{"gene":"LRP2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1983,"finding":"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.","method":"Immunocytochemistry (immunoperoxidase and immunofluorescence) on cryostat sections; immunoprecipitation from 35S-methionine-labeled kidney fractions","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal immunoprecipitation and immunocytochemistry at EM resolution, foundational localization paper replicated widely","pmids":["6337231"],"is_preprint":false},{"year":1992,"finding":"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.","method":"Ligand blotting, 45Ca2+ blotting, light and electron microscopic autoradiography, in vivo microperfusion of rat proximal tubules with 125I-labeled 40 kDa protein","journal":"The journal of histochemistry and cytochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding assay plus in vivo functional endocytosis assay with direct localization, replicated across multiple methods","pmids":["1382088"],"is_preprint":false},{"year":1992,"finding":"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.","method":"Nitrocellulose blot binding assays, competition experiments in fibroblasts measuring cholesteryl ester synthesis, cross-competition binding studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding assays with functional readout (cholesteryl ester synthesis), multiple ligands tested, replicated with multiple methods","pmids":["1464627"],"is_preprint":false},{"year":1991,"finding":"LRP2/gp330 is a receptor for plasminogen; plasminogen binds to gp330 in a time-dependent, saturable, and specifically inhibitable manner.","method":"Western blot binding analysis, ELISA binding assay with inhibition by excess gp330 and partial inhibition by benzamidine","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with characterization of specificity, single lab, two complementary methods","pmids":["1645711"],"is_preprint":false},{"year":1992,"finding":"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.","method":"In vitro kinetic enzyme assay (urokinase-catalyzed plasminogen activation with chromogenic substrate S-2251), ELISA binding assay","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution of enzymatic activation with kinetic parameters, single lab, single study","pmids":["1280065"],"is_preprint":false},{"year":1992,"finding":"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).","method":"Immunoprecipitation from kidney extracts, immunoblotting on purified complex, copurification by detergent extraction and centrifugation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal immunoprecipitation with copurification data, multiple antibodies used, foundational paper replicated by subsequent work","pmids":["1495959"],"is_preprint":false},{"year":1993,"finding":"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.","method":"Pulse-chase radiolabeling, endoglycosidase H digestion, coprecipitation, sucrose velocity gradient centrifugation","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biochemical methods (pulse-chase, glycosidase treatment, sedimentation), rigorous assembly mechanism established","pmids":["8322889"],"is_preprint":false},{"year":1994,"finding":"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.","method":"cDNA cloning and sequencing (complete sequence), domain architecture analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — complete cDNA sequence with domain identification, widely replicated","pmids":["7937880"],"is_preprint":false},{"year":1995,"finding":"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.","method":"Immunohistochemistry on fixed and snap-frozen kidney tissue, RAP-IgG fusion protein binding assays, redistribution experiments","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — localization experiments with functional interpretation, artifactual redistribution controlled for, multiple antibody approaches","pmids":["8223699"],"is_preprint":false},{"year":1995,"finding":"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.","method":"Cell-based endocytosis assay using radiolabeled ligands in immortalized rat type II pneumocytes, inhibition with polyclonal antibodies to gp330 and with RAP","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional cellular endocytosis assay with specific antibody inhibition and RAP blockade, multiple ligands tested","pmids":["7673355"],"is_preprint":false},{"year":1996,"finding":"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.","method":"In vivo microinfusion of rat proximal tubules with 125I-labeled albumin and colloidal gold-BSA, megalin-Sepharose binding assay, immunoelectron microscopy","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo functional uptake assay combined with direct in vitro binding, multiple inhibitory conditions tested","pmids":["8898021"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Megalin knockout mouse generation, phenotypic analysis of brain development","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined developmental phenotype, widely replicated","pmids":["8710893"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Complete cDNA cloning and sequencing of human gp330, motif analysis of cytoplasmic tail","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — sequence-based domain identification without functional validation of signaling motifs, but structural determination of complete sequence","pmids":["8706697"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Solid phase binding assays with purified rat megalin and 125I-labeled Tg, ELISA competition assays","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro binding assay with purified protein and Kd determination, multiple inhibitors tested, confirmed by subsequent study","pmids":["9492085"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Chemical cross-linking followed by immunoprecipitation, heparin-release binding assay, ELISA, functional endocytosis assay in FRTL-5 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cross-linking/IP, functional endocytosis assay), two cell lines tested, specific inhibition confirmed","pmids":["10212279"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Cell-based uptake/degradation assay with 125I-labeled Lp(a), DiI-Lp(a) fluorescence imaging, surface plasmon resonance (BIAcore) with purified megalin","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding with direct affinity measurement plus functional cell-based uptake assay, RAP inhibition control, isogenic cell pair used","pmids":["10073957"],"is_preprint":false},{"year":2000,"finding":"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).","method":"Polarized FRTL-5 cell culture on permeable filters, transepithelial transport assay, Western blot; in vivo goiter model with aminotriazole","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional transcytosis assay in polarized cells with specific inhibition, supported by in vivo correlate","pmids":["10702280"],"is_preprint":false},{"year":1997,"finding":"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.","method":"Immunoelectron microscopy of podocytes in pHN rat model; in vitro inhibition of apo E-betaVLDL binding and internalization using eluted antibodies from glomeruli","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo and in vitro evidence combined, direct functional inhibition of endocytosis demonstrated","pmids":["9410908"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Conditional megalin knockout in neuroepithelium vs. yolk sac, immunohistochemistry for BMP4 and Shh, analysis of cell populations in forebrain","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional tissue-specific knockout with defined molecular pathway (BMP4 clearance → Shh loss), epistatic dissection","pmids":["15623804"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Conditional LRP2 knockout in adult mice, immunohistochemistry for BMP4/pSMAD1/5/8/ID3, BrdU proliferation assay, neuroblast counting","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with defined downstream signaling readout (pSMAD1/5/8, ID3), functional neurogenesis assay","pmids":["20460439"],"is_preprint":false},{"year":2012,"finding":"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.","method":"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","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, loss- and gain-of-function with defined signaling readout, multiple approaches in vivo and in vitro","pmids":["22340494"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Morpholino knockdown in zebrafish, tracer clearance assay, immunostaining for Rab4-positive endosomes","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockdown with defined functional endocytic readout, co-receptor and adaptor epistasis established","pmids":["16638803"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Review citing experimental findings: phosphorylation by GSK3, shedding and gamma-secretase cleavage assays (cited from prior experimental literature)","journal":"Biological research","confidence":"Low","confidence_rationale":"Tier 4 / Weak — review paper summarizing mechanisms; no primary experiments described in this abstract","pmids":["21720686"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Whole-embryo culture uptake assays in Lrp2−/− mice, folate concentration measurement, Alx3 expression analysis, neural tube closure phenotyping","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional uptake assay in knockout tissue, molecular pathway (folate deficiency → Alx3 downregulation → NTD) established","pmids":["24639464"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Retina-specific Lrp2 conditional knockout mice, immunostaining for SHH, proliferation assays (BrdU/Ki67), progenitor cell pool quantification","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional tissue-specific knockout with defined SHH signaling and proliferative readouts, context-dependent switch from LRP2 as SHH activator to clearance receptor demonstrated","pmids":["26439398"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Central (ICV) clusterin administration in mice, hypothalamic LRP2 knockdown (AAV), co-immunoprecipitation of LRP2 with LepRb in neurons, food intake and body weight measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of LRP2/LepRb complex, in vivo knockdown with feeding phenotype, multiple complementary approaches","pmids":["23673647"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Cultured neuron binding and endocytosis assays, hypothalamic LRP2 knockdown, ICV clusterin/leptin co-administration with STAT3 phosphorylation readout","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional endocytosis assay with receptor binding measurement, in vivo knockdown with signaling readout, corroborates findings of companion paper","pmids":["24825475"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conservation demonstrated in two model organisms, Co-IP of novel interactors, functional morphogenesis readout","pmids":["33500317"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Genetic mapping in multiplex families, LRP2 sequencing, identification of pathogenic mutations","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional cloning with multiple family validation, directly links LRP2 receptor dysfunction to human disease","pmids":["17632512"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Site-directed mutagenesis of SBEs, chromatin immunoprecipitation (ChIP), EMSA, luciferase reporter assays, TGF-βRI inhibitor treatment in two epithelial cell lines","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP, EMSA, mutagenesis, and reporter assays together establish transcriptional mechanism, validated in two cell lines","pmids":["31120873"],"is_preprint":false},{"year":2011,"finding":"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.","method":"EMSA, luciferase reporter assay, PPAR agonist/antagonist treatments in epithelial cell lines, in vivo mouse kidney megalin expression analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — EMSA and reporter assay establish direct PPAR binding, functional regulation confirmed in vivo","pmids":["21311715"],"is_preprint":false},{"year":2023,"finding":"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.","method":"High-resolution cryoelectron microscopy at two pH conditions, structural analysis of missense variants, isolation of LRP2 from mouse kidney","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structures at two functional pH states with variant analysis, mechanistically definitive","pmids":["36750096"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Targeted Mesd knockout mouse, immunostaining for LRP2 localization in visceral endoderm, in vitro LRP domain maturation assay","journal":"Developmental dynamics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with direct localization and functional endocytic readout, in vitro domain maturation assay","pmids":["21337463"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Immunocytochemistry, FACS-based receptor identification, neutralizing antibody inhibition of endocytosis, EDTA-mediated Ca2+ chelation in hepatic stellate cells","journal":"Clinica chimica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional inhibition assay with antibody and Ca2+ chelation, multiple lines of evidence, single lab","pmids":["18194670"],"is_preprint":false},{"year":2020,"finding":"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.","method":"siRNA knockdown in iPSC-CMs, RNAi in Drosophila, morpholino knockdown in zebrafish, proliferation and differentiation assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-species loss-of-function with defined proliferation/differentiation readout, consistent across organisms, single study","pmids":["33006316"],"is_preprint":false},{"year":2020,"finding":"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.","method":"LRP2-deficient mouse models, immunohistochemistry for SHF markers (Nkx2.5, Isl1), cardiomyocyte differentiation marker staining, morphometric analysis of outflow tract","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined molecular mechanism (SHH-dependent progenitor maintenance) with specific cellular and morphological readouts in knockout model","pmids":["32901292"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A modification site identified with reader protein pulldown and functional rescue, single lab study","pmids":["35716070"],"is_preprint":false},{"year":1989,"finding":"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.","method":"Colchicine treatment in vivo, immunocytochemistry (immunoperoxidase and immunofluorescence), intravenous injection of anti-gp330 antiserum to test for basolateral membrane insertion","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological disruption of microtubules with specific localization readout and functional antibody test, replicated in subsequent study","pmids":["2669509"],"is_preprint":false},{"year":1990,"finding":"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.","method":"Monoclonal antibody inhibition of cell attachment, detergent-solubilized gp330 binding to matrix proteins, cell proliferation assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional cell adhesion assay with specific antibody inhibition and direct binding, but limited mechanistic depth","pmids":["1691715"],"is_preprint":false}],"current_model":"LRP2/megalin is a giant homodimeric endocytic receptor (cryo-EM structure resolved) that undergoes pH-dependent conformational change between ligand-binding (extracellular pH) and ligand-shedding (endosomal pH) states; it internalizes a broad repertoire of ligands—including albumin, thyroglobulin, lipoprotein particles (Lp(a), apoE-VLDL), plasminogen/plasmin, folate-FOLR1 complexes, clusterin/ApoJ, vitamin D-binding protein, and BMP4—via clathrin-coated pits on the apical surface of epithelial cells, with its (FX)NPXY cytoplasmic internalization motifs and adaptor proteins Dab2, Shroom3, and Gipc1 coordinating endosomal trafficking; RAP acts as an ER chaperone for its folding and surface delivery, MESD is required for its β-propeller/EGF domain maturation and apical targeting, GSK3 phosphorylates its cytoplasmic tail to regulate surface availability, and TGF-β1/SMAD2/3 and PPAR transcriptionally regulate its expression; in development LRP2 functions as a context-dependent morphogen co-receptor, acting as an auxiliary activating SHH receptor in the forebrain ventral midline and heart second heart field, but as a clearance receptor for BMP4 in neuroepithelium/ependyma and for SHH in the retinal margin; LRP2 deficiency in humans causes Donnai-Barrow/FOAR syndrome."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1983,"claim":"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","pmids":["6337231"],"confidence":"High","gaps":["Ligands and molecular function undefined","No sequence or domain architecture yet"]},{"year":1990,"claim":"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","pmids":["2669509","1691715"],"confidence":"Medium","gaps":["Matrix-binding site on the receptor not mapped","Physiological relevance of adhesion vs endocytosis unresolved"]},{"year":1992,"claim":"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","pmids":["1382088","1495959","8322889","1464627"],"confidence":"High","gaps":["Distinction between RAP's chaperone role and its ligand-blocking role not fully separated at this stage"]},{"year":1994,"claim":"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","pmids":["7937880","8706697"],"confidence":"High","gaps":["Functional validation of putative signaling motifs (PI3K, PKC sites) not performed","Structure of the assembled ectodomain unknown"]},{"year":1995,"claim":"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","pmids":["8223699","7673355"],"confidence":"High","gaps":["Endosomal trafficking machinery and recycling not yet defined"]},{"year":1996,"claim":"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","pmids":["8710893","8898021"],"confidence":"High","gaps":["Molecular pathway linking megalin loss to forebrain defect not yet identified","Cargo specificity in the proximal tubule incomplete"]},{"year":1999,"claim":"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","pmids":["9492085","10212279","10073957","10702280","1645711","1280065","9410908"],"confidence":"High","gaps":["Relative in vivo flux through each ligand pathway not quantified","Tissue-specific cargo prioritization unresolved"]},{"year":2007,"claim":"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","pmids":["17632512","18194670"],"confidence":"High","gaps":["Genotype-phenotype correlations for specific variants not detailed","Mechanism converting receptor loss to multi-organ phenotype only partly defined"]},{"year":2010,"claim":"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","pmids":["15623804","20460439","16638803","21337463"],"confidence":"High","gaps":["How a single receptor switches between clearance and signaling roles not mechanistically explained","Endosomal fate determining degradation vs signaling unclear"]},{"year":2014,"claim":"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","pmids":["22340494","26439398","23673647","24825475","24639464"],"confidence":"High","gaps":["Determinants selecting activating vs clearance SHH outcomes remain unresolved","Structural basis of LRP2-LepRb coupling not defined"]},{"year":2020,"claim":"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","pmids":["34?","32901292","33500317","31120873","21311715","35716070","33006316"],"confidence":"High","gaps":["How intracellular adaptors integrate endocytosis with cytoskeletal apical constriction not mechanistically resolved","Crosstalk between transcriptional (TGF-beta/PPAR) and post-transcriptional (m6A) regulation untested"]},{"year":2023,"claim":"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","pmids":["36750096"],"confidence":"High","gaps":["Structural basis for ligand-specific binding sites not all mapped","How cytoplasmic adaptor engagement couples to ectodomain conformation unknown"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying model for the activating-vs-clearance switch","Coupling between ectodomain pH-conformational cycle and intracellular trafficking adaptors not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[1,9,10,14,15,33]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,20,24,25]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,15]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[20,25,26]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,7,10,31]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,21,37]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[21,31]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,8,32]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,9,10,16,21]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,18,20,24,27,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[20,25,26,35]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[16,31,32,37]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[28]}],"complexes":["LRP2 homodimer","LRP2/RAP complex (HNAC)"],"partners":["RAP","MESD","DAB2","SHROOM3","GIPC1","LEPRB","PTCH1","CUBN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P98164","full_name":"Low-density lipoprotein receptor-related protein 2","aliases":["Glycoprotein 330","gp330","Megalin"],"length_aa":4655,"mass_kda":522.0,"function":"Multiligand endocytic receptor (By similarity). Acts together with CUBN to mediate endocytosis of high-density lipoproteins (By similarity). Mediates receptor-mediated uptake of polybasic drugs such as aprotinin, aminoglycosides and polymyxin B (By similarity). In the kidney, mediates the tubular uptake and clearance of leptin (By similarity). Also mediates transport of leptin across the blood-brain barrier through endocytosis at the choroid plexus epithelium (By similarity). Endocytosis of leptin in neuronal cells is required for hypothalamic leptin signaling and leptin-mediated regulation of feeding and body weight (By similarity). Mediates endocytosis and subsequent lysosomal degradation of CST3 in kidney proximal tubule cells (By similarity). Mediates renal uptake of 25-hydroxyvitamin D3 in complex with the vitamin D3 transporter GC/DBP (By similarity). Mediates renal uptake of metallothionein-bound heavy metals (PubMed:15126248). Together with CUBN, mediates renal reabsorption of myoglobin (By similarity). Mediates renal uptake and subsequent lysosomal degradation of APOM (By similarity). Plays a role in kidney selenium homeostasis by mediating renal endocytosis of selenoprotein SEPP1 (By similarity). Mediates renal uptake of the antiapoptotic protein BIRC5/survivin which may be important for functional integrity of the kidney (PubMed:23825075). Mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (By similarity). Mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH (By similarity). Also mediates ShhN transcytosis (By similarity). In the embryonic neuroepithelium, mediates endocytic uptake and degradation of BMP4, is required for correct SHH localization in the ventral neural tube and plays a role in patterning of the ventral telencephalon (By similarity). Required at the onset of neurulation to sequester SHH on the apical surface of neuroepithelial cells of the rostral diencephalon ventral midline and to control PTCH1-dependent uptake and intracellular trafficking of SHH (By similarity). During neurulation, required in neuroepithelial cells for uptake of folate bound to the folate receptor FOLR1 which is necessary for neural tube closure (By similarity). In the adult brain, negatively regulates BMP signaling in the subependymal zone which enables neurogenesis to proceed (By similarity). In astrocytes, mediates endocytosis of ALB which is required for the synthesis of the neurotrophic factor oleic acid (By similarity). Involved in neurite branching (By similarity). During optic nerve development, required for SHH-mediated migration and proliferation of oligodendrocyte precursor cells (By similarity). Mediates endocytic uptake and clearance of SHH in the retinal margin which protects retinal progenitor cells from mitogenic stimuli and keeps them quiescent (By similarity). Plays a role in reproductive organ development by mediating uptake in reproductive tissues of androgen and estrogen bound to the sex hormone binding protein SHBG (By similarity). Mediates endocytosis of angiotensin-2 (By similarity). Also mediates endocytosis of angiotensis 1-7 (By similarity). Binds to the complex composed of beta-amyloid protein 40 and CLU/APOJ and mediates its endocytosis and lysosomal degradation (By similarity). Required for embryonic heart development (By similarity). Required for normal hearing, possibly through interaction with estrogen in the inner ear (By similarity)","subcellular_location":"Apical cell membrane; Endosome lumen; Membrane, coated pit; Cell projection, dendrite; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/P98164/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRP2","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRP2","total_profiled":1310},"omim":[{"mim_id":"619020","title":"LRP2-BINDING PROTEIN; LRP2BP","url":"https://www.omim.org/entry/619020"},{"mim_id":"618882","title":"IMERSLUND-GRASBECK SYNDROME 2; IGS2","url":"https://www.omim.org/entry/618882"},{"mim_id":"610947","title":"CORONARY ARTERY DISEASE, AUTOSOMAL DOMINANT 2; ADCAD2","url":"https://www.omim.org/entry/610947"},{"mim_id":"605747","title":"LOW DENSITY LIPOPROTEIN RECEPTOR ADAPTOR PROTEIN 1; LDLRAP1","url":"https://www.omim.org/entry/605747"},{"mim_id":"605072","title":"GIPC PDZ DOMAIN-CONTAINING FAMILY, MEMBER 1; GIPC1","url":"https://www.omim.org/entry/605072"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cell Junctions","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"kidney","ntpm":32.5},{"tissue":"parathyroid gland","ntpm":42.1},{"tissue":"retina","ntpm":27.1}],"url":"https://www.proteinatlas.org/search/LRP2"},"hgnc":{"alias_symbol":["gp330","DBS"],"prev_symbol":[]},"alphafold":{"accession":"P98164","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P98164","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRP2","jax_strain_url":"https://www.jax.org/strain/search?query=LRP2"},"sequence":{"accession":"P98164","fasta_url":"https://rest.uniprot.org/uniprotkb/P98164.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P98164/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P98164"}},"corpus_meta":[{"pmid":"6337231","id":"PMC_6337231","title":"Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats.","date":"1983","source":"The Journal of experimental 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chylomicron remnant clearance.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1464627","citation_count":426,"is_preprint":false},{"pmid":"7510321","id":"PMC_7510321","title":"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).","date":"1994","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/7510321","citation_count":299,"is_preprint":false},{"pmid":"17632512","id":"PMC_17632512","title":"Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17632512","citation_count":264,"is_preprint":false},{"pmid":"8898021","id":"PMC_8898021","title":"Megalin/gp330 mediates uptake of albumin in renal proximal tubule.","date":"1996","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8898021","citation_count":243,"is_preprint":false},{"pmid":"7579068","id":"PMC_7579068","title":"The Heymann nephritis antigenic complex: megalin (gp330) and RAP.","date":"1995","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/7579068","citation_count":183,"is_preprint":false},{"pmid":"9071320","id":"PMC_9071320","title":"Tissue distribution of human gp330/megalin, a putative Ca(2+)-sensing protein.","date":"1997","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/9071320","citation_count":175,"is_preprint":false},{"pmid":"1382088","id":"PMC_1382088","title":"Renal tubule gp330 is a calcium binding receptor for endocytic uptake of protein.","date":"1992","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/1382088","citation_count":161,"is_preprint":false},{"pmid":"21720686","id":"PMC_21720686","title":"New insights into the roles of megalin/LRP2 and the regulation of its functional expression.","date":"2011","source":"Biological research","url":"https://pubmed.ncbi.nlm.nih.gov/21720686","citation_count":155,"is_preprint":false},{"pmid":"1495959","id":"PMC_1495959","title":"gp330 associates with a 44-kDa protein in the rat kidney to form the Heymann nephritis antigenic complex.","date":"1992","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1495959","citation_count":150,"is_preprint":false},{"pmid":"15623804","id":"PMC_15623804","title":"LRP2/megalin is required for patterning of the ventral telencephalon.","date":"2005","source":"Development (Cambridge, 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biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8706697","citation_count":125,"is_preprint":false},{"pmid":"1645711","id":"PMC_1645711","title":"Identification of the rat Heymann nephritis autoantigen (GP330) as a receptor site for plasminogen.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1645711","citation_count":117,"is_preprint":false},{"pmid":"20460439","id":"PMC_20460439","title":"LRP2 in ependymal cells regulates BMP signaling in the adult neurogenic niche.","date":"2010","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/20460439","citation_count":117,"is_preprint":false},{"pmid":"22934024","id":"PMC_22934024","title":"LRP-1 and LRP-2 receptors function in the membrane neuron. Trafficking mechanisms and proteolytic processing in Alzheimer's disease.","date":"2012","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22934024","citation_count":94,"is_preprint":false},{"pmid":"2408041","id":"PMC_2408041","title":"Molecular cloning of a cDNA encoding a major pathogenic domain of the Heymann nephritis antigen gp330.","date":"1990","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2408041","citation_count":93,"is_preprint":false},{"pmid":"22340494","id":"PMC_22340494","title":"LRP2 is an auxiliary SHH receptor required to condition the forebrain ventral midline for inductive signals.","date":"2012","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/22340494","citation_count":90,"is_preprint":false},{"pmid":"10702280","id":"PMC_10702280","title":"Role of megalin (gp330) in transcytosis of thyroglobulin by thyroid cells. A novel function in the control of thyroid hormone release.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10702280","citation_count":87,"is_preprint":false},{"pmid":"8483924","id":"PMC_8483924","title":"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.","date":"1993","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8483924","citation_count":83,"is_preprint":false},{"pmid":"18083160","id":"PMC_18083160","title":"Dynamic expression of Lrp2 pathway members reveals progressive epithelial differentiation of primitive endoderm in mouse blastocyst.","date":"2007","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18083160","citation_count":81,"is_preprint":false},{"pmid":"21379331","id":"PMC_21379331","title":"Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21379331","citation_count":81,"is_preprint":false},{"pmid":"16828734","id":"PMC_16828734","title":"The role of megalin (LRP-2/Gp330) during development.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16828734","citation_count":71,"is_preprint":false},{"pmid":"2669509","id":"PMC_2669509","title":"Colchicine-induced redistribution of an apical membrane glycoprotein (gp330) in proximal tubules.","date":"1989","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/2669509","citation_count":70,"is_preprint":false},{"pmid":"2444109","id":"PMC_2444109","title":"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.","date":"1987","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/2444109","citation_count":70,"is_preprint":false},{"pmid":"9541123","id":"PMC_9541123","title":"Regulation of gp330/megalin expression by vitamins A and D.","date":"1998","source":"European journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/9541123","citation_count":69,"is_preprint":false},{"pmid":"16638803","id":"PMC_16638803","title":"Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros.","date":"2006","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/16638803","citation_count":66,"is_preprint":false},{"pmid":"9492085","id":"PMC_9492085","title":"Megalin (gp330): a putative endocytic receptor for thyroglobulin (Tg).","date":"1998","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9492085","citation_count":66,"is_preprint":false},{"pmid":"7673355","id":"PMC_7673355","title":"gp330 on type II pneumocytes mediates endocytosis leading to degradation of pro-urokinase, plasminogen activator inhibitor-1 and urokinase-plasminogen activator inhibitor-1 complex.","date":"1995","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/7673355","citation_count":65,"is_preprint":false},{"pmid":"23673647","id":"PMC_23673647","title":"Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway.","date":"2013","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/23673647","citation_count":63,"is_preprint":false},{"pmid":"10222122","id":"PMC_10222122","title":"Glycoprotein 330/megalin (LRP-2) has low prevalence as mRNA and protein in brain microvessels and choroid plexus.","date":"1999","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10222122","citation_count":58,"is_preprint":false},{"pmid":"10212279","id":"PMC_10212279","title":"Megalin (gp330) is an endocytic receptor for thyroglobulin on cultured fisher rat thyroid cells.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10212279","citation_count":57,"is_preprint":false},{"pmid":"8342605","id":"PMC_8342605","title":"Detection of two forms of GP330. 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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.\",\n      \"method\": \"Immunocytochemistry (immunoperoxidase and immunofluorescence) on cryostat sections; immunoprecipitation from 35S-methionine-labeled kidney fractions\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal immunoprecipitation and immunocytochemistry at EM resolution, foundational localization paper replicated widely\",\n      \"pmids\": [\"6337231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"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.\",\n      \"method\": \"Ligand blotting, 45Ca2+ blotting, light and electron microscopic autoradiography, in vivo microperfusion of rat proximal tubules with 125I-labeled 40 kDa protein\",\n      \"journal\": \"The journal of histochemistry and cytochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding assay plus in vivo functional endocytosis assay with direct localization, replicated across multiple methods\",\n      \"pmids\": [\"1382088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"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.\",\n      \"method\": \"Nitrocellulose blot binding assays, competition experiments in fibroblasts measuring cholesteryl ester synthesis, cross-competition binding studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding assays with functional readout (cholesteryl ester synthesis), multiple ligands tested, replicated with multiple methods\",\n      \"pmids\": [\"1464627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"LRP2/gp330 is a receptor for plasminogen; plasminogen binds to gp330 in a time-dependent, saturable, and specifically inhibitable manner.\",\n      \"method\": \"Western blot binding analysis, ELISA binding assay with inhibition by excess gp330 and partial inhibition by benzamidine\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with characterization of specificity, single lab, two complementary methods\",\n      \"pmids\": [\"1645711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinetic enzyme assay (urokinase-catalyzed plasminogen activation with chromogenic substrate S-2251), ELISA binding assay\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution of enzymatic activation with kinetic parameters, single lab, single study\",\n      \"pmids\": [\"1280065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"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).\",\n      \"method\": \"Immunoprecipitation from kidney extracts, immunoblotting on purified complex, copurification by detergent extraction and centrifugation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal immunoprecipitation with copurification data, multiple antibodies used, foundational paper replicated by subsequent work\",\n      \"pmids\": [\"1495959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"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.\",\n      \"method\": \"Pulse-chase radiolabeling, endoglycosidase H digestion, coprecipitation, sucrose velocity gradient centrifugation\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biochemical methods (pulse-chase, glycosidase treatment, sedimentation), rigorous assembly mechanism established\",\n      \"pmids\": [\"8322889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA cloning and sequencing (complete sequence), domain architecture analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — complete cDNA sequence with domain identification, widely replicated\",\n      \"pmids\": [\"7937880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry on fixed and snap-frozen kidney tissue, RAP-IgG fusion protein binding assays, redistribution experiments\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — localization experiments with functional interpretation, artifactual redistribution controlled for, multiple antibody approaches\",\n      \"pmids\": [\"8223699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-based endocytosis assay using radiolabeled ligands in immortalized rat type II pneumocytes, inhibition with polyclonal antibodies to gp330 and with RAP\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional cellular endocytosis assay with specific antibody inhibition and RAP blockade, multiple ligands tested\",\n      \"pmids\": [\"7673355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo microinfusion of rat proximal tubules with 125I-labeled albumin and colloidal gold-BSA, megalin-Sepharose binding assay, immunoelectron microscopy\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo functional uptake assay combined with direct in vitro binding, multiple inhibitory conditions tested\",\n      \"pmids\": [\"8898021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Megalin knockout mouse generation, phenotypic analysis of brain development\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined developmental phenotype, widely replicated\",\n      \"pmids\": [\"8710893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Complete cDNA cloning and sequencing of human gp330, motif analysis of cytoplasmic tail\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — sequence-based domain identification without functional validation of signaling motifs, but structural determination of complete sequence\",\n      \"pmids\": [\"8706697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Solid phase binding assays with purified rat megalin and 125I-labeled Tg, ELISA competition assays\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro binding assay with purified protein and Kd determination, multiple inhibitors tested, confirmed by subsequent study\",\n      \"pmids\": [\"9492085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Chemical cross-linking followed by immunoprecipitation, heparin-release binding assay, ELISA, functional endocytosis assay in FRTL-5 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cross-linking/IP, functional endocytosis assay), two cell lines tested, specific inhibition confirmed\",\n      \"pmids\": [\"10212279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-based uptake/degradation assay with 125I-labeled Lp(a), DiI-Lp(a) fluorescence imaging, surface plasmon resonance (BIAcore) with purified megalin\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding with direct affinity measurement plus functional cell-based uptake assay, RAP inhibition control, isogenic cell pair used\",\n      \"pmids\": [\"10073957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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).\",\n      \"method\": \"Polarized FRTL-5 cell culture on permeable filters, transepithelial transport assay, Western blot; in vivo goiter model with aminotriazole\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional transcytosis assay in polarized cells with specific inhibition, supported by in vivo correlate\",\n      \"pmids\": [\"10702280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoelectron microscopy of podocytes in pHN rat model; in vitro inhibition of apo E-betaVLDL binding and internalization using eluted antibodies from glomeruli\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo and in vitro evidence combined, direct functional inhibition of endocytosis demonstrated\",\n      \"pmids\": [\"9410908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional megalin knockout in neuroepithelium vs. yolk sac, immunohistochemistry for BMP4 and Shh, analysis of cell populations in forebrain\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional tissue-specific knockout with defined molecular pathway (BMP4 clearance → Shh loss), epistatic dissection\",\n      \"pmids\": [\"15623804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional LRP2 knockout in adult mice, immunohistochemistry for BMP4/pSMAD1/5/8/ID3, BrdU proliferation assay, neuroblast counting\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with defined downstream signaling readout (pSMAD1/5/8, ID3), functional neurogenesis assay\",\n      \"pmids\": [\"20460439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, loss- and gain-of-function with defined signaling readout, multiple approaches in vivo and in vitro\",\n      \"pmids\": [\"22340494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Morpholino knockdown in zebrafish, tracer clearance assay, immunostaining for Rab4-positive endosomes\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockdown with defined functional endocytic readout, co-receptor and adaptor epistasis established\",\n      \"pmids\": [\"16638803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Review citing experimental findings: phosphorylation by GSK3, shedding and gamma-secretase cleavage assays (cited from prior experimental literature)\",\n      \"journal\": \"Biological research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — review paper summarizing mechanisms; no primary experiments described in this abstract\",\n      \"pmids\": [\"21720686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-embryo culture uptake assays in Lrp2−/− mice, folate concentration measurement, Alx3 expression analysis, neural tube closure phenotyping\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional uptake assay in knockout tissue, molecular pathway (folate deficiency → Alx3 downregulation → NTD) established\",\n      \"pmids\": [\"24639464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Retina-specific Lrp2 conditional knockout mice, immunostaining for SHH, proliferation assays (BrdU/Ki67), progenitor cell pool quantification\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional tissue-specific knockout with defined SHH signaling and proliferative readouts, context-dependent switch from LRP2 as SHH activator to clearance receptor demonstrated\",\n      \"pmids\": [\"26439398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Central (ICV) clusterin administration in mice, hypothalamic LRP2 knockdown (AAV), co-immunoprecipitation of LRP2 with LepRb in neurons, food intake and body weight measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of LRP2/LepRb complex, in vivo knockdown with feeding phenotype, multiple complementary approaches\",\n      \"pmids\": [\"23673647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Cultured neuron binding and endocytosis assays, hypothalamic LRP2 knockdown, ICV clusterin/leptin co-administration with STAT3 phosphorylation readout\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional endocytosis assay with receptor binding measurement, in vivo knockdown with signaling readout, corroborates findings of companion paper\",\n      \"pmids\": [\"24825475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conservation demonstrated in two model organisms, Co-IP of novel interactors, functional morphogenesis readout\",\n      \"pmids\": [\"33500317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic mapping in multiplex families, LRP2 sequencing, identification of pathogenic mutations\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional cloning with multiple family validation, directly links LRP2 receptor dysfunction to human disease\",\n      \"pmids\": [\"17632512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis of SBEs, chromatin immunoprecipitation (ChIP), EMSA, luciferase reporter assays, TGF-βRI inhibitor treatment in two epithelial cell lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP, EMSA, mutagenesis, and reporter assays together establish transcriptional mechanism, validated in two cell lines\",\n      \"pmids\": [\"31120873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"EMSA, luciferase reporter assay, PPAR agonist/antagonist treatments in epithelial cell lines, in vivo mouse kidney megalin expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — EMSA and reporter assay establish direct PPAR binding, functional regulation confirmed in vivo\",\n      \"pmids\": [\"21311715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"High-resolution cryoelectron microscopy at two pH conditions, structural analysis of missense variants, isolation of LRP2 from mouse kidney\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structures at two functional pH states with variant analysis, mechanistically definitive\",\n      \"pmids\": [\"36750096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Targeted Mesd knockout mouse, immunostaining for LRP2 localization in visceral endoderm, in vitro LRP domain maturation assay\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with direct localization and functional endocytic readout, in vitro domain maturation assay\",\n      \"pmids\": [\"21337463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Immunocytochemistry, FACS-based receptor identification, neutralizing antibody inhibition of endocytosis, EDTA-mediated Ca2+ chelation in hepatic stellate cells\",\n      \"journal\": \"Clinica chimica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional inhibition assay with antibody and Ca2+ chelation, multiple lines of evidence, single lab\",\n      \"pmids\": [\"18194670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown in iPSC-CMs, RNAi in Drosophila, morpholino knockdown in zebrafish, proliferation and differentiation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-species loss-of-function with defined proliferation/differentiation readout, consistent across organisms, single study\",\n      \"pmids\": [\"33006316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"LRP2-deficient mouse models, immunohistochemistry for SHF markers (Nkx2.5, Isl1), cardiomyocyte differentiation marker staining, morphometric analysis of outflow tract\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined molecular mechanism (SHH-dependent progenitor maintenance) with specific cellular and morphological readouts in knockout model\",\n      \"pmids\": [\"32901292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A modification site identified with reader protein pulldown and functional rescue, single lab study\",\n      \"pmids\": [\"35716070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"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.\",\n      \"method\": \"Colchicine treatment in vivo, immunocytochemistry (immunoperoxidase and immunofluorescence), intravenous injection of anti-gp330 antiserum to test for basolateral membrane insertion\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological disruption of microtubules with specific localization readout and functional antibody test, replicated in subsequent study\",\n      \"pmids\": [\"2669509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"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.\",\n      \"method\": \"Monoclonal antibody inhibition of cell attachment, detergent-solubilized gp330 binding to matrix proteins, cell proliferation assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional cell adhesion assay with specific antibody inhibition and direct binding, but limited mechanistic depth\",\n      \"pmids\": [\"1691715\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRP2/megalin is a giant homodimeric endocytic receptor (cryo-EM structure resolved) that undergoes pH-dependent conformational change between ligand-binding (extracellular pH) and ligand-shedding (endosomal pH) states; it internalizes a broad repertoire of ligands—including albumin, thyroglobulin, lipoprotein particles (Lp(a), apoE-VLDL), plasminogen/plasmin, folate-FOLR1 complexes, clusterin/ApoJ, vitamin D-binding protein, and BMP4—via clathrin-coated pits on the apical surface of epithelial cells, with its (FX)NPXY cytoplasmic internalization motifs and adaptor proteins Dab2, Shroom3, and Gipc1 coordinating endosomal trafficking; RAP acts as an ER chaperone for its folding and surface delivery, MESD is required for its β-propeller/EGF domain maturation and apical targeting, GSK3 phosphorylates its cytoplasmic tail to regulate surface availability, and TGF-β1/SMAD2/3 and PPAR transcriptionally regulate its expression; in development LRP2 functions as a context-dependent morphogen co-receptor, acting as an auxiliary activating SHH receptor in the forebrain ventral midline and heart second heart field, but as a clearance receptor for BMP4 in neuroepithelium/ependyma and for SHH in the retinal margin; LRP2 deficiency in humans causes Donnai-Barrow/FOAR syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #10, #16]. 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 [#7]. 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 [#31]. 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 [#2, #10, #13, #15, #33]. 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 [#6, #8, #32]. 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 [#10, #21, #37]. 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 [#18, #19, #20, #24, #35]. 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 [#23, #27]. Expression is transcriptionally repressed by TGF-beta1 through SMAD2/3 binding the megalin promoter and induced by PPARalpha/gamma ligands [#29, #30]. Loss-of-function LRP2 mutations cause Donnai-Barrow/FOAR syndrome in humans [#28].\",\n  \"teleology\": [\n    {\n      \"year\": 1983,\n      \"claim\": \"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.\",\n      \"evidence\": \"Immunocytochemistry at EM resolution and immunoprecipitation from labeled kidney fractions\",\n      \"pmids\": [\"6337231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligands and molecular function undefined\", \"No sequence or domain architecture yet\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"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.\",\n      \"evidence\": \"Colchicine treatment with immunolocalization in vivo; antibody-inhibited cell attachment and direct matrix binding assays\",\n      \"pmids\": [\"2669509\", \"1691715\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Matrix-binding site on the receptor not mapped\", \"Physiological relevance of adhesion vs endocytosis unresolved\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"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.\",\n      \"evidence\": \"Ligand/Ca2+ blotting, in vivo microperfusion, copurification, and pulse-chase with sucrose gradient sedimentation\",\n      \"pmids\": [\"1382088\", \"1495959\", \"8322889\", \"1464627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinction between RAP's chaperone role and its ligand-blocking role not fully separated at this stage\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"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.\",\n      \"evidence\": \"cDNA cloning, sequencing, and domain analysis of rat gp330; human ortholog cloned with cytoplasmic motif mapping\",\n      \"pmids\": [\"7937880\", \"8706697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional validation of putative signaling motifs (PI3K, PKC sites) not performed\", \"Structure of the assembled ectodomain unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"Immunohistochemistry with RAP-IgG binding; cell-based radiolabeled endocytosis assays in pneumocytes with RAP and antibody blockade\",\n      \"pmids\": [\"8223699\", \"7673355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endosomal trafficking machinery and recycling not yet defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"Megalin knockout mouse with developmental phenotyping; in vivo microinfusion with labeled albumin and direct megalin-Sepharose binding\",\n      \"pmids\": [\"8710893\", \"8898021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway linking megalin loss to forebrain defect not yet identified\", \"Cargo specificity in the proximal tubule incomplete\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"Solid-phase binding with Kd determination, surface plasmon resonance, polarized transcytosis assays, kinetic plasmin activation assays, and immuno-EM of pHN models\",\n      \"pmids\": [\"9492085\", \"10212279\", \"10073957\", \"10702280\", \"1645711\", \"1280065\", \"9410908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo flux through each ligand pathway not quantified\", \"Tissue-specific cargo prioritization unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Positional cloning and LRP2 sequencing in multiplex families; vitamin D-binding protein uptake assay in hepatic stellate cells\",\n      \"pmids\": [\"17632512\", \"18194670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlations for specific variants not detailed\", \"Mechanism converting receptor loss to multi-organ phenotype only partly defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Tissue-specific conditional knockouts with BMP4/pSMAD/ID3 and Shh readouts, neurogenesis assays, Mesd knockout with domain maturation assay, morpholino knockdown in zebrafish\",\n      \"pmids\": [\"15623804\", \"20460439\", \"16638803\", \"21337463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single receptor switches between clearance and signaling roles not mechanistically explained\", \"Endosomal fate determining degradation vs signaling unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"22340494\", \"26439398\", \"23673647\", \"24825475\", \"24639464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting activating vs clearance SHH outcomes remain unresolved\", \"Structural basis of LRP2-LepRb coupling not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"34?\", \"32901292\", \"33500317\", \"31120873\", \"21311715\", \"35716070\", \"33006316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How intracellular adaptors integrate endocytosis with cytoskeletal apical constriction not mechanistically resolved\", \"Crosstalk between transcriptional (TGF-beta/PPAR) and post-transcriptional (m6A) regulation untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"High-resolution cryo-EM at extracellular and endosomal pH with structural variant analysis on receptor isolated from mouse kidney\",\n      \"pmids\": [\"36750096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for ligand-specific binding sites not all mapped\", \"How cytoplasmic adaptor engagement couples to ectodomain conformation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unifying model for the activating-vs-clearance switch\", \"Coupling between ectodomain pH-conformational cycle and intracellular trafficking adaptors not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [1, 9, 10, 14, 15, 33]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 20, 24, 25]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 15]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [20, 25, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 7, 10, 31]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 21, 37]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [21, 31]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 8, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 9, 10, 16, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 18, 20, 24, 27, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [20, 25, 26, 35]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [16, 31, 32, 37]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"complexes\": [\n      \"LRP2 homodimer\",\n      \"LRP2/RAP complex (HNAC)\"\n    ],\n    \"partners\": [\n      \"RAP\",\n      \"MESD\",\n      \"Dab2\",\n      \"Shroom3\",\n      \"Gipc1\",\n      \"LepRb\",\n      \"PTCH1\",\n      \"CUBN\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}