Affinage

LRP2

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

Length
4655 aa
Mass
522.0 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRP2 (megalin) is a giant multi-ligand endocytic receptor of the LDL receptor family that functions as a central mediator of apical endocytosis, transcytosis, and morphogen signaling in polarized epithelial and neuroepithelial cells. The receptor contains 36 complement-type ligand-binding repeats organized into four extracellular domains, a single transmembrane segment, and a cytoplasmic tail with two FXNPXY internalization motifs; it operates as a pH-sensitive homodimer that binds ligands at cell-surface pH and releases them upon endosomal acidification (PMID:36750096, PMID:8706697). Through Ca²⁺-dependent binding regulated by the chaperone RAP, LRP2 internalizes a broad ligand repertoire—including lipoproteins, thyroglobulin, plasminogen, BMP4, SHH, and clusterin—routing them to lysosomes for degradation or mediating transcytosis, and it acts context-dependently as either a morphogen clearance receptor (BMP4 in dorsal neuroepithelium, SHH in retinal margin) or a signaling co-receptor (SHH in forebrain, clusterin/leptin receptor in hypothalamus) (PMID:15623804, PMID:22340494, PMID:26439398, PMID:23673647, PMID:10702280). Loss-of-function mutations cause holoprosencephaly and neural tube defects in mice, and Donnai–Barrow syndrome in humans, while its intracellular domain coordinates apical constriction during neurulation through interactions with Shroom3 and Gipc1 adaptors (PMID:8710893, PMID:33500317, PMID:36750096).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1983 High

    Establishing LRP2/gp330 as a membrane glycoprotein of clathrin-coated pits in kidney epithelial cells resolved the identity of the Heymann nephritis antigen and placed it in the endocytic pathway.

    Evidence Immunoprecipitation, immunofluorescence, and immunoelectron microscopy on rat kidney sections

    PMID:6337231

    Open questions at the time
    • Ligand identity unknown
    • Molecular structure undetermined
    • Function beyond immune target not established
  2. 1991 High

    Identification of plasminogen, RAP, and lipoprotein ligands revealed that LRP2 is a multi-ligand endocytic receptor with distinct but overlapping binding sites, regulated universally by the 39-kDa RAP chaperone.

    Evidence Ligand blotting, ELISA competition, and cross-competition assays with purified gp330 and multiple ligands; in vivo microperfusion demonstrating RAP endocytosis into lysosomes

    PMID:1280065 PMID:1382088 PMID:1464627 PMID:1645711

    Open questions at the time
    • Full ligand-binding domain mapping not achieved
    • Endocytic trafficking itinerary beyond lysosomes not resolved
    • RAP mechanism of inhibition not structurally defined
  3. 1993 High

    Demonstrating that LRP2 and RAP assemble as a heterodimeric complex in the ER through Ca²⁺-dependent steps established that RAP functions as an intracellular chaperone, not merely an extracellular competitor.

    Evidence Pulse-chase radiolabeling, sucrose gradient sedimentation, and endoglycosidase H digestion in rat kidney tubule fragments

    PMID:1495959 PMID:8322889

    Open questions at the time
    • Whether RAP dissociates before or upon exit from ER/Golgi not resolved
    • Structural basis of Ca²⁺-dependent assembly unknown
  4. 1995 High

    Detailed subcellular mapping by immunoelectron microscopy across species confirmed LRP2 cycles through apical coated pits, endocytic vacuoles, dense apical tubules, and lysosomes, and that microtubule integrity is required for its apical polarization and endocytic function.

    Evidence Multi-species immunoelectron microscopy with morphometry; in vivo colchicine perturbation with functional peroxidase endocytosis assay

    PMID:2669509 PMID:7543847 PMID:7656901

    Open questions at the time
    • Motor proteins mediating microtubule-dependent transport not identified
    • Sorting signals for apical targeting beyond FXNPXY motifs not mapped
  5. 1996 High

    Cloning of the complete human LRP2 sequence revealed its domain architecture (36 ligand-binding repeats, 16 EGF repeats, two FXNPXY motifs, signaling motifs), and LRP2 knockout mice demonstrated that the receptor is essential for forebrain development, linking endocytic receptor function to morphogenesis.

    Evidence Full-length cDNA cloning from human tissues; LRP2 knockout mouse with holoprosencephaly phenotype

    PMID:8706697 PMID:8710893

    Open questions at the time
    • Which ligand(s) mediate the forebrain phenotype not determined
    • Contribution of individual binding domains not dissected
  6. 1999 High

    Discovery that LRP2 mediates both endocytosis and apical-to-basolateral transcytosis of thyroglobulin in thyroid cells, with transcytosis diverting Tg from lysosomal degradation, established a non-degradative trafficking function that regulates thyroid hormone release.

    Evidence Polarized FRTL-5 transcytosis assays with RAP and antibody inhibition; chemical cross-linking confirming surface Tg–megalin complexes

    PMID:10212279 PMID:10702280 PMID:9492085

    Open questions at the time
    • Sorting signals distinguishing transcytotic from degradative routing not identified
    • In vivo thyroid phenotype in megalin-deficient animals not reported
  7. 2005 High

    Conditional knockout studies resolved the forebrain phenotype mechanism: LRP2 acts as a BMP4 clearance receptor in the dorsal neuroepithelium; its loss elevates BMP4 signaling, which suppresses ventral SHH expression, causing holoprosencephaly.

    Evidence Conditional and complete LRP2 knockout mice with in situ hybridization for BMP4 and SHH, cell population analysis

    PMID:15623804

    Open questions at the time
    • Direct BMP4 binding affinity and stoichiometry not measured
    • Whether other BMP family members are also cleared not tested
  8. 2011 High

    A dual role for LRP2 in morphogen signaling was established: it acts as a SHH co-receptor in the forebrain (enhancing SHH/Patched-1 signaling) but as a SHH clearance receptor in the retinal margin, demonstrating context-dependent function.

    Evidence LRP2 knockout mice, cephalic explant assays, overexpression/loss-of-function with SHH pathway readouts; conditional retinal KO with BrdU proliferation assays

    PMID:22340494 PMID:26439398

    Open questions at the time
    • Structural determinants of co-receptor vs. clearance mode not identified
    • Whether LRP2 directly binds SHH or acts via Patched-1 complex not fully resolved
  9. 2013 High

    LRP2 was shown to function beyond classical endocytosis as a signaling scaffold: clusterin binding to LRP2 promotes its association with the leptin receptor in hypothalamic neurons, potentiating STAT3 activation and anorexigenic signaling.

    Evidence Co-immunoprecipitation of LRP2 with leptin receptor, siRNA knockdown, in vivo central clusterin administration with STAT3 readout

    PMID:23673647 PMID:24825475

    Open questions at the time
    • Whether LRP2-leptin receptor interaction is direct or mediated by clusterin bridging not resolved
    • Downstream intracellular trafficking route of the ternary complex not characterized
  10. 2021 High

    Identification of Shroom3 and Gipc1 as intracellular binding partners of LRP2's cytoplasmic domain established a non-endocytic structural role: LRP2 orchestrates apical constriction and planar cell polarity (Vangl2 localization) required for neural tube closure.

    Evidence LRP2 loss-of-function in mouse and Xenopus, co-immunoprecipitation with Shroom3/Gipc1, immunofluorescence for Vangl2 and apical markers

    PMID:33500317

    Open questions at the time
    • Whether Shroom3/Gipc1 binding is simultaneous or competitive not resolved
    • Which cytoplasmic motifs mediate Shroom3 vs. Gipc1 interaction not mapped
  11. 2023 High

    Cryo-EM structures at two pH states revealed that LRP2 functions as a homodimer with a pH-dependent conformational switch: an open ligand-binding state at neutral pH and a closed ligand-release state at endosomal pH, with disease-associated mutations disrupting dimerization.

    Evidence High-resolution cryo-EM of native LRP2 from mouse kidney at pH 7.4 and pH 5.0; mapping of human Donnai–Barrow syndrome missense variants onto structure

    PMID:36750096

    Open questions at the time
    • Ligand-bound structures not yet solved
    • How individual domains contribute to multi-ligand binding not structurally resolved
    • Dynamics of pH transition in intact endosomes not captured

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for multi-ligand selectivity across LRP2's four binding domains, the sorting determinants that route LRP2-ligand complexes to transcytosis versus degradation, and the mechanism by which the same receptor switches between morphogen co-receptor and clearance receptor roles in different tissues.
  • No ligand-bound cryo-EM structure
  • Sorting signals for transcytotic vs. degradative pathway not mapped
  • Tissue-specific co-factors determining co-receptor vs. clearance function unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 9 GO:0008289 lipid binding 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 3 GO:0031410 cytoplasmic vesicle 3 GO:0005764 lysosome 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 7 R-HSA-1266738 Developmental Biology 5 R-HSA-1430728 Metabolism 5 R-HSA-162582 Signal Transduction 3
Partners
BMP4CLUCUBNDAB2GIPC1LRPAP1SHHSHROOM3
Complex memberships
LRP2-RAP chaperone complexLRP2-cubilin receptor complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1983 LRP2/gp330 localizes to clathrin-coated pits on glomerular epithelial cells (podocytes) and proximal tubule cells, where it concentrates and serves as the site of immune complex formation in Heymann nephritis; it is synthesized by glomerular epithelial cells and traffics through ER, Golgi, and multivesicular bodies to coated pits. Immunoprecipitation of radiolabeled kidney extracts, indirect immunofluorescence, immunoperoxidase electron microscopy on cryostat sections The Journal of experimental medicine High 6337231
1990 A C-terminal domain of gp330 (encoded by clone 14, ~319 amino acids) contains a major pathogenic epitope responsible for antibody binding and subepithelial immune deposit formation in Heymann nephritis; antibodies against this domain induce both passive and active Heymann nephritis in rats. cDNA library screening with eluted glomerular IgG, expression of fusion protein, passive and active immunization of rats, immunoblotting Proceedings of the National Academy of Sciences of the United States of America High 2408041
1991 LRP2/gp330 functions as a receptor for plasminogen; binding is saturable and specifically inhibitable, and is not exclusively through lysine-binding sites, indicating additional interaction sites. Western blot ligand binding, ELISA saturation and competition assays, cDNA library screening with antibody to purified serum protein The Journal of biological chemistry High 1645711
1992 LRP2/gp330 acts as a Ca2+-binding endocytic receptor in renal proximal tubule; it binds the 40-kDa RAP protein in a Ca2+-dependent, heparin-sensitive manner, and mediates endocytosis of RAP into lysosomes as demonstrated by in vivo tubular microperfusion. Ligand blotting, 45Ca2+ blotting, light and electron microscopic autoradiography, in vivo microperfusion of rat proximal tubules with 125I-labeled ligand The journal of histochemistry and cytochemistry High 1382088
1992 LRP2/gp330 shares multiple ligand-binding specificities with LRP1, binding plasminogen activator-inhibitor complexes, lactoferrin, and apolipoprotein E-enriched beta-VLDL; all ligand binding to both receptors is inhibited by the 39-kDa RAP protein, identifying RAP as a universal regulator of ligand binding. Cross-competition shows at least three distinct but overlapping binding sites on LRP. Nitrocellulose ligand blotting with purified rat kidney gp330, cell-based cholesteryl ester synthesis assay, cross-competition experiments in cultured human fibroblasts The Journal of biological chemistry High 1464627
1992 LRP2/gp330 forms a stable heterodimeric complex with a 44-kDa protein (RAP/alpha2-MRAP) in the rat kidney, constituting the Heymann nephritis antigenic complex (HNAC); the complex is stable to detergent extraction, and RAP shares immunological identity with the C14 fusion protein. Immunoprecipitation with specific antibodies, immunoblotting, long-term centrifugation stability tests Proceedings of the National Academy of Sciences of the United States of America High 1495959
1992 Once plasminogen is bound to gp330, urokinase can convert it to plasmin at an accelerated rate; plasmin remains bound to gp330 in an active state and is protected from inactivation by alpha2-antiplasmin while bound. In vitro enzyme kinetics (Km/Vmax analysis), ELISA binding assays, chromogenic substrate cleavage assays Archives of biochemistry and biophysics High 1280065
1993 LRP2/gp330 and its associated 44-kDa protein (RAP) assemble in the endoplasmic reticulum; the complex forms in two steps: first a Ca2+-dependent 19.3S heterodimer within 30 min of synthesis, then a larger 38.6S heterooligomer >60 min post-synthesis, both steps preceding Golgi processing (Endo H-resistant glycosylation). Pulse-chase radiolabeling of rat kidney tubule fragments, immunoprecipitation with specific antibodies, sucrose velocity gradient centrifugation, endoglycosidase H digestion The American journal of physiology High 8322889
1993 LRP2/gp330 mediates endocytosis of pro-urokinase, PAI-1, and urokinase:PAI-1 complexes in type II pneumocytes; RAP completely inhibits this internalization and degradation, and anti-gp330 antibodies inhibit 30–50%, confirming gp330-dependent clearance of plasminogen activation system components. Radiolabeled ligand internalization and degradation assays in cultured type II pneumocytes, antibody inhibition, RAP competition Journal of cell science High 7673355
1993 LRP2/gp330 binds a distinct 45-kDa protein (RAP) as a separate ligand from plasminogen; gp330 has two separate and non-competing binding sites for plasminogen and the 45-kDa RAP, demonstrating multi-site ligand architecture. ELISA binding assays, competitive inhibition experiments, cDNA library screening, sequence analysis The Journal of biological chemistry Medium 7681839
1995 Megalin/gp330 localizes primarily to apical coated pits, small and large endocytic vacuoles, and dense apical tubules in proximal tubule cells, with segmental variation; it is also found in lysosomes (especially segments 1 and 2) and brush border microvilli, consistent with a protein scavenger receptor role cycling through the early endocytic pathway. Light and electron microscope immunocytochemistry on cryosections and Lowicryl sections from rat, rabbit, and human kidney European journal of cell biology High 7656901
1989 Microtubule integrity is required for polarized apical localization of LRP2/gp330 in proximal tubule cells; colchicine treatment disperses gp330-containing vesicles throughout the cytoplasm, though gp330 is not inserted into the basolateral membrane, indicating microtubules drive apical accumulation but other factors govern membrane fusion. In vivo colchicine treatment of rats, immunocytochemistry (immunofluorescence and immunoperoxidase), intravenous antibody injection to test basolateral access The American journal of physiology High 2669509
1995 Microtubule disruption by colchicine blocks apical endocytosis, impairs endocytic invagination formation, disrupts membrane recycling (dense apical tubules), and redistributes gp330 from the apical endocytic apparatus to dispersed cytoplasmic vesicles, without altering other brush border markers. In vivo colchicine treatment, electron microscopy, morphometry, immunocytochemistry, functional peroxidase endocytosis assay European journal of cell biology High 7543847
1996 Complete primary structure of human gp330/LRP2 was determined: 4655 amino acids, single transmembrane domain, 36 LDLR ligand-binding repeats in four domains, 16 EGF-like repeats, two FXNPXY internalization signals in the cytoplasmic tail, and multiple signaling motifs (SH2, SH3, PKC, CKII sites) suggesting potential intracellular signaling capacity. cDNA cloning, RT-PCR, sequence analysis of human parathyroid, kidney, placenta, epididymis, and lung European journal of biochemistry High 8706697
1996 Megalin/LRP2 knockout mice exhibit holoprosencephaly, loss of olfactory bulbs, forebrain fusion, and perinatal death from respiratory insufficiency, demonstrating that megalin-mediated endocytic uptake (possibly of cholesterol-carrying lipoproteins) in neuroepithelium is essential for forebrain development. Knockout mouse generation, pathological analysis of brain and epithelial tissues, phenotypic characterization Proceedings of the National Academy of Sciences of the United States of America High 8710893
1997 Antibodies that cause passive Heymann nephritis inhibit the binding and internalization of apolipoprotein E-enriched beta-VLDL by megalin/LRP2 in podocytes, causing accumulation of apo E and apo B within subepithelial immune deposits; constitutive lipoprotein uptake via megalin occurs through clathrin-coated pits and multivesicular bodies in normal podocytes. Immunoelectron microscopy, immunofluorescence, in vitro binding and internalization assays with antibodies eluted from nephritic glomeruli The Journal of clinical investigation High 9410908
1998 Megalin/gp330 binds thyroglobulin (Tg) with high affinity (Kd ~9.2 nM) in a Ca2+-dependent manner; binding is inhibited by other megalin ligands (lactoferrin, lipoprotein lipase, apolipoprotein J) and by RAP, indicating a shared binding site and suggesting megalin mediates Tg endocytosis in thyroid cells. Solid-phase binding assays with purified rat megalin and 125I-labeled Tg, EDTA/heparin release, SDS-PAGE, immunoblotting Endocrinology High 9492085
1999 Megalin/gp330 mediates endocytosis of thyroglobulin in Fisher rat thyroid (FRTL-5) cells; chemical cross-linking and immunoprecipitation confirmed Tg binding to surface megalin, and cell internalization assays showed RAP and anti-megalin antibody inhibited Tg uptake by ~60–80%, demonstrating megalin-dependent endocytosis. Chemical cross-linking with immunoprecipitation, 125I-Tg binding at 4°C followed by heparin release, ELISA quantification of internalized Tg at 37°C The Journal of biological chemistry High 10212279
1999 Megalin/gp330 mediates transcytosis of intact thyroglobulin from the apical to basolateral side of thyroid cells; blocking megalin with RAP or anti-megalin antibody redirects Tg to lysosomal degradation (increasing T3 release), while megalin-mediated transcytosis diverts Tg from proteolysis, thus regulating thyroid hormone release. Polarized FRTL-5 cells on permeable filters in dual-chamber devices, 125I-Tg transcytosis assays, RAP and antibody competition, in vivo goiter model with aminotriazole The Journal of biological chemistry High 10702280
1999 Megalin/gp330 binds and mediates cellular uptake and degradation of lipoprotein(a) in vitro; purified megalin on a sensor chip binds Lp(a) in a Ca2+-dependent manner, and megalin-expressing yolk sac cells show 2-fold higher uptake and degradation of Lp(a) versus megalin-null controls, an effect abolished by RAP. Surface plasmon resonance with purified megalin, fluorescent DiI-Lp(a) uptake imaging, 125I-Lp(a) internalization/degradation assays comparing megalin-expressing vs. LRP/megalin double-knockout cell lines Arteriosclerosis, thrombosis, and vascular biology High 10073957
2005 Megalin/LRP2 expression in the neuroepithelium (not the yolk sac) is required for forebrain development; megalin deficiency leads to increased BMP4 expression and signaling in the dorsal neuroepithelium and consequent loss of 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 and complete megalin knockout mice, in situ hybridization for BMP4 and SHH, immunohistochemistry, cell population analysis in forebrain Development (Cambridge, England) High 15623804
2006 Megalin/LRP2 and its co-receptor cubilin are conserved in the zebrafish larval pronephros; knockdown of megalin/LRP2 eliminates Rab4-positive endosomes in proximal pronephric duct epithelium and abrogates apical endocytosis; knockdown of the megalin adaptor Disabled-2 (Dab2) also blocks renal clearance, establishing that renal tubular endocytosis is a ligand-induced process requiring megalin activity and its intracellular adaptors. Morpholino knockdown in zebrafish, fluorescent tracer clearance assays, immunofluorescence for Rab4 endosomes, genetic epistasis with Dab2 knockdown Journal of cell science High 16638803
2010 MESD chaperone is required for proper folding of the beta-propeller/EGF domain common to LRP family members and for apical localization of LRP2/megalin in the visceral endoderm; loss of MESD results in mislocalization of megalin and impaired endocytic function in visceral endoderm. Targeted Mesd knockout mice, immunofluorescence localization of LRP2, in vitro maturation assays for beta-propeller/EGF domains Developmental dynamics Medium 21337463
2011 LRP2/megalin functions as an auxiliary SHH receptor in the rostral diencephalon ventral midline (RDVM) during forebrain development; LRP2 sequesters SHH at the apical surface and controls internalization and cellular trafficking of SHH/patched-1 complexes; LRP2 loss causes failure to respond to SHH despite intact patched-1 and smoothened expression, while LRP2 overexpression increases SHH signaling capacity. LRP2 knockout mice, cephalic explant assays, overexpression of LRP2 variants in cells, SHH binding assays, epistasis analysis with patched-1 and smoothened Developmental cell High 22340494
2011 LRP2 acts as an endocytic clearance receptor for SHH in the developing retina, preventing spread of SHH activity from central retina into the retinal margin; loss of LRP2 increases sensitivity of retinal margin progenitors to SHH, causing expansion of the progenitor pool and hyperproliferation. Conditional LRP2 knockout mice (retina-specific), immunohistochemistry, BrdU incorporation assays for proliferation, SHH pathway activity measurements Developmental cell High 26439398
2011 LRP2 regulates megalin-mediated hypothalamic clusterin (ApoJ) signaling: LRP2 acts as the primary receptor mediating clusterin endocytosis in hypothalamic neurons; clusterin binding to LRP2 enhances association of LRP2 with the long-form leptin receptor, potentiating leptin-induced STAT3 activation and anorexigenic signaling. Central administration of clusterin in mice, co-immunoprecipitation of LRP2 with leptin receptor in neurons, siRNA knockdown of LRP2 and leptin receptor, STAT3 phosphorylation assays Nature communications High 23673647
2014 Clusterin/ApoJ enhances leptin receptor endocytosis and STAT3 signaling through LRP2; LRP2-mediated endocytosis of the clusterin-leptin complex is required for full anorexigenic leptin action; inhibition of hypothalamic LRP2 or endocytosis blocks clusterin-enhanced leptin signaling. Co-administration experiments in cultured neurons, endocytosis inhibition assays, LRP2 siRNA knockdown, STAT3 activation measurements, receptor binding assays EMBO reports High 24825475
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 and repress transcription; histone deacetylase inhibition (TSA) counteracts TGF-β1-mediated repression. Site-directed mutagenesis of SBEs, chromatin immunoprecipitation (ChIP), promoter reporter assays, siRNA knockdown, TGF-βRI inhibitor experiments in kidney and gallbladder epithelial cell lines PloS one High 31120873
2021 LRP2 is required for neural tube closure through two mechanisms: (1) its intracellular domain functions as a hub interacting with Shroom3 and Gipc1 adaptors to orchestrate endocytic membrane removal for apical constriction; (2) LRP2 regulates proper localization of the PCP protein Vangl2, essential for planar cell polarity during neurulation; these functions are conserved between mouse and Xenopus. Lrp2 loss-of-function in mouse and Xenopus, morphological analysis of neural tube closure, co-immunoprecipitation of LRP2 with Shroom3 and Gipc1, immunofluorescence for Vangl2 and apical constriction markers Development (Cambridge, England) High 33500317
2022 Mettl3-mediated m6A modification of Lrp2 mRNA enhances its stability and translation efficiency through the m6A reader protein Ythdc2, promoting neurogenesis; depletion of Mettl3 reduces m6A abundance and Lrp2 expression; overexpression of Lrp2 rescues neurogenesis defects caused by Mettl3 depletion. Mettl3/Mettl14 knockout in neural stem cells, Lrp2 overexpression rescue experiments, m6A sequencing, m6A reader (Ythdc2) interaction studies, behavioral analysis FASEB journal Medium 35716070
2023 Cryo-EM structures of LRP2 isolated from mouse kidney at extracellular and endosomal pH reveal that LRP2 functions as a homodimer; at cell-surface pH, LRP2 adopts a conformation for ligand binding; at endosomal pH, conformational transformation mediates ligand shedding; pH-sensitive sites are located at both homodimer and intra-protomer interfaces; a subset of human disease-associated missense variants impairs homodimer assembly. High-resolution cryo-electron microscopy of native LRP2 isolated from mouse kidney, structural analysis at two pH conditions, correlation of structural findings with human disease missense variants Cell High 36750096
2011 GSK3 phosphorylates the cytoplasmic domain of megalin/LRP2, and megalin surface availability is regulated by multiple mechanisms: ectodomain shedding at the cell surface, subsequent intramembrane proteolysis by gamma-secretase, and exosome secretion. Review citing biochemical data on phosphorylation, shedding, and gamma-secretase cleavage from primary literature; described in a review article Biological research Low 21720686
2016 miR-146a directly represses LRP2 translation in SH-SY5Y neuronal cells; overexpression of miR-146a decreases LRP2 protein levels, reducing Akt activation and increasing caspase-3-dependent apoptosis. miR-146a overexpression in SH-SY5Y cells, Western blot for LRP2 and downstream signaling (Akt, caspase-3), predicted target site analysis FEBS letters Medium 27241555
2020 LRP2 is required for cardiomyocyte proliferation and differentiation; siRNA knockdown in human iPSC-derived cardiomyocytes and RNAi in developing Drosophila and zebrafish hearts demonstrates that LRP2 loss reduces cardiomyocyte proliferation, consistent with hypoplastic heart defects. siRNA knockdown in hiPSC-CMs, RNAi in Drosophila and zebrafish hearts, proliferation assays, cross-species functional platform eLife Medium 33006316

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1983 Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. The Journal of experimental medicine 500 6337231
1996 Defective forebrain development in mice lacking gp330/megalin. Proceedings of the National Academy of Sciences of the United States of America 427 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
2007 Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nature genetics 260 17632512
2007 Mechanisms of action of deep brain stimulation(DBS) . Neuroscience and biobehavioral reviews 243 17706780
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 173 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 151 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 124 8706697
1991 Identification of the rat Heymann nephritis autoantigen (GP330) as a receptor site for plasminogen. The Journal of biological chemistry 117 1645711
2010 Parkinson’s disease DBS: what, when, who and why? The time has come to tailor DBS targets. Expert review of neurotherapeutics 116 21384698
1999 Dependence of Dbl and Dbs transformation on MEK and NF-kappaB activation. Molecular and cellular biology 100 10523665
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 LRP-1 and LRP-2 receptors function in the membrane neuron. Trafficking mechanisms and proteolytic processing in Alzheimer's disease. Frontiers in physiology 92 22934024
2012 LRP2 is an auxiliary SHH receptor required to condition the forebrain ventral midline for inductive signals. Developmental cell 90 22340494
2019 DBS: a fast and informative segmentation algorithm for DNA copy number analysis. BMC bioinformatics 87 30606105
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 86 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
2003 Multifunctional roles for the PH domain of Dbs in regulating Rho GTPase activation. The Journal of biological chemistry 71 12637522
1998 Regulation of gp330/megalin expression by vitamins A and D. European journal of clinical investigation 69 9541123
1989 Colchicine-induced redistribution of an apical membrane glycoprotein (gp330) in proximal tubules. The American journal of physiology 69 2669509
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 66 7673355
2006 Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros. Journal of cell science 65 16638803
2013 Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway. Nature communications 62 23673647
1999 Megalin (gp330) is an endocytic receptor for thyroglobulin on cultured fisher rat thyroid cells. The Journal of biological chemistry 57 10212279
1999 Glycoprotein 330/megalin (LRP-2) has low prevalence as mRNA and protein in brain microvessels and choroid plexus. Experimental neurology 57 10222122
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
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
2023 Structures of LRP2 reveal a molecular machine for endocytosis. Cell 51 36750096
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
2016 Multiplexed longitudinal measurement of protein biomarkers in DBS using an automated SISCAPA workflow. Bioanalysis 43 27420772
2018 Study of measurement of the alcohol biomarker phosphatidylethanol (PEth) in dried blood spot (DBS) samples and application of a volumetric DBS device. Clinica chimica acta; international journal of clinical chemistry 42 29309773
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 42 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
2010 Influence of different extraction methods and PCR techniques on the sensitivity of HCMV-DNA detection in dried blood spot (DBS) filter cards. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 41 20570211
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
2021 Changing Gears - DBS For Dopaminergic Desensitization in Parkinson's Disease? Annals of neurology 40 34235776
2017 HIV-1 viral load measurement in venous blood and fingerprick blood using Abbott RealTime HIV-1 DBS assay. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 38 28531553
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
2009 The rho-specific guanine nucleotide exchange factor Dbs regulates breast cancer cell migration. The Journal of biological chemistry 36 19366686
1993 Biosynthesis of the gp330/44-kDa Heymann nephritis antigenic complex: assembly takes place in the ER. The American journal of physiology 36 8322889
2014 Clusterin/ApoJ enhances central leptin signaling through Lrp2-mediated endocytosis. EMBO reports 35 24825475
2021 Neural tube closure requires the endocytic receptor Lrp2 and its functional interaction with intracellular scaffolds. Development (Cambridge, England) 34 33500317
2017 Endocytic receptor LRP2/megalin-of holoprosencephaly and renal Fanconi syndrome. Pflugers Archiv : European journal of physiology 34 28497274
2024 NAc-DBS corrects depression-like behaviors in CUMS mouse model via disinhibition of DA neurons in the VTA. Molecular psychiatry 33 38361128
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
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 31 26872844
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
2003 Pleckstrin homology domain-mediated activation of the rho-specific guanine nucleotide exchange factor Dbs by Rac1. The Journal of biological chemistry 28 14701795
2019 Participation of the SMAD2/3 signalling pathway in the down regulation of megalin/LRP2 by transforming growth factor beta (TGF-ß1). PloS one 27 31120873
2003 Critical role of the pleckstrin homology domain in Dbs signaling and growth regulation. The Journal of biological chemistry 27 12637530
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 25 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
2010 Evaluating and defining sample preparation procedures for DBS LC-MS/MS assays. Bioanalysis 25 21083341
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
2020 Metformin Inhibits Proliferation of Human Thyroid Cancer TPC-1 Cells by Decreasing LRP2 to Suppress the JNK Pathway. OncoTargets and therapy 22 32021253
2019 Development and validation of LC-MS/MS method for imatinib and norimatinib monitoring by finger-prick DBS in gastrointestinal stromal tumor patients. PloS one 22 31743371
2017 Impaired vitreous composition and retinal pigment epithelium function in the FoxG1::LRP2 myopic mice. Biochimica et biophysica acta. Molecular basis of disease 22 28366874
2017 Genetic variation in the gene LRP2 increases relapse risk in multiple sclerosis. Journal of neurology, neurosurgery, and psychiatry 22 28739605
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
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 21 35716070
2021 Striatal Afferent BDNF Is Disrupted by Synucleinopathy and Partially Restored by STN DBS. The Journal of neuroscience : the official journal of the Society for Neuroscience 21 33472823
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
2011 Application of DBS for the quantitative assessment of a protein biologic using on-card digestion LC-MS/MS or immunoassay. Bioanalysis 21 22011176
1999 Serum antibodies against megalin (GP330) in patients with autoimmune thyroiditis. The Journal of clinical endocrinology and metabolism 19 10404822
2023 Lateral cerebellothalamic tract activation underlies DBS therapy for Essential Tremor. Brain stimulation 18 36746367
2022 Structural connectivity of the ANT region based on human ex-vivo and HCP data. Relevance for DBS in ANT for epilepsy. NeuroImage 17 35948264
2010 The national DBS brain tissue network pilot study: need for more tissue and more standardization. Cell and tissue banking 17 20589432
2006 Ccpg1, a novel scaffold protein that regulates the activity of the Rho guanine nucleotide exchange factor Dbs. Molecular and cellular biology 17 17000758
2000 Characterization of the N-linked oligosaccharides of megalin (gp330) from rat kidney. Glycobiology 17 10704528
2018 Detection of mucopolysaccharidosis III-A (Sanfilippo Syndrome-A) in dried blood spots (DBS) by tandem mass spectrometry. Molecular genetics and metabolism 15 30006231
2010 Liquid chromatography/tandem mass spectrometry sensitivity enhancement via online sample dilution and trapping: applications in microdosing and dried blood spot (DBS) bioanalysis. Rapid communications in mass spectrometry : RCM 15 20740533
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