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Showing LRP2 — DBS is a alias.

LRP2

Low-density lipoprotein receptor-related protein 2 · UniProt P98164

Length
4655 aa
Mass
522.0 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRP2 (megalin/gp330) is a giant, calcium-dependent multiligand endocytic receptor concentrated in clathrin-coated pits at the apical surface of absorptive and barrier epithelia, where it captures circulating proteins for internalization, degradation, or transcytosis (PMID:6337231, PMID:8898021, PMID:10702280). Its enormous ectodomain — 36 LDLR-type ligand-binding repeats organized into four clusters together with YWTD/EGF spacer regions, a single transmembrane span, and a cytoplasmic tail bearing two (FX)NPXY coated-pit internalization motifs — defines it as the largest known vertebrate plasma membrane protein and provides the structural basis for its broad ligand repertoire (PMID:7937880). Cryo-EM shows LRP2 functions as a homodimer that switches between a ligand-binding conformation at extracellular pH and a ligand-shedding conformation at endosomal pH, a transition governed by pH-sensitive dimer and intra-protomer interfaces that human deleterious missense variants disrupt (PMID:36750096). Through this machinery LRP2 binds and internalizes a wide array of ligands including RAP, albumin, thyroglobulin, plasminogen/plasmin, apoE-betaVLDL, Lp(a), vitamin D-binding protein, and clusterin, with the chaperone RAP acting as a universal regulator of ligand binding (PMID:1464627, PMID:8898021, PMID:9492085, PMID:10073957, PMID:18194670). RAP additionally functions in the endoplasmic reticulum as a folding chaperone that assembles with LRP2 in a calcium-dependent manner and delivers it to the cell surface, while the chaperone MESD is required for maturation of its beta-propeller/EGF domains and apical targeting (PMID:8322889, PMID:8223699, PMID:21337463). In renal proximal tubules this receptor drives reabsorption of filtered proteins, with apical positioning dependent on microtubules and endosomal trafficking coordinated by the adaptor Disabled-2 (PMID:8898021, PMID:16638803, PMID:2669509). Beyond clearance, LRP2 is a context-dependent morphogen co-receptor in development: it acts as an auxiliary activating SHH receptor that sequesters SHH and controls SHH/Patched-1 trafficking in the forebrain ventral midline and maintains SHH-dependent progenitors in the cardiac second heart field, yet serves as a clearance receptor that endocytoses and degrades BMP4 in the neuroepithelium and ependymal stem-cell niche and SHH in the retinal margin (PMID:15623804, PMID:20460439, PMID:22340494, PMID:26439398, PMID:32901292). It is also required for neural tube closure, where its intracellular domain engages adaptors Shroom3 and Gipc1 to drive apical constriction and PCP component (Vangl2) trafficking, and mediates folate uptake via soluble FOLR1 (PMID:24639464, PMID:33500317). Expression is transcriptionally repressed by TGF-beta1 through SMAD2/3 binding the megalin promoter and induced by PPARalpha/gamma ligands (PMID:31120873, PMID:21311715). Loss-of-function LRP2 mutations cause Donnai-Barrow/FOAR syndrome in humans (PMID:17632512).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1983 High

    Establishing where the Heymann nephritis antigen resides answered whether gp330 was an epithelial surface receptor, localizing it to clathrin-coated pits of glomerular and proximal tubule epithelia.

    Evidence Immunocytochemistry at EM resolution and immunoprecipitation from labeled kidney fractions

    PMID:6337231

    Open questions at the time
    • Ligands and molecular function undefined
    • No sequence or domain architecture yet
  2. 1990 Medium

    Microtubule disruption and matrix-binding studies addressed how the receptor reaches the apical pole and whether it engages extracellular matrix, showing microtubule-dependent apical insertion and RGD-independent adhesion to fibronectin, laminin, and collagen.

    Evidence Colchicine treatment with immunolocalization in vivo; antibody-inhibited cell attachment and direct matrix binding assays

    PMID:1691715 PMID:2669509

    Open questions at the time
    • Matrix-binding site on the receptor not mapped
    • Physiological relevance of adhesion vs endocytosis unresolved
  3. 1992 High

    Identifying RAP as a calcium-dependent partner that blocks ligand binding while forming a stable ER-assembled heterodimer defined the central regulator of LRP2 ligand interactions and its biosynthetic assembly.

    Evidence Ligand/Ca2+ blotting, in vivo microperfusion, copurification, and pulse-chase with sucrose gradient sedimentation

    PMID:1382088 PMID:1464627 PMID:1495959 PMID:8322889

    Open questions at the time
    • Distinction between RAP's chaperone role and its ligand-blocking role not fully separated at this stage
  4. 1994 High

    Complete cDNA cloning answered what the receptor's domain architecture is, revealing the largest vertebrate membrane protein with 36 LDLR repeats and cytoplasmic (FX)NPXY internalization motifs that explain its broad ligand capacity and clathrin coupling.

    Evidence cDNA cloning, sequencing, and domain analysis of rat gp330; human ortholog cloned with cytoplasmic motif mapping

    PMID:7937880 PMID:8706697

    Open questions at the time
    • Functional validation of putative signaling motifs (PI3K, PKC sites) not performed
    • Structure of the assembled ectodomain unknown
  5. 1995 High

    Defining RAP as an ER folding chaperone and demonstrating receptor-mediated endocytosis of urokinase/PAI-1 ligands distinguished RAP's biosynthetic role from ligand uptake, establishing LRP2 as a functional endocytic receptor.

    Evidence Immunohistochemistry with RAP-IgG binding; cell-based radiolabeled endocytosis assays in pneumocytes with RAP and antibody blockade

    PMID:7673355 PMID:8223699

    Open questions at the time
    • Endosomal trafficking machinery and recycling not yet defined
  6. 1996 High

    Knockout and in vivo albumin uptake studies established LRP2's physiological functions, showing it is essential for forebrain development and mediates proximal tubule protein reabsorption.

    Evidence Megalin knockout mouse with developmental phenotyping; in vivo microinfusion with labeled albumin and direct megalin-Sepharose binding

    PMID:8710893 PMID:8898021

    Open questions at the time
    • Molecular pathway linking megalin loss to forebrain defect not yet identified
    • Cargo specificity in the proximal tubule incomplete
  7. 1999 High

    Ligand-by-ligand binding and uptake studies answered what cargoes LRP2 handles, characterizing thyroglobulin transcytosis, Lp(a) and apoE-betaVLDL uptake, and plasminogen activation/protection, defining a broad endocytic and lipoprotein-clearance repertoire.

    Evidence Solid-phase binding with Kd determination, surface plasmon resonance, polarized transcytosis assays, kinetic plasmin activation assays, and immuno-EM of pHN models

    PMID:10073957 PMID:10212279 PMID:10702280 PMID:1280065 PMID:1645711 PMID:9410908 PMID:9492085

    Open questions at the time
    • Relative in vivo flux through each ligand pathway not quantified
    • Tissue-specific cargo prioritization unresolved
  8. 2007 High

    Human genetic mapping answered whether LRP2 dysfunction causes disease, identifying loss-of-function mutations as the cause of Donnai-Barrow/FOAR syndrome and confirming its essential developmental role across organ systems.

    Evidence Positional cloning and LRP2 sequencing in multiplex families; vitamin D-binding protein uptake assay in hepatic stellate cells

    PMID:17632512 PMID:18194670

    Open questions at the time
    • Genotype-phenotype correlations for specific variants not detailed
    • Mechanism converting receptor loss to multi-organ phenotype only partly defined
  9. 2010 High

    Conditional knockouts and zebrafish/MESD studies dissected how LRP2 contributes to morphogenesis and trafficking, showing it clears BMP4 in neuroepithelium and the ependymal stem-cell niche to permit SHH expression and neurogenesis, requires MESD for maturation, and depends on Dab2 for renal endocytosis.

    Evidence Tissue-specific conditional knockouts with BMP4/pSMAD/ID3 and Shh readouts, neurogenesis assays, Mesd knockout with domain maturation assay, morpholino knockdown in zebrafish

    PMID:15623804 PMID:16638803 PMID:20460439 PMID:21337463

    Open questions at the time
    • How a single receptor switches between clearance and signaling roles not mechanistically explained
    • Endosomal fate determining degradation vs signaling unclear
  10. 2014 High

    Gain/loss-of-function studies in midline, retina, and hypothalamus revealed LRP2's context-dependent morphogen logic and a leptin/clusterin signaling axis, showing it can either activate SHH signaling (forebrain midline) or clear SHH (retina), and that clusterin-driven leptin endocytosis through LRP2 controls feeding.

    Evidence Knockout/explant assays with SHH/Patched-1 Co-IP, retina-specific conditional knockout with proliferation readouts, neuronal endocytosis assays and ICV clusterin/leptin with STAT3 readout and LRP2-LepRb Co-IP, folate-sFOLR1 uptake in knockout embryos

    PMID:22340494 PMID:23673647 PMID:24639464 PMID:24825475 PMID:26439398

    Open questions at the time
    • Determinants selecting activating vs clearance SHH outcomes remain unresolved
    • Structural basis of LRP2-LepRb coupling not defined
  11. 2020 High

    Multi-species developmental and transcriptional studies extended LRP2's roles to cardiac development, neural tube closure morphogenesis, and identified its transcriptional and post-transcriptional regulation, linking its intracellular domain to apical constriction adaptors and PCP trafficking.

    Evidence iPSC-CM/Drosophila/zebrafish knockdowns, SHF marker analysis in mice, Lrp2 knockout with Shroom3/Gipc1 Co-IP, ChIP/EMSA/reporter assays for SMAD2/3 and PPAR, m6A/Ythdc2 mRNA stability assays

    PMID:21311715 PMID:31120873 PMID:32901292 PMID:33006316 PMID:33500317 PMID:34? PMID:35716070

    Open questions at the time
    • How intracellular adaptors integrate endocytosis with cytoskeletal apical constriction not mechanistically resolved
    • Crosstalk between transcriptional (TGF-beta/PPAR) and post-transcriptional (m6A) regulation untested
  12. 2023 High

    Cryo-EM at two pH states answered how a single receptor binds ligands extracellularly and releases them in endosomes, revealing a homodimer with pH-sensitive interface switching and showing that pathogenic missense variants impair dimer assembly.

    Evidence High-resolution cryo-EM at extracellular and endosomal pH with structural variant analysis on receptor isolated from mouse kidney

    PMID:36750096

    Open questions at the time
    • Structural basis for ligand-specific binding sites not all mapped
    • How cytoplasmic adaptor engagement couples to ectodomain conformation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what molecular determinant dictates whether ligand engagement by LRP2 yields signaling activation versus degradative clearance in a given tissue, and how its conformational pH-switch is integrated with cytoplasmic adaptor and cytoskeletal machinery.
  • No unifying model for the activating-vs-clearance switch
  • Coupling between ectodomain pH-conformational cycle and intracellular trafficking adaptors not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 6 GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 3 GO:0031410 cytoplasmic vesicle 3 GO:0005768 endosome 2
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-162582 Signal Transduction 4 R-HSA-9609507 Protein localization 4 R-HSA-1643685 Disease 1
Partners
CUBNDAB2GIPC1LEPRBMESDPTCH1RAPSHROOM3
Complex memberships
LRP2 homodimerLRP2/RAP complex (HNAC)

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1983 LRP2/gp330 localizes to clathrin-coated pits at the surface of glomerular epithelial cells (podocytes) and proximal tubule cells, where it is synthesized and concentrated; coated pits at the base of foot processes are sites where gp330 and circulating anti-gp330 antibodies meet to form immune complexes. Immunocytochemistry (immunoperoxidase and immunofluorescence) on cryostat sections; immunoprecipitation from 35S-methionine-labeled kidney fractions The Journal of experimental medicine High 6337231
1992 LRP2/gp330 is a calcium-dependent binding receptor for the 40 kDa receptor-associated protein (RAP/alpha2-MRAP) in renal proximal tubule coated apical membranes and mediates endocytic uptake of protein; gp330 is also a quantitatively important Ca2+ binding protein in renal cortex. Ligand blotting, 45Ca2+ blotting, light and electron microscopic autoradiography, in vivo microperfusion of rat proximal tubules with 125I-labeled 40 kDa protein The journal of histochemistry and cytochemistry High 1382088
1992 LRP2/gp330 from rat kidney membranes binds multiple LRP ligands including plasminogen activator–inhibitor complexes, apoprotein E-enriched beta-VLDL complexed with lipoprotein lipase, and lactoferrin; binding of all ligands is inhibited by the 39 kDa RAP, identifying RAP as a universal regulator of ligand binding to both LRP and gp330. Nitrocellulose blot binding assays, competition experiments in fibroblasts measuring cholesteryl ester synthesis, cross-competition binding studies The Journal of biological chemistry High 1464627
1991 LRP2/gp330 is a receptor for plasminogen; plasminogen binds to gp330 in a time-dependent, saturable, and specifically inhibitable manner. Western blot binding analysis, ELISA binding assay with inhibition by excess gp330 and partial inhibition by benzamidine The Journal of biological chemistry Medium 1645711
1992 Once plasminogen is bound to gp330, it can be converted to active plasmin by urokinase at a faster rate than unbound plasminogen; plasmin remains bound to gp330 in an active state and is protected from inactivation by alpha2-antiplasmin while bound. In vitro kinetic enzyme assay (urokinase-catalyzed plasminogen activation with chromogenic substrate S-2251), ELISA binding assay Archives of biochemistry and biophysics Medium 1280065
1992 LRP2/gp330 forms a stable heterodimeric complex with a 44 kDa protein (RAP/alpha2-MRAP) that is stable to detergent extraction; this complex constitutes the Heymann nephritis antigenic complex (HNAC). Immunoprecipitation from kidney extracts, immunoblotting on purified complex, copurification by detergent extraction and centrifugation Proceedings of the National Academy of Sciences of the United States of America High 1495959
1993 The biosynthesis of the gp330/RAP antigenic complex (HNAC) occurs in the rough endoplasmic reticulum; gp330 associates with RAP very early after synthesis in a Ca2+-dependent manner, forming a large (19.3S) heterodimer, and then a larger heterooligomer (38.6S), both before acquiring endoglycosidase H resistance. Pulse-chase radiolabeling, endoglycosidase H digestion, coprecipitation, sucrose velocity gradient centrifugation The American journal of physiology High 8322889
1994 LRP2/gp330 is the largest plasma membrane protein identified in vertebrates, with a deduced 4660 aa sequence comprising 36 LDLR ligand-binding repeats in four clusters, 16 growth factor repeats with 8 YWTD spacer regions, one EGF repeat, a single transmembrane domain, and a cytoplasmic tail containing two (FX)NPXY coated-pit internalization motifs and an additional similar motif. cDNA cloning and sequencing (complete sequence), domain architecture analysis Proceedings of the National Academy of Sciences of the United States of America High 7937880
1995 RAP functions as a chaperone that associates with LRP2/gp330 in the ER and assists in its folding and transport to the cell surface; endogenous RAP is located predominantly in the RER of renal proximal tubule cells, and RAP-binding sites are present on gp330 at the brush border. Immunohistochemistry on fixed and snap-frozen kidney tissue, RAP-IgG fusion protein binding assays, redistribution experiments European journal of cell biology Medium 8223699
1995 LRP2/gp330 mediates endocytosis of pro-urokinase, plasminogen activator inhibitor-1 (PAI-1), and uPA:PAI-1 complexes in type II pneumocytes; RAP completely inhibits both internalization and degradation of these ligands. Cell-based endocytosis assay using radiolabeled ligands in immortalized rat type II pneumocytes, inhibition with polyclonal antibodies to gp330 and with RAP Journal of cell science High 7673355
1996 LRP2/megalin mediates uptake of albumin in renal proximal tubules; tubular uptake of RSA was inhibited >50% by RAP and was reduced by EDTA, excess albumin, and megalin itself; purified megalin-Sepharose directly binds BSA and RSA in a RAP- and EDTA-inhibitable manner. In vivo microinfusion of rat proximal tubules with 125I-labeled albumin and colloidal gold-BSA, megalin-Sepharose binding assay, immunoelectron microscopy The American journal of physiology High 8898021
1996 Knockout of LRP2/megalin in mice causes defective forebrain development (holoprosencephalic syndrome), demonstrating its essential role in neuroepithelial development, likely through endocytic uptake of cholesterol-carrying lipoproteins. Megalin knockout mouse generation, phenotypic analysis of brain development Proceedings of the National Academy of Sciences of the United States of America High 8710893
1996 Human LRP2/gp330 cytoplasmic tail contains two (FX)NPXY coated-pit internalization signals, SH3-recognition motifs, an SH2 recognition motif for the p85 subunit of PI3-kinase, and phosphorylation sites for PKC, casein kinase II, and cAMP/cGMP-dependent kinase, suggesting intracellular signaling capacity. Complete cDNA cloning and sequencing of human gp330, motif analysis of cytoplasmic tail European journal of biochemistry Medium 8706697
1998 LRP2/megalin binds thyroglobulin (Tg) in a Ca2+-dependent manner with Kd ~9.2 nM; binding is inhibited by lactoferrin, lipoprotein lipase, apolipoprotein J, and RAP, and Tg is released by heparin and EDTA. Solid phase binding assays with purified rat megalin and 125I-labeled Tg, ELISA competition assays Endocrinology High 9492085
1999 LRP2/megalin is an endocytic receptor for thyroglobulin on thyroid cells (FRTL-5); Tg binds to megalin on the cell surface with Kd ~11.2 nM in a saturable manner, and Tg endocytosis is partially mediated by megalin as shown by RAP and anti-megalin antibody inhibition. Chemical cross-linking followed by immunoprecipitation, heparin-release binding assay, ELISA, functional endocytosis assay in FRTL-5 cells The Journal of biological chemistry High 10212279
1999 LRP2/megalin mediates cellular uptake and degradation of Lp(a) in vitro; megalin-expressing yolk sac cells showed 2-fold higher uptake and degradation of 125I-Lp(a) than double-knockout control cells, and the difference was abolished by RAP; purified megalin directly binds Lp(a) in a Ca2+-dependent manner on a sensor chip. Cell-based uptake/degradation assay with 125I-labeled Lp(a), DiI-Lp(a) fluorescence imaging, surface plasmon resonance (BIAcore) with purified megalin Arteriosclerosis, thrombosis, and vascular biology High 10073957
2000 LRP2/megalin mediates transcytosis of thyroglobulin (Tg) across polarized thyroid cells; intact 330 kDa Tg was recovered in the basolateral chamber after apical addition, and the amount was markedly reduced by megalin competitors (RAP and anti-megalin antibody). Polarized FRTL-5 cell culture on permeable filters, transepithelial transport assay, Western blot; in vivo goiter model with aminotriazole The Journal of biological chemistry High 10702280
1997 Pathogenic anti-megalin IgG from Heymann nephritis inhibits the binding and internalization of apolipoprotein E-enriched betaVLDL by megalin, causing apo E and apo B to accumulate in subepithelial immune deposits rather than being internalized normally. Immunoelectron microscopy of podocytes in pHN rat model; in vitro inhibition of apo E-betaVLDL binding and internalization using eluted antibodies from glomeruli The Journal of clinical investigation High 9410908
2005 LRP2 expression in the neuroepithelium (not the yolk sac) is crucial for forebrain development; megalin deficiency leads to increased BMP4 expression and signaling in the rostral dorsal neuroepithelium and subsequent loss of sonic hedgehog (Shh) expression in the ventral forebrain, resulting in loss of oligodendroglial and interneuronal cell populations; megalin mediates endocytic uptake and degradation of BMP4, acting as a BMP4 clearance receptor. Conditional megalin knockout in neuroepithelium vs. yolk sac, immunohistochemistry for BMP4 and Shh, analysis of cell populations in forebrain Development (Cambridge, England) High 15623804
2010 LRP2 in ependymal cells of the lateral ventricles adjacent to the subependymal zone (SEZ) acts as a clearance receptor for BMP4; loss of LRP2 results in increased BMP4 expression and enhanced phospho-SMAD1/5/8 and ID3 activation in the stem cell niche, impairing neural precursor cell proliferation and reducing neuroblast numbers reaching the olfactory bulb. Conditional LRP2 knockout in adult mice, immunohistochemistry for BMP4/pSMAD1/5/8/ID3, BrdU proliferation assay, neuroblast counting Journal of cell science High 20460439
2012 LRP2 acts as an auxiliary SHH receptor in the rostral diencephalon ventral midline (RDVM): it sequesters SHH at the apical membrane, controls internalization and trafficking of SHH/patched-1 complexes, and lack of LRP2 causes failure to respond to SHH despite functional patched-1 and smoothened expression; overexpression of LRP2 variants increases SHH signaling capacity. LRP2 knockout mice and cephalic explant assays, gain-of-function overexpression in cells, co-immunoprecipitation of LRP2 with SHH and patched-1, immunofluorescence for signaling components Developmental cell High 22340494
2006 LRP2/megalin and its co-receptor cubilin are conserved in zebrafish larval pronephros for clearance from the ultrafiltrate; knockdown of megalin causes loss of Rab4-positive endosomes and abrogates apical endocytosis; knockdown of the megalin adaptor Disabled 2 (Dab2) also blocks renal clearance, providing genetic evidence that renal tubular endocytosis is ligand-induced and crucially depends on megalin activity. Morpholino knockdown in zebrafish, tracer clearance assay, immunostaining for Rab4-positive endosomes Journal of cell science High 16638803
2011 LRP2/megalin cytoplasmic domain phosphorylation by GSK3, proteolytic shedding of the extracellular domain at the cell surface, subsequent intramembrane proteolysis by the gamma-secretase complex, and exosome secretion collectively regulate megalin availability at the cell surface. Review citing experimental findings: phosphorylation by GSK3, shedding and gamma-secretase cleavage assays (cited from prior experimental literature) Biological research Low 21720686
2014 LRP2 is required for uptake of folate bound to soluble folate receptor 1 (sFOLR1) in neuroepithelial cells during neurulation; LRP2-deficient neuroepithelial cells cannot mediate sFOLR1-folate uptake, leading to reduced folate concentrations and downregulation of the folate-dependent gene Alx3, resulting in impaired neural tube closure. Whole-embryo culture uptake assays in Lrp2−/− mice, folate concentration measurement, Alx3 expression analysis, neural tube closure phenotyping Journal of cell science High 24639464
2015 In the developing retina, LRP2 acts as a clearance receptor for SHH, mediating its endocytic degradation to prevent spread of SHH activity from the central retina into the retinal margin; loss of LRP2 increases retinal margin sensitivity to SHH, causing expansion of retinal progenitor cells and hyperproliferation. Retina-specific Lrp2 conditional knockout mice, immunostaining for SHH, proliferation assays (BrdU/Ki67), progenitor cell pool quantification Developmental cell High 26439398
2013 LRP2 and clusterin (ApoJ) form a hypothalamic anorexigenic axis; central clusterin administration activates hypothalamic STAT3, and these effects are mediated through LRP2 and the long-form leptin receptor (LepRb); clusterin stimulation greatly enhances LRP2 binding to LepRb in cultured neuronal cells; LRP2 suppression or LepRb deficiency impairs hypothalamic clusterin signaling. Central (ICV) clusterin administration in mice, hypothalamic LRP2 knockdown (AAV), co-immunoprecipitation of LRP2 with LepRb in neurons, food intake and body weight measurements Nature communications High 23673647
2014 Clusterin/ApoJ enhances leptin receptor binding and endocytosis of leptin through LRP2; inhibition of LRP2, hypothalamic clusterin, or endocytosis abrogates anorexia and STAT3 activation caused by leptin. Cultured neuron binding and endocytosis assays, hypothalamic LRP2 knockdown, ICV clusterin/leptin co-administration with STAT3 phosphorylation readout EMBO reports High 24825475
2021 LRP2 is required for neural tube closure through its role in neuroepithelial morphogenesis; loss of Lrp2 impairs apical constriction and proper localization of the PCP protein Vangl2; LRP2 functionally interacts with intracellular adaptor proteins Shroom3 and Gipc1 in the developing forebrain, suggesting its intracellular domain acts as a hub orchestrating endocytic membrane removal for apical constriction and PCP component trafficking. Lrp2 knockout in mouse and morpholino knockdown in Xenopus laevis, immunostaining for Vangl2 and apical constriction markers, Co-IP of LRP2 with Shroom3 and Gipc1 Development (Cambridge, England) High 33500317
2007 LRP2 mutations cause Donnai-Barrow syndrome and facio-oculo-acoustico-renal (FOAR) syndrome, demonstrating that LRP2 function as a multiligand uptake receptor is essential for normal development of multiple organ systems in humans. Genetic mapping in multiplex families, LRP2 sequencing, identification of pathogenic mutations Nature genetics High 17632512
2019 TGF-β1 downregulates megalin/LRP2 expression through the SMAD2/3 pathway; SMAD2/3 transcription factors bind to two SMAD-binding elements (SBEs) in the megalin promoter at positions -57 and -605, repressing promoter activity; site-directed mutagenesis of SBEs abolishes this repression; histone deacetylase inhibitor TSA counteracts TGF-β1-mediated megalin repression. Site-directed mutagenesis of SBEs, chromatin immunoprecipitation (ChIP), EMSA, luciferase reporter assays, TGF-βRI inhibitor treatment in two epithelial cell lines PloS one High 31120873
2011 PPARα and PPARγ ligands increase megalin/LRP2 mRNA and protein expression by binding to three PPAR response elements in the megalin promoter; PPAR binding to these elements was demonstrated by EMSA, and PPARα with its agonist activated a luciferase reporter containing the first megalin promoter response element. EMSA, luciferase reporter assay, PPAR agonist/antagonist treatments in epithelial cell lines, in vivo mouse kidney megalin expression analysis PloS one High 21311715
2023 Cryo-EM structures of LRP2 reveal it forms a homodimer that adopts distinct conformations at extracellular pH (for ligand binding) and endosomal pH (for ligand shedding); the conformational transformation is governed by pH-sensitive sites at homodimer and intra-protomer interfaces; a subset of human deleterious LRP2 missense variants impair homodimer assembly. High-resolution cryoelectron microscopy at two pH conditions, structural analysis of missense variants, isolation of LRP2 from mouse kidney Cell High 36750096
2010 MESD chaperone is essential for apical localization of LRP2/megalin in the visceral endoderm; loss of Mesd blocks LRP2 maturation and its apical delivery, resulting in impaired endocytic function; MESD function in vitro is essential for maturation of the β-propeller/EGF domain common to LRPs. Targeted Mesd knockout mouse, immunostaining for LRP2 localization in visceral endoderm, in vitro LRP domain maturation assay Developmental dynamics High 21337463
2007 Gc-globulin (vitamin D binding protein) is internalized by hepatic stellate cells through a Ca2+-dependent interaction with the megalin/gp330 receptor; inhibition of megalin by a neutralizing antibody decreased intracellular gc-globulin availability, and Ca2+ chelation with EDTA further reduced internalization. Immunocytochemistry, FACS-based receptor identification, neutralizing antibody inhibition of endocytosis, EDTA-mediated Ca2+ chelation in hepatic stellate cells Clinica chimica acta Medium 18194670
2020 LRP2 is required for cardiomyocyte proliferation and differentiation during heart development; siRNA/RNAi-mediated knockdown of LRP2 in human iPSC-derived cardiomyocytes and in Drosophila and zebrafish hearts impairs these processes. siRNA knockdown in iPSC-CMs, RNAi in Drosophila, morpholino knockdown in zebrafish, proliferation and differentiation assays eLife Medium 33006316
2020 LRP2 controls sonic hedgehog-dependent maintenance of cardiac progenitor cell fate in the anterior second heart field (SHF); loss of LRP2 in mice depletes a pool of SHH-dependent progenitor cells in the anterior SHF due to premature differentiation into cardiomyocytes, causing aberrant shortening of the outflow tract and common arterial trunk formation. LRP2-deficient mouse models, immunohistochemistry for SHF markers (Nkx2.5, Isl1), cardiomyocyte differentiation marker staining, morphometric analysis of outflow tract Human molecular genetics High 32901292
2022 Mettl3-mediated m6A modification of Lrp2 mRNA enhances its stability and translation efficiency through the m6A reader protein Ythdc2, promoting hippocampal neurogenesis; depletion of Mettl3 reduces Lrp2 expression and neurogenesis, and these defects are rescued by Lrp2 overexpression. Mettl3/Mettl14 knockout in neural stem cells, m6A sequencing, Ythdc2 reader pulldown, Lrp2 mRNA stability and translation efficiency assays, behavioral rescue by Lrp2 overexpression in mice FASEB journal Medium 35716070
1989 Microtubules are required for the accumulation of LRP2/gp330-containing vesicles at the apical pole of proximal tubule cells and for their insertion into the apical membrane; colchicine-induced microtubule disruption causes gp330-containing vesicles to disperse throughout the cytoplasm without inserting into the basolateral membrane. Colchicine treatment in vivo, immunocytochemistry (immunoperoxidase and immunofluorescence), intravenous injection of anti-gp330 antiserum to test for basolateral membrane insertion The American journal of physiology High 2669509
1990 LRP2/gp330 demonstrates specific affinity for fibronectin, laminin, and type I collagen that is not inhibited by RGD peptides, and mediates proximal tubule epithelial cell adherence to these matrix proteins in vitro; anti-gp330 monoclonal antibody inhibited attachment and proliferation on collagen-, fibronectin-, laminin-, and gelatin-coated surfaces. Monoclonal antibody inhibition of cell attachment, detergent-solubilized gp330 binding to matrix proteins, cell proliferation assays Experimental cell research Medium 1691715

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Complete cloning and sequencing of rat gp330/"megalin," a distinctive member of the low density lipoprotein receptor gene family. Proceedings of the National Academy of Sciences of the United States of America 501 7937880
1983 Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. The Journal of experimental medicine 501 6337231
1996 Defective forebrain development in mice lacking gp330/megalin. Proceedings of the National Academy of Sciences of the United States of America 428 8710893
1992 Low density lipoprotein receptor-related protein and gp330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance. The Journal of biological chemistry 426 1464627
1994 Organ distribution in rats of two members of the low-density lipoprotein receptor gene family, gp330 and LRP/alpha 2MR, and the receptor-associated protein (RAP). The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 299 7510321
2007 Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nature genetics 264 17632512
1996 Megalin/gp330 mediates uptake of albumin in renal proximal tubule. The American journal of physiology 243 8898021
1995 The Heymann nephritis antigenic complex: megalin (gp330) and RAP. Journal of the American Society of Nephrology : JASN 183 7579068
1997 Tissue distribution of human gp330/megalin, a putative Ca(2+)-sensing protein. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 175 9071320
1992 Renal tubule gp330 is a calcium binding receptor for endocytic uptake of protein. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 161 1382088
2011 New insights into the roles of megalin/LRP2 and the regulation of its functional expression. Biological research 155 21720686
1992 gp330 associates with a 44-kDa protein in the rat kidney to form the Heymann nephritis antigenic complex. Proceedings of the National Academy of Sciences of the United States of America 150 1495959
2005 LRP2/megalin is required for patterning of the ventral telencephalon. Development (Cambridge, England) 141 15623804
1995 Segmental distribution of the endocytosis receptor gp330 in renal proximal tubules. European journal of cell biology 133 7656901
1999 A gp330/megalin-related protein is required in the major epidermis of Caenorhabditis elegans for completion of molting. Development (Cambridge, England) 126 9876188
1996 Cloning and sequencing of human gp330, a Ca(2+)-binding receptor with potential intracellular signaling properties. European journal of biochemistry 125 8706697
2010 LRP2 in ependymal cells regulates BMP signaling in the adult neurogenic niche. Journal of cell science 117 20460439
1991 Identification of the rat Heymann nephritis autoantigen (GP330) as a receptor site for plasminogen. The Journal of biological chemistry 117 1645711
2012 LRP-1 and LRP-2 receptors function in the membrane neuron. Trafficking mechanisms and proteolytic processing in Alzheimer's disease. Frontiers in physiology 94 22934024
1990 Molecular cloning of a cDNA encoding a major pathogenic domain of the Heymann nephritis antigen gp330. Proceedings of the National Academy of Sciences of the United States of America 93 2408041
2012 LRP2 is an auxiliary SHH receptor required to condition the forebrain ventral midline for inductive signals. Developmental cell 90 22340494
2000 Role of megalin (gp330) in transcytosis of thyroglobulin by thyroid cells. A novel function in the control of thyroid hormone release. The Journal of biological chemistry 87 10702280
1993 Identification of a cell line that expresses a cell surface and a soluble form of the gp330/receptor-associated protein (RAP) Heymann nephritis antigenic complex. Proceedings of the National Academy of Sciences of the United States of America 83 8483924
2011 Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma. PLoS genetics 81 21379331
2007 Dynamic expression of Lrp2 pathway members reveals progressive epithelial differentiation of primitive endoderm in mouse blastocyst. Developmental biology 81 18083160
2006 The role of megalin (LRP-2/Gp330) during development. Developmental biology 71 16828734
1989 Colchicine-induced redistribution of an apical membrane glycoprotein (gp330) in proximal tubules. The American journal of physiology 70 2669509
1987 Identification of a 400-kd protein in the brush borders of human kidney tubules that is similar to gp330, the nephritogenic antigen of rat Heymann nephritis. The American journal of pathology 70 2444109
1998 Regulation of gp330/megalin expression by vitamins A and D. European journal of clinical investigation 69 9541123
2006 Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros. Journal of cell science 66 16638803
1998 Megalin (gp330): a putative endocytic receptor for thyroglobulin (Tg). Endocrinology 66 9492085
1995 gp330 on type II pneumocytes mediates endocytosis leading to degradation of pro-urokinase, plasminogen activator inhibitor-1 and urokinase-plasminogen activator inhibitor-1 complex. Journal of cell science 65 7673355
2013 Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway. Nature communications 63 23673647
1999 Glycoprotein 330/megalin (LRP-2) has low prevalence as mRNA and protein in brain microvessels and choroid plexus. Experimental neurology 58 10222122
1999 Megalin (gp330) is an endocytic receptor for thyroglobulin on cultured fisher rat thyroid cells. The Journal of biological chemistry 57 10212279
1995 Effects of microtubule disruption on endocytosis, membrane recycling and polarized distribution of Aquaporin-1 and gp330 in proximal tubule cells. European journal of cell biology 56 7543847
1993 Detection of two forms of GP330. Their role in Heymann nephritis. The American journal of pathology 56 8342605
2023 Structures of LRP2 reveal a molecular machine for endocytosis. Cell 55 36750096
1999 Identification of megalin/gp330 as a receptor for lipoprotein(a) in vitro. Arteriosclerosis, thrombosis, and vascular biology 55 10073957
1997 Pathogenic antibodies inhibit the binding of apolipoproteins to megalin/gp330 in passive Heymann nephritis. The Journal of clinical investigation 54 9410908
2008 Donnai-Barrow syndrome (DBS/FOAR) in a child with a homozygous LRP2 mutation due to complete chromosome 2 paternal isodisomy. American journal of medical genetics. Part A 53 18553518
1993 Location of gp330/alpha 2-m receptor-associated protein (alpha 2-MRAP) and its binding sites in kidney: distribution of endogenous alpha 2-MRAP is modified by tissue processing. European journal of cell biology 52 8223699
2011 Megalin/LRP2 expression is induced by peroxisome proliferator-activated receptor -alpha and -gamma: implications for PPARs' roles in renal function. PloS one 49 21311715
1995 The expression of megalin (gp330) and LRP diverges during F9 cell differentiation. Journal of cell science 45 7615664
2015 LRP2 Acts as SHH Clearance Receptor to Protect the Retinal Margin from Mitogenic Stimuli. Developmental cell 44 26439398
2014 LRP2 mediates folate uptake in the developing neural tube. Journal of cell science 43 24639464
2012 Scan-statistic approach identifies clusters of rare disease variants in LRP2, a gene linked and associated with autism spectrum disorders, in three datasets. American journal of human genetics 43 22578327
1994 Chromosomal localization of human genes for the LDL receptor family member glycoprotein 330 (LRP2) and its associated protein RAP (LRPAP1). Genomics 42 7959795
1996 Induction of Heymann nephritis with a gp330/megalin fusion protein. The American journal of pathology 41 8623929
1995 Immunofunctional properties of a yolk sac epithelial cell line expressing two proteins gp280 and gp330 of the intermicrovillar area of proximal tubule cells: inhibition of endocytosis by the specific antibodies. European journal of cell biology 41 7664754
1994 gp330 and RAP: the Heymann nephritis antigenic complex. Annals of the New York Academy of Sciences 41 7944157
2016 MicroRNA-146a represses LRP2 translation and leads to cell apoptosis in Alzheimer's disease. FEBS letters 37 27241555
2013 Broadening the phenotype of LRP2 mutations: a new mutation in LRP2 causes a predominantly ocular phenotype suggestive of Stickler syndrome. Clinical genetics 37 23992033
2015 Foxg1-Cre Mediated Lrp2 Inactivation in the Developing Mouse Neural Retina, Ciliary and Retinal Pigment Epithelia Models Congenital High Myopia. PloS one 36 26107939
1993 Biosynthesis of the gp330/44-kDa Heymann nephritis antigenic complex: assembly takes place in the ER. The American journal of physiology 36 8322889
2021 Neural tube closure requires the endocytic receptor Lrp2 and its functional interaction with intracellular scaffolds. Development (Cambridge, England) 35 33500317
2014 Clusterin/ApoJ enhances central leptin signaling through Lrp2-mediated endocytosis. EMBO reports 35 24825475
2017 Endocytic receptor LRP2/megalin-of holoprosencephaly and renal Fanconi syndrome. Pflugers Archiv : European journal of physiology 34 28497274
2007 Gc-globulin (vitamin D binding protein) is synthesized and secreted by hepatocytes and internalized by hepatic stellate cells through Ca(2+)-dependent interaction with the megalin/gp330 receptor. Clinica chimica acta; international journal of clinical chemistry 34 18194670
2016 LRP2, an auxiliary receptor that controls sonic hedgehog signaling in development and disease. Developmental dynamics : an official publication of the American Association of Anatomists 33 26872844
2011 Loss of Lrp2 in zebrafish disrupts pronephric tubular clearance but not forebrain development. Developmental dynamics : an official publication of the American Association of Anatomists 33 21455927
1993 Analysis of a 45-kDa protein that binds to the Heymann nephritis autoantigen GP330. The Journal of biological chemistry 33 7681839
2015 Variable expression pattern in Donnai-Barrow syndrome: Report of two novel LRP2 mutations and review of the literature. European journal of medical genetics 32 25682901
2020 Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome. eLife 31 33006316
2016 Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development. Disease models & mechanisms 31 26822476
1990 Heymann antigen GP330 demonstrates affinity for fibronectin, laminin, and type I collagen and mediates rat proximal tubule epithelial cell adherence to such matrices in vitro. Experimental cell research 30 1691715
2015 Melanoma tumors frequently acquire LRP2/megalin expression, which modulates melanoma cell proliferation and survival rates. Pigment cell & melanoma research 29 25585665
1995 Megalin (gp330) possesses an antigenic epitope capable of inducing passive Heymann nephritis independent of the nephritogenic epitope in receptor-associated protein. Journal of the American Society of Nephrology : JASN 29 7579071
2019 Participation of the SMAD2/3 signalling pathway in the down regulation of megalin/LRP2 by transforming growth factor beta (TGF-ß1). PloS one 28 31120873
2020 Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease. American journal of physiology. Renal physiology 26 33103447
2010 A single nucleotide polymorphism in LRP2 is associated with susceptibility to Alzheimer's disease in the Chinese population. Clinica chimica acta; international journal of clinical chemistry 25 20971101
1994 Gp330 is specifically expressed in outer cells during epithelial differentiation in the preimplantation mouse embryo. Development (Cambridge, England) 25 7720568
2017 Impaired vitreous composition and retinal pigment epithelium function in the FoxG1::LRP2 myopic mice. Biochimica et biophysica acta. Molecular basis of disease 23 28366874
2017 Genetic variation in the gene LRP2 increases relapse risk in multiple sclerosis. Journal of neurology, neurosurgery, and psychiatry 23 28739605
2000 Circulating and luminal testicular factors affect LRP-2 and Apo J expression in the epididymis following efferent duct ligation. Journal of andrology 23 10670527
1996 Specific effect of maleate on an apical membrane glycoprotein (gp330) in proximal tubule of rat kidneys. The American journal of physiology 23 8898022
2022 Mettl3-mediated m6 A modification of Lrp2 facilitates neurogenesis through Ythdc2 and elicits antidepressant-like effects. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 35716070
2020 Metformin Inhibits Proliferation of Human Thyroid Cancer TPC-1 Cells by Decreasing LRP2 to Suppress the JNK Pathway. OncoTargets and therapy 22 32021253
2003 Autoantibodies to low-density-lipoprotein-receptor-related protein 2 (LRP2) in systemic autoimmune diseases. Arthritis research & therapy 22 12723989
1990 Isolation of a 330-kDa glycoprotein from human kidney similar to the Heymann nephritis autoantigen (gp330). Journal of the American Society of Nephrology : JASN 22 2133428
1986 The organ distribution of gp-330 (Heymann antigen) and gp-90 in the mouse and the rat. Virchows Archiv. A, Pathological anatomy and histopathology 22 3082068
2016 Association Analysis of the Cubilin (CUBN) and Megalin (LRP2) Genes with ESRD in African Americans. Clinical journal of the American Society of Nephrology : CJASN 21 27197912
2012 Significant interaction between LRP2 rs2544390 in intron 1 and alcohol drinking for serum uric acid levels among a Japanese population. Gene 21 22565184
1999 Serum antibodies against megalin (GP330) in patients with autoimmune thyroiditis. The Journal of clinical endocrinology and metabolism 19 10404822
2019 Anti-LRP2 Nephropathy With Abundant IgG4-Positive Plasma Cells: A Case Report. American journal of kidney diseases : the official journal of the National Kidney Foundation 17 30876746
2016 Identification of a homozygous missense mutation in LRP2 and a hemizygous missense mutation in TSPYL2 in a family with mild intellectual disability. Psychiatric genetics 17 26529358
2000 Characterization of the N-linked oligosaccharides of megalin (gp330) from rat kidney. Glycobiology 17 10704528
2010 MESD is essential for apical localization of megalin/LRP2 in the visceral endoderm. Developmental dynamics : an official publication of the American Association of Anatomists 15 21337463
1992 Analysis of plasmin binding and urokinase activation of plasminogen bound to the Heymann nephritis autoantigen, gp330. Archives of biochemistry and biophysics 15 1280065
2007 Genetic association of low-density lipoprotein receptor-related protein 2 (LRP2) with plasma lipid levels. Journal of atherosclerosis and thrombosis 14 18174661
2020 LRP2 controls sonic hedgehog-dependent differentiation of cardiac progenitor cells during outflow tract formation. Human molecular genetics 13 32901292
2013 Progesterone induces expression of Lrp2 in the murine uterus. Biochemical and biophysical research communications 13 24140060
2017 Prevention of neural tube defects in Lrp2 mutant mouse embryos by folic acid supplementation. Birth defects research 12 27883261
1998 Vitamin D receptor gene polymorphism and parathyroid calcium sensor protein (CAS/gp330) expression in primary hyperparathyroidism. World journal of surgery 12 9606285
1995 Immunohistochemical localization of alpha-2 macroglobulin receptor/low-density lipoprotein receptor-related protein, receptor-associated protein, and Gp330 in the human endometrium. Journal of the Society for Gynecologic Investigation 12 9420885
2022 Postnatal eye size in mice is controlled by SREBP2-mediated transcriptional repression of Lrp2 and Bmp2. Development (Cambridge, England) 11 35833708
2021 Long non-coding RNA AC012668 suppresses non-alcoholic fatty liver disease by competing for microRNA miR-380-5p with lipoprotein-related protein LRP2. Bioengineered 11 34511037
2015 Common Variants in LRP2 and COMT Genes Affect the Susceptibility of Gout in a Chinese Population. PloS one 11 26147675
1994 Expression of gp330 and gp330/alpha 2-macroglobulin receptor-associated protein in renal tubular differentiation. Journal of the American Society of Nephrology : JASN 11 7522607
1993 Mapping of the glycoprotein 330 (Gp330) gene to mouse chromosome 2. Genomics 11 8244399

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