Affinage

LMBR1L

Protein LMBR1L · UniProt Q6UX01

Length
489 aa
Mass
55.2 kDa
Annotated
2026-06-10
21 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2001 Medium

    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

    PMID:11287427

    Open questions at the time
    • No demonstration of a functional consequence of the interaction
    • Topology and stoichiometry not determined
    • Single-lab in vitro binding
  2. 2003 Medium

    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

    PMID:12591932

    Open questions at the time
    • Endocytic adaptor/machinery and cytoplasmic loop role not defined
    • Single cell type
    • Fate of internalized ligand not tracked
  3. 2007 Medium

    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

    PMID:17991420

    Open questions at the time
    • Ligand specificity later disputed
    • No structural basis for ligand recognition
  4. 2013 Medium

    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

    PMID:23964685

    Open questions at the time
    • Contradicts prior BLG/uteroglobin interactions
    • Oligomeric state in native membranes unresolved
    • Single lab
  5. 2017 Medium

    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

    PMID:28393844

    Open questions at the time
    • Mechanism connecting a membrane protein to nuclear AHRR localization unclear
    • No reciprocal structural mapping of the interaction
  6. 2019 High

    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

    PMID:31073040

    Open questions at the time
    • 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
  7. 2022 High

    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

    PMID:35146515

    Open questions at the time
    • Whether GP78/UBAC2 complex operates identically in endothelium not shown
    • Direct vs. indirect effect on LRP5 levels unresolved
  8. 2022 Low

    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

    PMID:34979047

    Open questions at the time
    • No functional rescue or direct androgen/SHBG binding assay
    • Causality not established beyond association
  9. 2023 Medium

    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

    PMID:37347778

    Open questions at the time
    • Molecular function of the X2 isoform in myeloid cells unknown
    • Connection to Wnt regulation not tested
  10. 2025 Medium

    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

    PMID:40465773

    Open questions at the time
    • Y2H interactors (Mad, Sara, Nup93, Nup358) not validated by orthogonal methods
    • How ICL3 interfaces with the GP78/UBAC2 ubiquitination machinery unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 3 GO:0098772 molecular function regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
AHRRFZD4FZD6GP78LRP5LRP6UBAC2

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 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. cDNA phage-display library screening, immunocytochemistry, Western blot of membrane fractions, in vitro binding assay with recombinant N-terminal LIMR fragment The Journal of biological chemistry Medium 11287427
2003 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. Antisense cDNA expression knockdown, 125I-Lcn-1 internalization assay, FITC-Lcn-1 fluorescence uptake assay The Journal of biological chemistry Medium 12591932
2007 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. LIMR antibody blocking, antisense RNA knockdown, heterologous LIMR expression in insect cells, FITC-BLG internalization assay Biochimica et biophysica acta Medium 17991420
2013 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. Recombinant expression in Drosophila S2 cells, detergent solubilization, surface plasmon resonance (SPR) Molecular membrane biology Medium 23964685
2017 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. Co-immunoprecipitation, overexpression and knockdown of LIMR/AHRR, NF-κB reporter assay, Western blot for nuclear AHRR localization Scientific reports Medium 28393844
2018 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. Anti-LIMR antibody blocking, ERK pathway inhibitor (PD98059), Western blot for EMT markers (α-SMA, E-cadherin), morphological observation Sheng li xue bao : [Acta physiologica Sinica] Low 30377686
2019 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. 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 Science (New York, N.Y.) High 31073040
2022 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. 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 of cell science High 35146515
2022 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. Exome sequencing, Western blot of transfected cells for surface expression Human mutation Low 34979047
2023 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. Genome-wide association mapping, whole genome sequencing, linkage analysis, splice site variant identification, RT-PCR for isoform expression, genotyping in 300 dogs PLoS genetics Medium 37347778
2025 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. 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 PloS one Medium 40465773

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism. Nature genetics 134 19136951
2011 Tear lipocalin: structure and function. The ocular surface 87 21791187
2001 Molecular cloning of a novel lipocalin-1 interacting human cell membrane receptor using phage display. The Journal of biological chemistry 62 11287427
2017 Long noncoding RNA LINC00305 promotes inflammation by activating the AHRR-NF-κB pathway in human monocytes. Scientific reports 57 28393844
2019 LMBR1L regulates lymphopoiesis through Wnt/β-catenin signaling. Science (New York, N.Y.) 48 31073040
2003 Antisense down-regulation of lipocalin-interacting membrane receptor expression inhibits cellular internalization of lipocalin-1 in human NT2 cells. The Journal of biological chemistry 45 12591932
2007 Lipocalin-interacting-membrane-receptor (LIMR) mediates cellular internalization of beta-lactoglobulin. Biochimica et biophysica acta 34 17991420
2013 Expression, characterization and ligand specificity of lipocalin-1 interacting membrane receptor (LIMR). Molecular membrane biology 19 23964685
2021 Pleiotropic genetic influence on birth weight and childhood obesity. Scientific reports 16 33420178
2021 Transcriptome-wide association study identifies multiple genes associated with childhood body mass index. International journal of obesity (2005) 13 33627773
2022 LMBR1L regulates the proliferation and migration of endothelial cells through Norrin/β-catenin signaling. Journal of cell science 11 35146515
2015 Fly LMBR1/LIMR-type protein Lilipod promotes germ-line stem cell self-renewal by enhancing BMP signaling. Proceedings of the National Academy of Sciences of the United States of America 11 26512105
2010 Effects of low-intensity microwave radiation on Tribolium castaneum physiological and biochemical characteristics and survival. Journal of insect physiology 5 20438733
2025 Expanding the Autosomal Recessive Gene Spectrum of Parkinson's Disease: A Study within the CPD10KGP. Movement disorders : official journal of the Movement Disorder Society 4 40959972
2023 Autosomal recessive hyposegmentation of granulocytes in Australian Shepherd Dogs indicates a role for LMBR1L in myeloid leukocytes. PLoS genetics 3 37347778
2022 Genomic variants reducing expression of two endocytic receptors in 46,XY differences of sex development. Human mutation 2 34979047
2018 [Enhancer trapping nearby rps26 gene in zebrafish mediated by the Tol2 transposon and it's annotation]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 2 29577695
2018 [LIMR is involved in the inhibitory effect of antiflammin-1 on epithelial-mesenchymal transition in A549 cells]. Sheng li xue bao : [Acta physiologica Sinica] 1 30377686
2025 The third intracellular loop of Drosophila Lilipod is required for protein function in vivo and can mediate protein-protein interactions in vitro. PloS one 0 40465773
2025 Phosphoprotein Profile of Ameloblastoma. Asian Pacific journal of cancer prevention : APJCP 0 40849725
2025 Evolutionary and structural bioinformatics identifies GPR89 as a conserved member of the LIMR protein superfamily. Computational and structural biotechnology journal 0 41282416

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