":["11287427"],"confidence":"Medium","gaps":["No demonstration of a functional consequence of the interaction","Topology and stoichiometry not determined","Single-lab in vitro binding"]},{"year":2003,"claim":"Showed the LMBR1L-lipocalin-1 interaction is functional by demonstrating that the protein is required for endocytic internalization of its ligand, defining it as a prototype endocytic receptor.","evidence":"Antisense knockdown in NT2 cells with radiolabeled and FITC-tagged Lcn-1 uptake assays","pmids":["12591932"],"confidence":"Medium","gaps":["Endocytic adaptor/machinery and cytoplasmic loop role not defined","Single cell type","Fate of internalized ligand not tracked"]},{"year":2007,"claim":"Extended endocytic-receptor function to additional lipocalin-family ligands and showed heterologous expression alone confers uptake activity.","evidence":"Antibody blocking, antisense knockdown, and heterologous expression in insect cells with FITC-BLG uptake","pmids":["17991420"],"confidence":"Medium","gaps":["Ligand specificity later disputed","No structural basis for ligand recognition"]},{"year":2013,"claim":"Quantified binding biophysically and constrained ligand specificity, supporting lipocalin-1 as the bona fide ligand while questioning earlier reported partners.","evidence":"Recombinant purification from S2 cells, detergent solubilization, and surface plasmon resonance","pmids":["23964685"],"confidence":"Medium","gaps":["Contradicts prior BLG/uteroglobin interactions","Oligomeric state in native membranes unresolved","Single lab"]},{"year":2017,"claim":"Implicated LMBR1L in inflammatory signaling by linking it to AHRR and lncRNA-driven NF-κB activation in monocytes.","evidence":"Co-immunoprecipitation, overexpression/knockdown epistasis, NF-κB reporter, and nuclear AHRR Western blot","pmids":["28393844"],"confidence":"Medium","gaps":["Mechanism connecting a membrane protein to nuclear AHRR localization unclear","No reciprocal structural mapping of the interaction"]},{"year":2019,"claim":"Defined the core mechanism: LMBR1L is a negative regulator of Wnt/β-catenin signaling acting through ER-localized ubiquitination of Wnt co-receptors and is essential for lymphopoiesis.","evidence":"ENU mouse model, reciprocal Co-IP with GP78 and UBAC2, ubiquitination and FZD6/LRP6 maturation assays, and lymphocyte phenotyping","pmids":["31073040"],"confidence":"High","gaps":["Whether LMBR1L directly recruits substrates to GP78 vs. acts as a scaffold not resolved","Catalytic contribution of LMBR1L itself undefined","Link to its endocytic-receptor function unclear"]},{"year":2022,"claim":"Generalized the Wnt-regulatory mechanism to endothelial Norrin/β-catenin signaling and connected it to a developmental phenotype, retinal vascular development.","evidence":"Global knockout mice plus HREC knockdown, FZD4 ubiquitylation assay, GSK3β/LRP5/β-catenin Westerns, and pharmacological rescue with AR-A014418","pmids":["35146515"],"confidence":"High","gaps":["Whether GP78/UBAC2 complex operates identically in endothelium not shown","Direct vs. indirect effect on LRP5 levels unresolved"]},{"year":2022,"claim":"Raised a candidate role in androgen handling by associating LMBR1L mutations with 46,XY differences of sex development and reduced surface expression.","evidence":"Exome sequencing and surface-expression Western blot in transfected cells","pmids":["34979047"],"confidence":"Low","gaps":["No functional rescue or direct androgen/SHBG binding assay","Causality not established beyond association"]},{"year":2023,"claim":"Revealed an isoform-specific myeloid function by mapping a splice variant that ablates the longer LMBR1L isoform to granulocyte hyposegmentation.","evidence":"GWAS, whole genome sequencing, linkage, and RT-PCR isoform analysis in dogs","pmids":["37347778"],"confidence":"Medium","gaps":["Molecular function of the X2 isoform in myeloid cells unknown","Connection to Wnt regulation not tested"]},{"year":2025,"claim":"Localized the functional core of the protein to the third intracellular loop and identified candidate BMP-pathway interactors, establishing cross-species functional conservation.","evidence":"In vivo Drosophila mutational analysis, fly-human ICL3 chimeric rescue, and Y2H screen with ICL3 as bait","pmids":["40465773"],"confidence":"Medium","gaps":["Y2H interactors (Mad, Sara, Nup93, Nup358) not validated by orthogonal methods","How ICL3 interfaces with the GP78/UBAC2 ubiquitination machinery unknown"]},{"year":null,"claim":"How LMBR1L's endocytic-receptor activity, its ER-localized Wnt co-receptor ubiquitination role, and its isoform-specific myeloid function are mechanistically unified within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking ICL3 to GP78/UBAC2 recruitment","Substrate-selection mechanism for FZD/LRP co-receptors undefined","Relationship between surface endocytic and ER-resident pools unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,7]}],"complexes":[],"partners":["GP78","UBAC2","FZD6","LRP6","FZD4","LRP5","AHRR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UX01","full_name":"Protein LMBR1L","aliases":["Limb region 1 protein homolog-like","Lipocalin-1-interacting membrane receptor","LIMR"],"length_aa":489,"mass_kda":55.2,"function":"Plays an essential role in lymphocyte development by negatively regulating the canonical Wnt signaling pathway (By similarity). In association with UBAC2 and E3 ubiquitin-protein ligase AMFR, promotes the ubiquitin-mediated degradation of CTNNB1 and Wnt receptors FZD6 and LRP6 (By similarity). LMBR1L stabilizes the beta-catenin destruction complex that is required for regulating CTNNB1 levels (By similarity). Acts as a LCN1 receptor and can mediate its endocytosis (PubMed:11287427, PubMed:12591932, PubMed:23964685)","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q6UX01/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LMBR1L","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LMBR1L","total_profiled":1310},"omim":[{"mim_id":"617489","title":"LONG INTERGENIC NONCODING RNA 305; LINC00305","url":"https://www.omim.org/entry/617489"},{"mim_id":"610007","title":"LIMB REGION 1 HOMOLOG-LIKE; LMBR1L","url":"https://www.omim.org/entry/610007"},{"mim_id":"606517","title":"ARYLHYDROCARBON RECEPTOR REPRESSOR; AHRR","url":"https://www.omim.org/entry/606517"}],"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/LMBR1L"},"hgnc":{"alias_symbol":["LIMR","FLJ10494","KIAA1174"],"prev_symbol":[]},"alphafold":{"accession":"Q6UX01","domains":[{"cath_id":"-","chopping":"2-228_294-455","consensus_level":"medium","plddt":84.2518,"start":2,"end":455}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UX01","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UX01-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UX01-F1-predicted_aligned_error_v6.png","plddt_mean":80.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LMBR1L","jax_strain_url":"https://www.jax.org/strain/search?query=LMBR1L"},"sequence":{"accession":"Q6UX01","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UX01.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UX01/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UX01"}},"corpus_meta":[{"pmid":"19136951","id":"PMC_19136951","title":"Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19136951","citation_count":134,"is_preprint":false},{"pmid":"21791187","id":"PMC_21791187","title":"Tear lipocalin: structure and function.","date":"2011","source":"The ocular surface","url":"https://pubmed.ncbi.nlm.nih.gov/21791187","citation_count":87,"is_preprint":false},{"pmid":"11287427","id":"PMC_11287427","title":"Molecular cloning of a novel lipocalin-1 interacting human cell membrane receptor using phage display.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11287427","citation_count":62,"is_preprint":false},{"pmid":"28393844","id":"PMC_28393844","title":"Long noncoding RNA LINC00305 promotes inflammation by activating the AHRR-NF-κB pathway in human monocytes.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28393844","citation_count":57,"is_preprint":false},{"pmid":"31073040","id":"PMC_31073040","title":"LMBR1L regulates lymphopoiesis through Wnt/β-catenin signaling.","date":"2019","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/31073040","citation_count":48,"is_preprint":false},{"pmid":"12591932","id":"PMC_12591932","title":"Antisense down-regulation of lipocalin-interacting membrane receptor expression inhibits cellular internalization of lipocalin-1 in human NT2 cells.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12591932","citation_count":45,"is_preprint":false},{"pmid":"17991420","id":"PMC_17991420","title":"Lipocalin-interacting-membrane-receptor (LIMR) mediates cellular internalization of beta-lactoglobulin.","date":"2007","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/17991420","citation_count":34,"is_preprint":false},{"pmid":"23964685","id":"PMC_23964685","title":"Expression, characterization and ligand specificity of lipocalin-1 interacting membrane receptor (LIMR).","date":"2013","source":"Molecular membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/23964685","citation_count":19,"is_preprint":false},{"pmid":"33420178","id":"PMC_33420178","title":"Pleiotropic genetic influence on birth weight and childhood obesity.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33420178","citation_count":16,"is_preprint":false},{"pmid":"33627773","id":"PMC_33627773","title":"Transcriptome-wide association study identifies multiple genes associated with childhood body mass index.","date":"2021","source":"International journal of obesity (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/33627773","citation_count":13,"is_preprint":false},{"pmid":"35146515","id":"PMC_35146515","title":"LMBR1L regulates the proliferation and migration of endothelial cells through Norrin/β-catenin signaling.","date":"2022","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/35146515","citation_count":11,"is_preprint":false},{"pmid":"26512105","id":"PMC_26512105","title":"Fly LMBR1/LIMR-type protein Lilipod promotes germ-line stem cell self-renewal by enhancing BMP signaling.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26512105","citation_count":11,"is_preprint":false},{"pmid":"20438733","id":"PMC_20438733","title":"Effects of low-intensity microwave radiation on Tribolium castaneum physiological and biochemical characteristics and survival.","date":"2010","source":"Journal of insect physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20438733","citation_count":5,"is_preprint":false},{"pmid":"40959972","id":"PMC_40959972","title":"Expanding the Autosomal Recessive Gene Spectrum of Parkinson's Disease: A Study within the CPD10KGP.","date":"2025","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/40959972","citation_count":4,"is_preprint":false},{"pmid":"37347778","id":"PMC_37347778","title":"Autosomal recessive hyposegmentation of granulocytes in Australian Shepherd Dogs indicates a role for LMBR1L in myeloid leukocytes.","date":"2023","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37347778","citation_count":3,"is_preprint":false},{"pmid":"34979047","id":"PMC_34979047","title":"Genomic variants reducing expression of two endocytic receptors in 46,XY differences of sex development.","date":"2022","source":"Human 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one","url":"https://pubmed.ncbi.nlm.nih.gov/40465773","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12320,"output_tokens":3328,"usd":0.04344,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10773,"output_tokens":3422,"usd":0.069708,"stage2_stop_reason":"end_turn"},"total_usd":0.113148,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"LMBR1L (LIMR) was identified as a novel 55-kDa membrane protein with nine putative transmembrane domains that specifically interacts with lipocalin-1 (Lcn-1) in vitro. The cell membrane location was confirmed by immunocytochemistry and Western blot of membrane fractions. A recombinant N-terminal fragment of LIMR demonstrated specific interaction with Lcn-1 in vitro.\",\n      \"method\": \"cDNA phage-display library screening, immunocytochemistry, Western blot of membrane fractions, in vitro binding assay with recombinant N-terminal LIMR fragment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (phage display, immunocytochemistry, fractionation, in vitro binding), single lab\",\n      \"pmids\": [\"11287427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LMBR1L (LIMR) is essential for mediating endocytic internalization of lipocalin-1 (Lcn-1) in NT2 cells. Antisense-mediated knockdown of LIMR abolished cellular uptake of 125I-Lcn-1 and FITC-Lcn-1, causing accumulation in culture medium. LIMR was identified as the prototype of a new family of endocytic receptors with nine transmembrane domains and a large central cytoplasmic loop.\",\n      \"method\": \"Antisense cDNA expression knockdown, 125I-Lcn-1 internalization assay, FITC-Lcn-1 fluorescence uptake assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (blocked endocytosis), multiple substrate tracking methods, single lab\",\n      \"pmids\": [\"12591932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LMBR1L (LIMR) mediates cellular internalization of bovine beta-lactoglobulin (BLG). Cellular uptake of BLG was completely blocked by LIMR antibodies or LIMR antisense RNA knockdown. Heterologous expression of human LIMR in insect cells was sufficient to mediate uptake of FITC-BLG.\",\n      \"method\": \"LIMR antibody blocking, antisense RNA knockdown, heterologous LIMR expression in insect cells, FITC-BLG internalization assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (antibody block, antisense KD, heterologous expression), single lab\",\n      \"pmids\": [\"17991420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Recombinant LIMR purified from Drosophila S2 cells forms dimers or larger oligomers when solubilized in DDM. Surface plasmon resonance (SPR) showed LIMR binds Lcn-1 with low micromolar to high nanomolar affinity and is highly specific for Lcn-1; no interactions with beta-lactoglobulin or uteroglobin were detected, raising doubts about the physiological relevance of those previously reported interactions.\",\n      \"method\": \"Recombinant expression in Drosophila S2 cells, detergent solubilization, surface plasmon resonance (SPR)\",\n      \"journal\": \"Molecular membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous biophysical SPR binding assay with purified protein, but single lab and contradicts prior findings\",\n      \"pmids\": [\"23964685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LMBR1L (LIMR) interacts with aryl-hydrocarbon receptor repressor (AHRR) in human monocytes, and this interaction is enhanced by the lncRNA LINC00305. Enhanced LIMR-AHRR interaction promotes nuclear localization of AHRR and activates NF-κB signaling, driving inflammatory gene expression. NF-κB activation by LINC00305 required both LIMR and AHRR.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown of LIMR/AHRR, NF-κB reporter assay, Western blot for nuclear AHRR localization\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, functional epistasis (NF-κB requires both LIMR and AHRR), multiple approaches, single lab\",\n      \"pmids\": [\"28393844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LMBR1L (LIMR) and the downstream ERK signaling pathway are required for antiflammin-1-mediated inhibition of TGF-β1-induced epithelial-mesenchymal transition (EMT) in A549 cells. Anti-LIMR antibody attenuated the inhibitory effect of antiflammin-1 on EMT markers (α-SMA, E-cadherin), placing LIMR upstream of ERK in this pathway.\",\n      \"method\": \"Anti-LIMR antibody blocking, ERK pathway inhibitor (PD98059), Western blot for EMT markers (α-SMA, E-cadherin), morphological observation\",\n      \"journal\": \"Sheng li xue bao : [Acta physiologica Sinica]\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — antibody blocking with pathway inhibitor, single lab, limited mechanistic resolution\",\n      \"pmids\": [\"30377686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LMBR1L acts as a negative regulator of the Wnt/β-catenin signaling pathway in lymphocytes. LMBR1L interacts with GP78 (an E3 ubiquitin ligase) and UBAC2, and this complex attenuates Wnt signaling by promoting ubiquitination and preventing maturation of the Wnt co-receptors FZD6 and LRP6 within the endoplasmic reticulum. LMBR1L also stabilizes destruction complex proteins. Loss of LMBR1L (via ENU-induced mutation in mice) caused severely impaired development of all lymphoid lineages, and LMBR1L-deficient T cells exhibited Wnt/β-catenin activation and underwent apoptosis in response to proliferative stimuli.\",\n      \"method\": \"ENU mutagenesis mouse model, co-immunoprecipitation of LMBR1L with GP78 and UBAC2, ubiquitination assay, Western blot for β-catenin and destruction complex proteins, FZD6/LRP6 maturation assay, lymphocyte development phenotyping\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, in vivo genetic model with defined lymphoid phenotype, multiple orthogonal methods, published in Science\",\n      \"pmids\": [\"31073040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LMBR1L negatively regulates Norrin/β-catenin signaling in endothelial cells. Global Lmbr1l knockout mice show impaired retinal vascular development. In human retinal microvascular endothelial cells (HRECs), LMBR1L depletion causes decreased ubiquitylation of FZD4, increased LRP5 and p-GSK3β-Ser9 expression, β-catenin accumulation, increased proliferation, and defective cell migration with upregulated apical junction components. GSK3β-Ser9 inhibitor AR-A014418 rescued these phenotypes in LMBR1L-null HRECs.\",\n      \"method\": \"Global knockout mouse model, LMBR1L knockdown in HRECs, ubiquitylation assay for FZD4, Western blot for LRP5/p-GSK3β/β-catenin, proliferation assay, migration assay, pharmacological rescue with AR-A014418\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model combined with in vitro KD, ubiquitylation assay, pharmacological rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35146515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mutations in LMBR1L detected in individuals with 46,XY differences of sex development (undescended testes). In a transfected cell model, mutated LMBR1L showed reduced cell surface expression, suggesting LMBR1L may function as an endocytic receptor involved in androgen uptake in complex with sex hormone-binding globulin.\",\n      \"method\": \"Exome sequencing, Western blot of transfected cells for surface expression\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single cell model with expression readout, no direct functional rescue or binding assay, single lab\",\n      \"pmids\": [\"34979047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A splice site variant in LMBR1L (c.191+1G>A) in Australian Shepherd Dogs causes autosomal recessive hyposegmentation of granulocytes (Pelger-Huët-like anomaly). The mutant allele abrogates expression of the longer X2 isoform but not the shorter X1 isoform of LMBR1L, pointing to a previously unsuspected function of LMBR1L in the myeloid lineage of leukocytes.\",\n      \"method\": \"Genome-wide association mapping, whole genome sequencing, linkage analysis, splice site variant identification, RT-PCR for isoform expression, genotyping in 300 dogs\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mapping with WGS identifying causal variant, isoform-specific expression analysis, in vivo association, single study\",\n      \"pmids\": [\"37347778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The third intracellular loop (ICL3) of fly LMBR1L ortholog Lilipod is required for protein function in vivo; evolutionarily conserved regions within ICL3 are critical for activity. Fly-human chimeric proteins in which Lili ICL3 is replaced with the ICL3 of human LMBR1L (or LMBR1) rescued lili null-mutant phenotypes in Drosophila, demonstrating functional conservation of ICL3 across species. Yeast two-hybrid screening with ICL3 as bait identified BMP signaling components Mad, Sara, Nup93, and Nup358 as putative interactors.\",\n      \"method\": \"In vivo mutational analysis in Drosophila, fly-human chimeric protein rescue assay in lili null mutants, Yeast 2-Hybrid (Y2H) screen with ICL3 as bait\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mutational rescue, chimeric protein functional assay, unbiased Y2H screen; Y2H interactions are not confirmed by orthogonal methods\",\n      \"pmids\": [\"40465773\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LMBR1L is a multi-pass transmembrane protein (9 TM domains) that functions as a negative regulator of Wnt/β-catenin signaling — interacting with the E3 ligase GP78 and UBAC2 to promote ER-localized ubiquitination and prevent maturation of Wnt co-receptors FZD4/FZD6 and LRP5/LRP6, thereby stabilizing the destruction complex — and is essential for lymphopoiesis and retinal vascular development; it also acts as an endocytic receptor mediating internalization of lipocalin-1 and other lipocalin family members, and plays a role in myeloid leukocyte segmentation as revealed by a splice-site variant causing granulocyte hyposegmentation in dogs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LMBR1L (LIMR) is a multi-pass transmembrane protein that functions as a negative regulator of Wnt/β-catenin signaling and as an endocytic receptor for secreted lipocalins [#0, #6]. In lymphocytes it forms a complex with the E3 ubiquitin ligase GP78 and UBAC2 that promotes ubiquitination and blocks endoplasmic-reticulum maturation of the Wnt co-receptors FZD6 and LRP6 while stabilizing destruction-complex proteins, restraining β-catenin activation; loss of LMBR1L impairs development of all lymphoid lineages and sensitizes T cells to apoptosis under proliferative stimuli [#6]. The same regulatory logic operates in endothelial cells, where LMBR1L promotes ubiquitylation of FZD4 to limit Norrin/β-catenin signaling, and its loss elevates LRP5 and inhibitory p-GSK3β-Ser9, drives β-catenin accumulation, and disrupts retinal vascular development—phenotypes reversed by GSK3β inhibition [#7]. Independently, LMBR1L acts at the cell surface as an endocytic receptor that mediates internalization of lipocalin-1, binding it with nanomolar-to-micromolar affinity and being required for its cellular uptake [#0, #1, #3]. A splice-site variant abolishing the longer LMBR1L isoform causes autosomal-recessive granulocyte hyposegmentation in dogs, revealing a role in myeloid leukocyte development [#9]. The third intracellular loop is the functionally critical and evolutionarily conserved module of the protein, sufficient to confer activity in cross-species rescue [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established LMBR1L as a membrane protein with a defined molecular partner, identifying lipocalin-1 as a specific binding ligand and placing the protein at the cell membrane.\",\n      \"evidence\": \"cDNA phage-display screening, immunocytochemistry, membrane fractionation, and in vitro binding with a recombinant N-terminal fragment\",\n      \"pmids\": [\"11287427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No demonstration of a functional consequence of the interaction\", \"Topology and stoichiometry not determined\", \"Single-lab in vitro binding\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed the LMBR1L-lipocalin-1 interaction is functional by demonstrating that the protein is required for endocytic internalization of its ligand, defining it as a prototype endocytic receptor.\",\n      \"evidence\": \"Antisense knockdown in NT2 cells with radiolabeled and FITC-tagged Lcn-1 uptake assays\",\n      \"pmids\": [\"12591932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endocytic adaptor/machinery and cytoplasmic loop role not defined\", \"Single cell type\", \"Fate of internalized ligand not tracked\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended endocytic-receptor function to additional lipocalin-family ligands and showed heterologous expression alone confers uptake activity.\",\n      \"evidence\": \"Antibody blocking, antisense knockdown, and heterologous expression in insect cells with FITC-BLG uptake\",\n      \"pmids\": [\"17991420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand specificity later disputed\", \"No structural basis for ligand recognition\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Quantified binding biophysically and constrained ligand specificity, supporting lipocalin-1 as the bona fide ligand while questioning earlier reported partners.\",\n      \"evidence\": \"Recombinant purification from S2 cells, detergent solubilization, and surface plasmon resonance\",\n      \"pmids\": [\"23964685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contradicts prior BLG/uteroglobin interactions\", \"Oligomeric state in native membranes unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Implicated LMBR1L in inflammatory signaling by linking it to AHRR and lncRNA-driven NF-κB activation in monocytes.\",\n      \"evidence\": \"Co-immunoprecipitation, overexpression/knockdown epistasis, NF-κB reporter, and nuclear AHRR Western blot\",\n      \"pmids\": [\"28393844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting a membrane protein to nuclear AHRR localization unclear\", \"No reciprocal structural mapping of the interaction\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the core mechanism: LMBR1L is a negative regulator of Wnt/β-catenin signaling acting through ER-localized ubiquitination of Wnt co-receptors and is essential for lymphopoiesis.\",\n      \"evidence\": \"ENU mouse model, reciprocal Co-IP with GP78 and UBAC2, ubiquitination and FZD6/LRP6 maturation assays, and lymphocyte phenotyping\",\n      \"pmids\": [\"31073040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LMBR1L directly recruits substrates to GP78 vs. acts as a scaffold not resolved\", \"Catalytic contribution of LMBR1L itself undefined\", \"Link to its endocytic-receptor function unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Generalized the Wnt-regulatory mechanism to endothelial Norrin/β-catenin signaling and connected it to a developmental phenotype, retinal vascular development.\",\n      \"evidence\": \"Global knockout mice plus HREC knockdown, FZD4 ubiquitylation assay, GSK3β/LRP5/β-catenin Westerns, and pharmacological rescue with AR-A014418\",\n      \"pmids\": [\"35146515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GP78/UBAC2 complex operates identically in endothelium not shown\", \"Direct vs. indirect effect on LRP5 levels unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Raised a candidate role in androgen handling by associating LMBR1L mutations with 46,XY differences of sex development and reduced surface expression.\",\n      \"evidence\": \"Exome sequencing and surface-expression Western blot in transfected cells\",\n      \"pmids\": [\"34979047\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional rescue or direct androgen/SHBG binding assay\", \"Causality not established beyond association\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an isoform-specific myeloid function by mapping a splice variant that ablates the longer LMBR1L isoform to granulocyte hyposegmentation.\",\n      \"evidence\": \"GWAS, whole genome sequencing, linkage, and RT-PCR isoform analysis in dogs\",\n      \"pmids\": [\"37347778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular function of the X2 isoform in myeloid cells unknown\", \"Connection to Wnt regulation not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Localized the functional core of the protein to the third intracellular loop and identified candidate BMP-pathway interactors, establishing cross-species functional conservation.\",\n      \"evidence\": \"In vivo Drosophila mutational analysis, fly-human ICL3 chimeric rescue, and Y2H screen with ICL3 as bait\",\n      \"pmids\": [\"40465773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Y2H interactors (Mad, Sara, Nup93, Nup358) not validated by orthogonal methods\", \"How ICL3 interfaces with the GP78/UBAC2 ubiquitination machinery unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LMBR1L's endocytic-receptor activity, its ER-localized Wnt co-receptor ubiquitination role, and its isoform-specific myeloid function are mechanistically unified within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking ICL3 to GP78/UBAC2 recruitment\", \"Substrate-selection mechanism for FZD/LRP co-receptors undefined\", \"Relationship between surface endocytic and ER-resident pools unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GP78\", \"UBAC2\", \"FZD6\", \"LRP6\", \"FZD4\", \"LRP5\", \"AHRR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}