{"gene":"LRP1B","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"LRP1B (mLRP1B4 minireceptor) binds, internalizes, and mediates degradation of multiple LRP1 ligands including receptor-associated protein, urokinase plasminogen activator, tissue-type plasminogen activator, and plasminogen activator inhibitor type-1, but with markedly diminished internalization kinetics compared to LRP1.","method":"Stable cell line expression of domain IV minireceptor (mLRP1B4); ligand binding, internalization, and degradation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro ligand binding, internalization, and degradation assays with stably expressed minireceptor; multiple ligands tested; single lab but multiple orthogonal functional assays","pmids":["11384978"],"is_preprint":false},{"year":2004,"finding":"LRP1B protein exists as a single ~600 kDa polypeptide (unlike LRP1 which is cleaved by furin), and the intracellular domain binds two proteins identified by yeast two-hybrid: PSD-95 (postsynaptic density protein 95) and AIP (aryl hydrocarbon receptor-interacting protein).","method":"Immunoblotting of LRP1b knockout/knockin mouse tissues; yeast two-hybrid screen with LRP1b intracellular domain as bait","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid identification of binding partners confirmed in a knockout mouse study; two orthogonal approaches (blotting + Y2H) in a single study","pmids":["15082773"],"is_preprint":false},{"year":2004,"finding":"LRP1B attenuates smooth muscle cell migration by binding and internalizing urokinase-type plasminogen activator receptor (uPAR), thereby reducing membrane levels of uPAR and PDGFRβ; functional inhibition of LRP1B with anti-LRP1B IgY increased PDGFRβ protein levels, ERK1/2 phosphorylation, and SMC migration/invasion.","method":"Cell surface assays, internalization assays, co-immunoprecipitation, metabolic labeling, anti-LRP1B antibody functional inhibition, migration/invasion assays in cultured SMCs","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (co-IP, metabolic labeling, functional antibody inhibition, migration assay) in a single study establishing mechanism","pmids":["15166012"],"is_preprint":false},{"year":2005,"finding":"LRP1B expression is negatively correlated with PDGFRβ levels in intimal smooth muscle cells from atherosclerotic plaques; functional inhibition of LRP1B increases PDGFRβ-mediated ERK1/2 phosphorylation and SMC migration, confirming LRP1B regulates SMC migration through PDGFRβ catabolism.","method":"Isolation and culture of SMC subpopulations from rabbit aortic plaques; anti-LRP1B IgY functional inhibition; Western blot; migration/invasion assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional antibody inhibition in primary cells with phenotypic readout; replicates and extends prior mechanistic finding (PMID 15166012)","pmids":["15882972"],"is_preprint":false},{"year":2008,"finding":"Six intracellular binding partners of LRP1B were identified by yeast two-hybrid and confirmed by co-immunoprecipitation. PICK1 binds the C-terminus of LRP1B; the LRP1B cytoplasmic domain is phosphorylated by PKCα ~100-fold more efficiently than LRP1; PICK1 binding inhibits PKCα-mediated phosphorylation of LRP1B but not LRP1.","method":"Yeast two-hybrid screen; co-immunoprecipitation; in vitro kinase assay with PKCα","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal co-IP confirming Y2H hits; in vitro kinase assay directly measuring phosphorylation; two orthogonal methods in one study","pmids":["19071120"],"is_preprint":false},{"year":2010,"finding":"The soluble extracellular domain of LRP1B, when released into the extracellular space, is sufficient to support embryonic viability in mice (truncation alleles releasing the ECD are viable whereas null mutations cause early embryonic lethality), suggesting the LRP1B ECD functions as a scavenger for signaling ligands in the extracellular space.","method":"Gene targeting in mice creating transmembrane/intracellular domain truncation alleles vs. null alleles; embryonic lethality phenotyping; blastocyst culture","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis using multiple engineered alleles in vivo; two distinct truncation lines compared to null; single lab","pmids":["20383322"],"is_preprint":false},{"year":2010,"finding":"LRP1B inactivation in thyroid cancer cells leads to reduced matrix metalloproteinase 2 (MMP2) in the extracellular medium and decreased invasion; restoration of LRP1B expression impairs tumor growth in vitro and in vivo and inhibits cell invasion, placing LRP1B as a modulator of the extracellular environment.","method":"CpG island reporter methylation assays; miRNA target validation; LRP1B restoration (transfection); in vitro invasion assay; in vivo tumor growth assay; MMP2 measurement in conditioned medium","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (in vitro + in vivo) with LRP1B restoration; single lab; MMP2 reduction mechanistically linked to reduced invasion","pmids":["21057533"],"is_preprint":false},{"year":2011,"finding":"LRP1B ectodomains directly bind fibrinogen (confirmed by co-immunoprecipitation) and apoE-carrying lipoproteins (lipoprotein binding assay); cells expressing an LRP1B minireceptor bind and internalize VLDL.","method":"Affinity chromatography from human plasma with FLAG-tagged LRP1B ectodomains; mass spectrometry; co-immunoprecipitation; lipoprotein binding assay; internalization assay with LRP1B minireceptor cells","journal":"Atherosclerosis","confidence":"High","confidence_rationale":"Tier 1 / Moderate — co-IP confirms MS-identified ligand (fibrinogen); functional internalization assay for VLDL; multiple orthogonal methods in single study","pmids":["21420681"],"is_preprint":false},{"year":2012,"finding":"LRP1B expression is required for C1q-mediated neuroprotection against fibrillar and oligomeric amyloid-β toxicity; silencing LRP1B expression inhibits C1q-mediated neuroprotection in primary neurons; LRP1B expression is induced in hippocampus of 3×Tg AD mice early (2 months) in a C1q-dependent manner.","method":"siRNA silencing of LRP1B in primary neurons; neurotoxicity assays with fAβ and oAβ; gene expression analysis; in vivo hippocampal expression in transgenic AD mice with and without C1q deficiency","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with specific neuroprotection readout; in vivo confirmation in C1q-deficient AD mice; single lab, two orthogonal approaches","pmids":["23150673"],"is_preprint":false},{"year":2012,"finding":"LRP1B mediates cellular uptake of liposomal doxorubicin but not free doxorubicin; reducing LRP1B expression decreased sensitivity of ovarian cancer cell lines to liposomal doxorubicin, while LRP1B overexpression increased sensitivity, functionally demonstrating LRP1B as an endocytic receptor for liposomes.","method":"Functional studies: LRP1B knockdown and overexpression in high-grade serous ovarian cancer cell lines; cytotoxicity assays with liposomal doxorubicin vs. free doxorubicin","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with specific drug sensitivity readout distinguishing liposomal vs. free doxorubicin; single lab","pmids":["22896685"],"is_preprint":false},{"year":2013,"finding":"Knockdown of LRP1B in HEK293 and renal cancer cells promotes anchorage-independent growth, cell migration, and invasion; silencing LRP1B alters expression of focal adhesion complex-associated proteins and increases Cdc42/RhoA activity, implicating LRP1B as a regulator of cytoskeletal dynamics via the RhoA/Cdc42 pathway.","method":"shRNA knockdown; anchorage-independent growth assay; migration and invasion assays; Western blot for focal adhesion proteins; Cdc42/RhoA activity assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA KD with multiple phenotypic readouts and pathway-level mechanistic follow-up (RhoA/Cdc42 activity); single lab","pmids":["23521319"],"is_preprint":false},{"year":2016,"finding":"Expression of full-length LRP1B (~600 kDa, single polypeptide) in non-small cell lung cancer cells with low endogenous LRP1B significantly reduced cellular proliferation, while siRNA-mediated knockdown in cells with higher endogenous LRP1B enhanced proliferation, confirming a growth-suppressing function.","method":"Full-length murine Lrp1b cDNA transfection in NSCLC cell lines; Western blot (600 kDa band); siRNA knockdown; proliferation assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (OE and KD) with proliferation readout; Western blot confirmation of full-length receptor; single lab","pmids":["27626682"],"is_preprint":false},{"year":2017,"finding":"LRP1B interacts with DVL2 (Dishevelled 2) and inhibits the DVL2–Axin interaction, thereby negatively regulating β-catenin/TCF Wnt signaling; LRP1B overexpression suppressed growth, migration, and metastasis of colon cancer cells.","method":"Co-immunoprecipitation (LRP1B-DVL2 interaction); competitive co-IP (DVL2-Axin); TCF reporter assay; growth, migration, and metastasis assays with LRP1B overexpression/knockdown","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishing protein-protein interaction plus pathway reporter assay; multiple functional readouts; single lab","pmids":["28408316"],"is_preprint":false},{"year":2020,"finding":"HSF1 directly regulates transcription of LRP1B; LRP1B knockdown in HCC cells decreases intracellular lipid content, downregulates lipid synthesis enzymes, upregulates β-oxidation enzymes, and activates AMPK signaling, demonstrating LRP1B's role in hepatic lipid metabolism.","method":"CRISPR-Cas9 knockdown and CRISPRa activation of LRP1B; Oil Red O staining; DiD staining + flow cytometry; transmission electron microscopy; qPCR and Western blot for metabolic enzymes; AMPK pathway analysis","journal":"Journal of hepatocellular carcinoma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional CRISPR manipulation with multiple lipid metabolism readouts; HSF1-LRP1B transcriptional link established; single lab","pmids":["33324588"],"is_preprint":false},{"year":2022,"finding":"LRP1B directly binds NCSTN (nicastrin) and affects its protein expression level, thereby regulating the PI3K/AKT signaling pathway; LRP1B knockdown promotes HCC cell proliferation and migration and enhances resistance to liposomal doxorubicin.","method":"Co-immunoprecipitation (LRP1B-NCSTN); Western blot for PI3K/AKT pathway components; in vitro and in vivo proliferation, migration, and drug resistance assays","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishing direct binding plus downstream pathway analysis and functional assays; single lab","pmids":["37492741"],"is_preprint":false},{"year":2022,"finding":"LRP1B deletion in HPV+ oropharyngeal squamous cell carcinoma cell lines (by CRISPR/Cas9) results in increased proliferation, clonogenic growth, migration, and resistance to both cisplatin and radiation in vitro and in vivo (xenograft model).","method":"siRNA knockdown; CRISPR/Cas9 deletion in four HPV+ cell lines; proliferation assays; clonogenic assay; migration assay; cisplatin and radiation resistance assays; cell line derived xenograft studies","journal":"Oral oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple phenotypic readouts across four cell lines plus in vivo validation; single lab","pmids":["37778229"],"is_preprint":false},{"year":2022,"finding":"LRP1B knockdown activates the PERK-ATF4-CHOP endoplasmic reticulum stress signaling pathway in HCC cells, thereby inhibiting HCC cell proliferation, migration, and invasion and increasing sensitivity to doxorubicin.","method":"siRNA/shRNA knockdown of LRP1B; Western blot and qPCR for PERK-ATF4-CHOP pathway components; proliferation, migration, invasion assays; doxorubicin sensitivity assay","journal":"Bioengineered","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach; pathway placement based on expression changes without direct mechanistic demonstration of how LRP1B engages ER stress pathway","pmids":["35389768"],"is_preprint":false},{"year":2023,"finding":"LRP1B knockdown in lung adenocarcinoma cells enhances secretion of IL-6 and IL-8 and activates the IL-6-JAK-STAT3 signaling pathway, as confirmed by ELISA, PCR, and Western blot, placing LRP1B as a suppressor of inflammation-driven malignant progression in LUAD.","method":"shRNA knockdown of LRP1B; ELISA for IL-6 and IL-8; qPCR and Western blot for JAK-STAT3 pathway components; transcriptomic enrichment analysis","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab; pathway placement based on expression changes post-KD with ELISA confirmation; no rescue or direct mechanistic link established","pmids":["37560001"],"is_preprint":false},{"year":2023,"finding":"Dual sgRNA CRISPR/Cas9 disruption of LRP1B in U87 glioblastoma cells results in altered cellular morphology, increased cellular and nuclear size, changes in ploidy, decreased cell growth in vitro and in vivo (CAM assay), and changes in the secretome profile.","method":"Dual sgRNA CRISPR/Cas9 editing; PCR and Sanger sequencing confirmation; qRT-PCR; proteomic secretome analysis; in vitro growth assays; in vivo CAM assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple functional readouts (in vitro and in vivo) and proteomic secretome characterization; single lab","pmids":["37511044"],"is_preprint":false},{"year":2024,"finding":"LRP1B regulates sensitivity of NSCLC cells to ferroptosis by modulating SLC7A11 expression through altering STAT3 phosphorylation; LRP1B knockdown promotes ferroptosis sensitivity and enhances anti-PD-1 immunotherapy efficacy in vivo.","method":"qRT-PCR, Western blotting, CCK-8 assay, flow cytometry for ferroptosis; ChIP assay; dual-luciferase reporter assay; in vivo mPD-1 immunotherapy experiment","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and dual-luciferase reporter establish transcriptional mechanism; in vivo immunotherapy validation; single lab with multiple orthogonal methods","pmids":["39660409"],"is_preprint":false},{"year":2025,"finding":"DNMT3B directly binds the LRP1B promoter and mediates its hypermethylation, suppressing LRP1B expression in pheochromocytoma; DNMT3B inhibition derepresses LRP1B and inhibits tumor progression; overexpression of DNMT3B reverses the inhibitory effect of LRP1B overexpression.","method":"ChIP (DNMT3B binding to LRP1B promoter); luciferase reporter assay; shRNA knockdown; clonal formation, migration assays; in vivo transplantation; RT-qPCR, Western blot, IHC","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter directly demonstrate DNMT3B-LRP1B promoter interaction; rescue experiment with epistasis; single lab","pmids":["40346661"],"is_preprint":false},{"year":2004,"finding":"Restoration of LRP1B expression in esophageal squamous cell carcinoma (ESC) cells reduced colony formation, providing functional evidence that LRP1B suppresses tumor cell growth; LRP1B silencing in ESC lines without homozygous deletion correlates with CpG island hypermethylation, and 5-aza-2'-deoxycytidine treatment restores LRP1B expression; histone acetylation status correlates directly with LRP1B expression.","method":"Array CGH; bisulfite-PCR and sequencing; 5-aza-2'-deoxycytidine treatment; colony formation assay after LRP1B restoration; histone acetylation analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — restoration-of-function with colony assay; epigenetic mechanism defined by bisulfite sequencing and demethylation rescue; single lab with multiple orthogonal methods","pmids":["15172977"],"is_preprint":false}],"current_model":"LRP1B is a ~600 kDa single-chain endocytic receptor of the LDL receptor family that internalizes multiple ligands (uPA, tPA, PAI-1, RAP, VLDL, fibrinogen, apoE-carrying lipoproteins) with slower kinetics than LRP1; its cytoplasmic domain is phosphorylated by PKCα ~100-fold more efficiently than LRP1 and this is inhibited by PICK1 binding; in smooth muscle cells it attenuates migration by promoting degradation of uPAR and PDGFRβ from the cell surface; in colon cancer cells it suppresses Wnt/β-catenin signaling by binding DVL2 and blocking the DVL2-Axin interaction; in HCC it binds NCSTN to regulate PI3K/AKT signaling and modulates lipid metabolism via AMPK; in NSCLC it suppresses ferroptosis by controlling STAT3 phosphorylation and SLC7A11 expression; its promoter is silenced by DNMT3B-mediated CpG hypermethylation and by specific miRNAs; the extracellular domain released into the extracellular space is sufficient for embryonic viability in mice and can scavenge signaling ligands; and its neuroprotective role downstream of C1q requires LRP1B expression for protection against amyloid-β toxicity."},"narrative":{"mechanistic_narrative":"LRP1B is a ~600 kDa single-chain endocytic receptor of the LDL receptor family that internalizes and degrades multiple ligands shared with LRP1 — including the receptor-associated protein, urokinase- and tissue-type plasminogen activators, and PAI-1 — but with markedly slower internalization kinetics [PMID:11384978]. Unlike LRP1, the protein is not furin-cleaved and exists as a single polypeptide whose released soluble ectodomain is itself sufficient for embryonic viability in mice, consistent with a function as an extracellular scavenger of signaling ligands [PMID:15082773, PMID:20383322]. Its ectodomains directly bind fibrinogen and apoE-carrying lipoproteins and mediate VLDL internalization [PMID:21420681]. The cytoplasmic tail is phosphorylated by PKCα ~100-fold more efficiently than that of LRP1, and this phosphorylation is blocked by PICK1 binding to the receptor C-terminus [PMID:19071120]. Through receptor-mediated catabolism of cell-surface partners, LRP1B restrains cell migration: in smooth muscle cells it binds and internalizes uPAR, lowering uPAR and PDGFRβ levels and dampening ERK1/2 signaling and migration [PMID:15166012, PMID:15882972]. Across diverse cancers LRP1B acts as a growth and invasion suppressor whose promoter is silenced by CpG hypermethylation; restoration of expression impairs colony formation, proliferation, invasion, and tumor growth [PMID:15172977, PMID:27626682, PMID:21057533]. Mechanistically it suppresses Wnt/β-catenin signaling by binding DVL2 and blocking the DVL2–Axin interaction [PMID:28408316], binds NCSTN to modulate PI3K/AKT signaling and lipid metabolism [PMID:37492741, PMID:33324588], and controls STAT3 phosphorylation and SLC7A11 to govern ferroptosis sensitivity [PMID:39660409]. LRP1B expression is also required for C1q-mediated neuroprotection against amyloid-β toxicity [PMID:23150673].","teleology":[{"year":2001,"claim":"Established that LRP1B is a functional endocytic receptor sharing LRP1 ligands, answering whether this homolog actually internalizes cargo and how it compares kinetically.","evidence":"Domain IV minireceptor (mLRP1B4) stable cell lines with ligand binding, internalization, and degradation assays","pmids":["11384978"],"confidence":"High","gaps":["Tested a minireceptor rather than full-length protein","Slow internalization kinetics mechanistically unexplained","Physiological ligand repertoire not exhausted"]},{"year":2004,"claim":"Defined the receptor's molecular architecture as an uncleaved single polypeptide and identified the first cytoplasmic-tail interactors, framing how the intracellular domain might signal.","evidence":"Immunoblotting of knockout/knockin mouse tissues and yeast two-hybrid with the intracellular domain (PSD-95, AIP)","pmids":["15082773"],"confidence":"Medium","gaps":["Functional consequences of PSD-95/AIP binding not established","No structural mapping of binding sites"]},{"year":2004,"claim":"Showed LRP1B is a tumor suppressor silenced epigenetically, explaining why it is recurrently lost in carcinomas without deletion.","evidence":"Array CGH, bisulfite sequencing, 5-aza demethylation rescue, and colony formation after LRP1B restoration in esophageal carcinoma cells","pmids":["15172977"],"confidence":"Medium","gaps":["Mechanism by which restored LRP1B suppresses growth not defined","Single tumor type"]},{"year":2005,"claim":"Linked LRP1B to control of smooth muscle migration through catabolism of uPAR and PDGFRβ, providing a concrete receptor-clearance mechanism.","evidence":"Co-IP, metabolic labeling, anti-LRP1B functional antibody, and migration/invasion assays in cultured and plaque-derived SMCs","pmids":["15166012","15882972"],"confidence":"High","gaps":["Whether clearance is via degradation vs. trafficking partially resolved","In vivo vascular phenotype not tested with genetic models"]},{"year":2008,"claim":"Identified PICK1 as a regulator of LRP1B phosphorylation and revealed the cytoplasmic tail is a far better PKCα substrate than LRP1, distinguishing the two receptors functionally.","evidence":"Yeast two-hybrid, reciprocal co-IP, and in vitro PKCα kinase assays","pmids":["19071120"],"confidence":"High","gaps":["Downstream effect of tail phosphorylation on trafficking unknown","PICK1 regulation not tested in vivo"]},{"year":2010,"claim":"Demonstrated genetically that the soluble ectodomain alone supports viability, establishing an extracellular scavenger function independent of the membrane-anchored receptor.","evidence":"Mouse truncation alleles releasing the ECD versus null alleles, with embryonic lethality phenotyping and blastocyst culture","pmids":["20383322"],"confidence":"Medium","gaps":["Specific scavenged ligands responsible for viability not identified","Relative contribution of membrane vs. soluble forms unresolved"]},{"year":2011,"claim":"Expanded the ligand repertoire to fibrinogen and apoE-lipoproteins/VLDL, connecting LRP1B to lipid and hemostatic ligand clearance.","evidence":"Affinity chromatography/MS, co-IP, lipoprotein binding, and VLDL internalization with minireceptor cells","pmids":["21420681"],"confidence":"High","gaps":["Physiological significance of lipoprotein uptake in vivo not shown","Affinity relative to LRP1 not quantified"]},{"year":2012,"claim":"Revealed a neuroprotective role requiring LRP1B downstream of C1q against amyloid-β toxicity, extending function beyond cancer/vascular contexts.","evidence":"siRNA silencing in primary neurons with Aβ neurotoxicity assays and hippocampal expression in C1q-deficient AD mice","pmids":["23150673"],"confidence":"Medium","gaps":["Molecular mechanism of LRP1B-mediated protection undefined","Whether LRP1B binds C1q directly not established"]},{"year":2012,"claim":"Showed LRP1B functions as an endocytic receptor for liposomal drug delivery, with direct therapeutic relevance for drug sensitivity.","evidence":"Bidirectional knockdown/overexpression in ovarian cancer lines with liposomal vs. free doxorubicin cytotoxicity assays","pmids":["22896685"],"confidence":"Medium","gaps":["Liposome recognition determinants not defined","Single tumor type"]},{"year":2013,"claim":"Connected LRP1B loss to cytoskeletal and adhesion remodeling via RhoA/Cdc42, providing a mechanism for the migratory/invasive phenotype.","evidence":"shRNA knockdown with anchorage-independent growth, migration/invasion assays, focal adhesion Western blots, and Cdc42/RhoA activity assays","pmids":["23521319"],"confidence":"Medium","gaps":["How surface receptor loss feeds into GTPase activation unknown","No rescue experiment reported"]},{"year":2017,"claim":"Defined a molecular mechanism for Wnt suppression: LRP1B binds DVL2 and blocks DVL2–Axin, linking the receptor to a canonical oncogenic pathway.","evidence":"Co-IP, competitive co-IP, TCF reporter assays, and growth/metastasis assays in colon cancer cells","pmids":["28408316"],"confidence":"Medium","gaps":["Whether the interaction is direct and which domain mediates it unclear","Subcellular site of DVL2 engagement not mapped"]},{"year":2022,"claim":"Established LRP1B as a tumor suppressor across multiple cancers acting through NCSTN/PI3K-AKT, lipid metabolism/AMPK, and ER stress, with loss conferring therapy resistance.","evidence":"Co-IP, CRISPR knockdown/activation, pathway Westerns, lipid imaging, and in vitro/in vivo drug- and radiation-resistance assays across HCC, OPSCC, and glioblastoma models","pmids":["37492741","33324588","37778229","37511044","35389768"],"confidence":"Medium","gaps":["Convergence of these multiple downstream pathways onto one mechanism not unified","ER stress link rests on expression changes without direct mechanistic demonstration"]},{"year":2024,"claim":"Showed LRP1B governs ferroptosis sensitivity and immunotherapy response via STAT3-driven SLC7A11 control, linking the receptor to redox/immune vulnerability.","evidence":"ChIP, dual-luciferase reporter, ferroptosis flow cytometry, and in vivo anti-PD-1 experiments in NSCLC","pmids":["39660409"],"confidence":"Medium","gaps":["How a surface receptor controls STAT3 phosphorylation not mechanistically defined","IL-6-JAK-STAT3 secretory link to ferroptosis only partially connected"]},{"year":2025,"claim":"Identified DNMT3B as a direct epigenetic silencer of LRP1B, closing the loop on how the tumor suppressor is inactivated.","evidence":"ChIP, luciferase reporter, shRNA, rescue/epistasis, and in vivo transplantation in pheochromocytoma","pmids":["40346661"],"confidence":"Medium","gaps":["Upstream signals driving DNMT3B recruitment unknown","Generality across other tumor types not tested"]},{"year":null,"claim":"It remains unresolved how the single endocytic/scavenging activity of LRP1B mechanistically gives rise to its many reported downstream signaling outputs (Wnt, PI3K/AKT, STAT3, AMPK, RhoA), and whether these reflect a common cargo-clearance mechanism.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying biochemical model linking receptor endocytosis to the diverse pathway effects","Structural basis of ligand and partner selectivity undetermined","In vivo physiological function of full-length receptor largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,7,9]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[5,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,12,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,7]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5,6,7]}],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,12,14,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,12,14,19]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,7,9]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13]}],"complexes":[],"partners":["UPAR","PDGFRB","PICK1","PKCALPHA","DVL2","NCSTN","FIBRINOGEN","PSD-95"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZR2","full_name":"Low-density lipoprotein receptor-related protein 1B","aliases":["Low-density lipoprotein receptor-related protein-deleted in tumor","LRP-DIT"],"length_aa":4599,"mass_kda":515.5,"function":"Potential cell surface proteins that bind and internalize ligands in the process of receptor-mediated endocytosis","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9NZR2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRP1B","classification":"Not Classified","n_dependent_lines":38,"n_total_lines":1208,"dependency_fraction":0.03145695364238411},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRP1B","total_profiled":1310},"omim":[{"mim_id":"614104","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 7; MRD7","url":"https://www.omim.org/entry/614104"},{"mim_id":"608766","title":"LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 1B; LRP1B","url":"https://www.omim.org/entry/608766"},{"mim_id":"600855","title":"DUAL-SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATED KINASE 1A; DYRK1A","url":"https://www.omim.org/entry/600855"},{"mim_id":"211980","title":"LUNG CANCER","url":"https://www.omim.org/entry/211980"},{"mim_id":"151400","title":"LEUKEMIA, CHRONIC LYMPHOCYTIC; CLL","url":"https://www.omim.org/entry/151400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":9.4},{"tissue":"thyroid 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ligand binding, internalization, and degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro ligand binding, internalization, and degradation assays with stably expressed minireceptor; multiple ligands tested; single lab but multiple orthogonal functional assays\",\n      \"pmids\": [\"11384978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LRP1B protein exists as a single ~600 kDa polypeptide (unlike LRP1 which is cleaved by furin), and the intracellular domain binds two proteins identified by yeast two-hybrid: PSD-95 (postsynaptic density protein 95) and AIP (aryl hydrocarbon receptor-interacting protein).\",\n      \"method\": \"Immunoblotting of LRP1b knockout/knockin mouse tissues; yeast two-hybrid screen with LRP1b intracellular domain as bait\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid identification of binding partners confirmed in a knockout mouse study; two orthogonal approaches (blotting + Y2H) in a single study\",\n      \"pmids\": [\"15082773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LRP1B attenuates smooth muscle cell migration by binding and internalizing urokinase-type plasminogen activator receptor (uPAR), thereby reducing membrane levels of uPAR and PDGFRβ; functional inhibition of LRP1B with anti-LRP1B IgY increased PDGFRβ protein levels, ERK1/2 phosphorylation, and SMC migration/invasion.\",\n      \"method\": \"Cell surface assays, internalization assays, co-immunoprecipitation, metabolic labeling, anti-LRP1B antibody functional inhibition, migration/invasion assays in cultured SMCs\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (co-IP, metabolic labeling, functional antibody inhibition, migration assay) in a single study establishing mechanism\",\n      \"pmids\": [\"15166012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LRP1B expression is negatively correlated with PDGFRβ levels in intimal smooth muscle cells from atherosclerotic plaques; functional inhibition of LRP1B increases PDGFRβ-mediated ERK1/2 phosphorylation and SMC migration, confirming LRP1B regulates SMC migration through PDGFRβ catabolism.\",\n      \"method\": \"Isolation and culture of SMC subpopulations from rabbit aortic plaques; anti-LRP1B IgY functional inhibition; Western blot; migration/invasion assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional antibody inhibition in primary cells with phenotypic readout; replicates and extends prior mechanistic finding (PMID 15166012)\",\n      \"pmids\": [\"15882972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Six intracellular binding partners of LRP1B were identified by yeast two-hybrid and confirmed by co-immunoprecipitation. PICK1 binds the C-terminus of LRP1B; the LRP1B cytoplasmic domain is phosphorylated by PKCα ~100-fold more efficiently than LRP1; PICK1 binding inhibits PKCα-mediated phosphorylation of LRP1B but not LRP1.\",\n      \"method\": \"Yeast two-hybrid screen; co-immunoprecipitation; in vitro kinase assay with PKCα\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal co-IP confirming Y2H hits; in vitro kinase assay directly measuring phosphorylation; two orthogonal methods in one study\",\n      \"pmids\": [\"19071120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The soluble extracellular domain of LRP1B, when released into the extracellular space, is sufficient to support embryonic viability in mice (truncation alleles releasing the ECD are viable whereas null mutations cause early embryonic lethality), suggesting the LRP1B ECD functions as a scavenger for signaling ligands in the extracellular space.\",\n      \"method\": \"Gene targeting in mice creating transmembrane/intracellular domain truncation alleles vs. null alleles; embryonic lethality phenotyping; blastocyst culture\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis using multiple engineered alleles in vivo; two distinct truncation lines compared to null; single lab\",\n      \"pmids\": [\"20383322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LRP1B inactivation in thyroid cancer cells leads to reduced matrix metalloproteinase 2 (MMP2) in the extracellular medium and decreased invasion; restoration of LRP1B expression impairs tumor growth in vitro and in vivo and inhibits cell invasion, placing LRP1B as a modulator of the extracellular environment.\",\n      \"method\": \"CpG island reporter methylation assays; miRNA target validation; LRP1B restoration (transfection); in vitro invasion assay; in vivo tumor growth assay; MMP2 measurement in conditioned medium\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (in vitro + in vivo) with LRP1B restoration; single lab; MMP2 reduction mechanistically linked to reduced invasion\",\n      \"pmids\": [\"21057533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LRP1B ectodomains directly bind fibrinogen (confirmed by co-immunoprecipitation) and apoE-carrying lipoproteins (lipoprotein binding assay); cells expressing an LRP1B minireceptor bind and internalize VLDL.\",\n      \"method\": \"Affinity chromatography from human plasma with FLAG-tagged LRP1B ectodomains; mass spectrometry; co-immunoprecipitation; lipoprotein binding assay; internalization assay with LRP1B minireceptor cells\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — co-IP confirms MS-identified ligand (fibrinogen); functional internalization assay for VLDL; multiple orthogonal methods in single study\",\n      \"pmids\": [\"21420681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LRP1B expression is required for C1q-mediated neuroprotection against fibrillar and oligomeric amyloid-β toxicity; silencing LRP1B expression inhibits C1q-mediated neuroprotection in primary neurons; LRP1B expression is induced in hippocampus of 3×Tg AD mice early (2 months) in a C1q-dependent manner.\",\n      \"method\": \"siRNA silencing of LRP1B in primary neurons; neurotoxicity assays with fAβ and oAβ; gene expression analysis; in vivo hippocampal expression in transgenic AD mice with and without C1q deficiency\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with specific neuroprotection readout; in vivo confirmation in C1q-deficient AD mice; single lab, two orthogonal approaches\",\n      \"pmids\": [\"23150673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LRP1B mediates cellular uptake of liposomal doxorubicin but not free doxorubicin; reducing LRP1B expression decreased sensitivity of ovarian cancer cell lines to liposomal doxorubicin, while LRP1B overexpression increased sensitivity, functionally demonstrating LRP1B as an endocytic receptor for liposomes.\",\n      \"method\": \"Functional studies: LRP1B knockdown and overexpression in high-grade serous ovarian cancer cell lines; cytotoxicity assays with liposomal doxorubicin vs. free doxorubicin\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with specific drug sensitivity readout distinguishing liposomal vs. free doxorubicin; single lab\",\n      \"pmids\": [\"22896685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockdown of LRP1B in HEK293 and renal cancer cells promotes anchorage-independent growth, cell migration, and invasion; silencing LRP1B alters expression of focal adhesion complex-associated proteins and increases Cdc42/RhoA activity, implicating LRP1B as a regulator of cytoskeletal dynamics via the RhoA/Cdc42 pathway.\",\n      \"method\": \"shRNA knockdown; anchorage-independent growth assay; migration and invasion assays; Western blot for focal adhesion proteins; Cdc42/RhoA activity assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA KD with multiple phenotypic readouts and pathway-level mechanistic follow-up (RhoA/Cdc42 activity); single lab\",\n      \"pmids\": [\"23521319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Expression of full-length LRP1B (~600 kDa, single polypeptide) in non-small cell lung cancer cells with low endogenous LRP1B significantly reduced cellular proliferation, while siRNA-mediated knockdown in cells with higher endogenous LRP1B enhanced proliferation, confirming a growth-suppressing function.\",\n      \"method\": \"Full-length murine Lrp1b cDNA transfection in NSCLC cell lines; Western blot (600 kDa band); siRNA knockdown; proliferation assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (OE and KD) with proliferation readout; Western blot confirmation of full-length receptor; single lab\",\n      \"pmids\": [\"27626682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LRP1B interacts with DVL2 (Dishevelled 2) and inhibits the DVL2–Axin interaction, thereby negatively regulating β-catenin/TCF Wnt signaling; LRP1B overexpression suppressed growth, migration, and metastasis of colon cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (LRP1B-DVL2 interaction); competitive co-IP (DVL2-Axin); TCF reporter assay; growth, migration, and metastasis assays with LRP1B overexpression/knockdown\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing protein-protein interaction plus pathway reporter assay; multiple functional readouts; single lab\",\n      \"pmids\": [\"28408316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HSF1 directly regulates transcription of LRP1B; LRP1B knockdown in HCC cells decreases intracellular lipid content, downregulates lipid synthesis enzymes, upregulates β-oxidation enzymes, and activates AMPK signaling, demonstrating LRP1B's role in hepatic lipid metabolism.\",\n      \"method\": \"CRISPR-Cas9 knockdown and CRISPRa activation of LRP1B; Oil Red O staining; DiD staining + flow cytometry; transmission electron microscopy; qPCR and Western blot for metabolic enzymes; AMPK pathway analysis\",\n      \"journal\": \"Journal of hepatocellular carcinoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional CRISPR manipulation with multiple lipid metabolism readouts; HSF1-LRP1B transcriptional link established; single lab\",\n      \"pmids\": [\"33324588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LRP1B directly binds NCSTN (nicastrin) and affects its protein expression level, thereby regulating the PI3K/AKT signaling pathway; LRP1B knockdown promotes HCC cell proliferation and migration and enhances resistance to liposomal doxorubicin.\",\n      \"method\": \"Co-immunoprecipitation (LRP1B-NCSTN); Western blot for PI3K/AKT pathway components; in vitro and in vivo proliferation, migration, and drug resistance assays\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing direct binding plus downstream pathway analysis and functional assays; single lab\",\n      \"pmids\": [\"37492741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LRP1B deletion in HPV+ oropharyngeal squamous cell carcinoma cell lines (by CRISPR/Cas9) results in increased proliferation, clonogenic growth, migration, and resistance to both cisplatin and radiation in vitro and in vivo (xenograft model).\",\n      \"method\": \"siRNA knockdown; CRISPR/Cas9 deletion in four HPV+ cell lines; proliferation assays; clonogenic assay; migration assay; cisplatin and radiation resistance assays; cell line derived xenograft studies\",\n      \"journal\": \"Oral oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple phenotypic readouts across four cell lines plus in vivo validation; single lab\",\n      \"pmids\": [\"37778229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LRP1B knockdown activates the PERK-ATF4-CHOP endoplasmic reticulum stress signaling pathway in HCC cells, thereby inhibiting HCC cell proliferation, migration, and invasion and increasing sensitivity to doxorubicin.\",\n      \"method\": \"siRNA/shRNA knockdown of LRP1B; Western blot and qPCR for PERK-ATF4-CHOP pathway components; proliferation, migration, invasion assays; doxorubicin sensitivity assay\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach; pathway placement based on expression changes without direct mechanistic demonstration of how LRP1B engages ER stress pathway\",\n      \"pmids\": [\"35389768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LRP1B knockdown in lung adenocarcinoma cells enhances secretion of IL-6 and IL-8 and activates the IL-6-JAK-STAT3 signaling pathway, as confirmed by ELISA, PCR, and Western blot, placing LRP1B as a suppressor of inflammation-driven malignant progression in LUAD.\",\n      \"method\": \"shRNA knockdown of LRP1B; ELISA for IL-6 and IL-8; qPCR and Western blot for JAK-STAT3 pathway components; transcriptomic enrichment analysis\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab; pathway placement based on expression changes post-KD with ELISA confirmation; no rescue or direct mechanistic link established\",\n      \"pmids\": [\"37560001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Dual sgRNA CRISPR/Cas9 disruption of LRP1B in U87 glioblastoma cells results in altered cellular morphology, increased cellular and nuclear size, changes in ploidy, decreased cell growth in vitro and in vivo (CAM assay), and changes in the secretome profile.\",\n      \"method\": \"Dual sgRNA CRISPR/Cas9 editing; PCR and Sanger sequencing confirmation; qRT-PCR; proteomic secretome analysis; in vitro growth assays; in vivo CAM assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple functional readouts (in vitro and in vivo) and proteomic secretome characterization; single lab\",\n      \"pmids\": [\"37511044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LRP1B regulates sensitivity of NSCLC cells to ferroptosis by modulating SLC7A11 expression through altering STAT3 phosphorylation; LRP1B knockdown promotes ferroptosis sensitivity and enhances anti-PD-1 immunotherapy efficacy in vivo.\",\n      \"method\": \"qRT-PCR, Western blotting, CCK-8 assay, flow cytometry for ferroptosis; ChIP assay; dual-luciferase reporter assay; in vivo mPD-1 immunotherapy experiment\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and dual-luciferase reporter establish transcriptional mechanism; in vivo immunotherapy validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39660409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNMT3B directly binds the LRP1B promoter and mediates its hypermethylation, suppressing LRP1B expression in pheochromocytoma; DNMT3B inhibition derepresses LRP1B and inhibits tumor progression; overexpression of DNMT3B reverses the inhibitory effect of LRP1B overexpression.\",\n      \"method\": \"ChIP (DNMT3B binding to LRP1B promoter); luciferase reporter assay; shRNA knockdown; clonal formation, migration assays; in vivo transplantation; RT-qPCR, Western blot, IHC\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter directly demonstrate DNMT3B-LRP1B promoter interaction; rescue experiment with epistasis; single lab\",\n      \"pmids\": [\"40346661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Restoration of LRP1B expression in esophageal squamous cell carcinoma (ESC) cells reduced colony formation, providing functional evidence that LRP1B suppresses tumor cell growth; LRP1B silencing in ESC lines without homozygous deletion correlates with CpG island hypermethylation, and 5-aza-2'-deoxycytidine treatment restores LRP1B expression; histone acetylation status correlates directly with LRP1B expression.\",\n      \"method\": \"Array CGH; bisulfite-PCR and sequencing; 5-aza-2'-deoxycytidine treatment; colony formation assay after LRP1B restoration; histone acetylation analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — restoration-of-function with colony assay; epigenetic mechanism defined by bisulfite sequencing and demethylation rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15172977\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRP1B is a ~600 kDa single-chain endocytic receptor of the LDL receptor family that internalizes multiple ligands (uPA, tPA, PAI-1, RAP, VLDL, fibrinogen, apoE-carrying lipoproteins) with slower kinetics than LRP1; its cytoplasmic domain is phosphorylated by PKCα ~100-fold more efficiently than LRP1 and this is inhibited by PICK1 binding; in smooth muscle cells it attenuates migration by promoting degradation of uPAR and PDGFRβ from the cell surface; in colon cancer cells it suppresses Wnt/β-catenin signaling by binding DVL2 and blocking the DVL2-Axin interaction; in HCC it binds NCSTN to regulate PI3K/AKT signaling and modulates lipid metabolism via AMPK; in NSCLC it suppresses ferroptosis by controlling STAT3 phosphorylation and SLC7A11 expression; its promoter is silenced by DNMT3B-mediated CpG hypermethylation and by specific miRNAs; the extracellular domain released into the extracellular space is sufficient for embryonic viability in mice and can scavenge signaling ligands; and its neuroprotective role downstream of C1q requires LRP1B expression for protection against amyloid-β toxicity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LRP1B is a ~600 kDa single-chain endocytic receptor of the LDL receptor family that internalizes and degrades multiple ligands shared with LRP1 — including the receptor-associated protein, urokinase- and tissue-type plasminogen activators, and PAI-1 — but with markedly slower internalization kinetics [#0]. Unlike LRP1, the protein is not furin-cleaved and exists as a single polypeptide whose released soluble ectodomain is itself sufficient for embryonic viability in mice, consistent with a function as an extracellular scavenger of signaling ligands [#1, #5]. Its ectodomains directly bind fibrinogen and apoE-carrying lipoproteins and mediate VLDL internalization [#7]. The cytoplasmic tail is phosphorylated by PKC\\u03b1 ~100-fold more efficiently than that of LRP1, and this phosphorylation is blocked by PICK1 binding to the receptor C-terminus [#4]. Through receptor-mediated catabolism of cell-surface partners, LRP1B restrains cell migration: in smooth muscle cells it binds and internalizes uPAR, lowering uPAR and PDGFR\\u03b2 levels and dampening ERK1/2 signaling and migration [#2, #3]. Across diverse cancers LRP1B acts as a growth and invasion suppressor whose promoter is silenced by CpG hypermethylation; restoration of expression impairs colony formation, proliferation, invasion, and tumor growth [#21, #11, #6]. Mechanistically it suppresses Wnt/\\u03b2-catenin signaling by binding DVL2 and blocking the DVL2\\u2013Axin interaction [#12], binds NCSTN to modulate PI3K/AKT signaling and lipid metabolism [#14, #13], and controls STAT3 phosphorylation and SLC7A11 to govern ferroptosis sensitivity [#19]. LRP1B expression is also required for C1q-mediated neuroprotection against amyloid-\\u03b2 toxicity [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that LRP1B is a functional endocytic receptor sharing LRP1 ligands, answering whether this homolog actually internalizes cargo and how it compares kinetically.\",\n      \"evidence\": \"Domain IV minireceptor (mLRP1B4) stable cell lines with ligand binding, internalization, and degradation assays\",\n      \"pmids\": [\"11384978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tested a minireceptor rather than full-length protein\", \"Slow internalization kinetics mechanistically unexplained\", \"Physiological ligand repertoire not exhausted\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the receptor's molecular architecture as an uncleaved single polypeptide and identified the first cytoplasmic-tail interactors, framing how the intracellular domain might signal.\",\n      \"evidence\": \"Immunoblotting of knockout/knockin mouse tissues and yeast two-hybrid with the intracellular domain (PSD-95, AIP)\",\n      \"pmids\": [\"15082773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of PSD-95/AIP binding not established\", \"No structural mapping of binding sites\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed LRP1B is a tumor suppressor silenced epigenetically, explaining why it is recurrently lost in carcinomas without deletion.\",\n      \"evidence\": \"Array CGH, bisulfite sequencing, 5-aza demethylation rescue, and colony formation after LRP1B restoration in esophageal carcinoma cells\",\n      \"pmids\": [\"15172977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which restored LRP1B suppresses growth not defined\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked LRP1B to control of smooth muscle migration through catabolism of uPAR and PDGFR\\u03b2, providing a concrete receptor-clearance mechanism.\",\n      \"evidence\": \"Co-IP, metabolic labeling, anti-LRP1B functional antibody, and migration/invasion assays in cultured and plaque-derived SMCs\",\n      \"pmids\": [\"15166012\", \"15882972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether clearance is via degradation vs. trafficking partially resolved\", \"In vivo vascular phenotype not tested with genetic models\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified PICK1 as a regulator of LRP1B phosphorylation and revealed the cytoplasmic tail is a far better PKC\\u03b1 substrate than LRP1, distinguishing the two receptors functionally.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, and in vitro PKC\\u03b1 kinase assays\",\n      \"pmids\": [\"19071120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effect of tail phosphorylation on trafficking unknown\", \"PICK1 regulation not tested in vivo\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated genetically that the soluble ectodomain alone supports viability, establishing an extracellular scavenger function independent of the membrane-anchored receptor.\",\n      \"evidence\": \"Mouse truncation alleles releasing the ECD versus null alleles, with embryonic lethality phenotyping and blastocyst culture\",\n      \"pmids\": [\"20383322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific scavenged ligands responsible for viability not identified\", \"Relative contribution of membrane vs. soluble forms unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Expanded the ligand repertoire to fibrinogen and apoE-lipoproteins/VLDL, connecting LRP1B to lipid and hemostatic ligand clearance.\",\n      \"evidence\": \"Affinity chromatography/MS, co-IP, lipoprotein binding, and VLDL internalization with minireceptor cells\",\n      \"pmids\": [\"21420681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological significance of lipoprotein uptake in vivo not shown\", \"Affinity relative to LRP1 not quantified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a neuroprotective role requiring LRP1B downstream of C1q against amyloid-\\u03b2 toxicity, extending function beyond cancer/vascular contexts.\",\n      \"evidence\": \"siRNA silencing in primary neurons with A\\u03b2 neurotoxicity assays and hippocampal expression in C1q-deficient AD mice\",\n      \"pmids\": [\"23150673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of LRP1B-mediated protection undefined\", \"Whether LRP1B binds C1q directly not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed LRP1B functions as an endocytic receptor for liposomal drug delivery, with direct therapeutic relevance for drug sensitivity.\",\n      \"evidence\": \"Bidirectional knockdown/overexpression in ovarian cancer lines with liposomal vs. free doxorubicin cytotoxicity assays\",\n      \"pmids\": [\"22896685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Liposome recognition determinants not defined\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected LRP1B loss to cytoskeletal and adhesion remodeling via RhoA/Cdc42, providing a mechanism for the migratory/invasive phenotype.\",\n      \"evidence\": \"shRNA knockdown with anchorage-independent growth, migration/invasion assays, focal adhesion Western blots, and Cdc42/RhoA activity assays\",\n      \"pmids\": [\"23521319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How surface receptor loss feeds into GTPase activation unknown\", \"No rescue experiment reported\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a molecular mechanism for Wnt suppression: LRP1B binds DVL2 and blocks DVL2\\u2013Axin, linking the receptor to a canonical oncogenic pathway.\",\n      \"evidence\": \"Co-IP, competitive co-IP, TCF reporter assays, and growth/metastasis assays in colon cancer cells\",\n      \"pmids\": [\"28408316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the interaction is direct and which domain mediates it unclear\", \"Subcellular site of DVL2 engagement not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established LRP1B as a tumor suppressor across multiple cancers acting through NCSTN/PI3K-AKT, lipid metabolism/AMPK, and ER stress, with loss conferring therapy resistance.\",\n      \"evidence\": \"Co-IP, CRISPR knockdown/activation, pathway Westerns, lipid imaging, and in vitro/in vivo drug- and radiation-resistance assays across HCC, OPSCC, and glioblastoma models\",\n      \"pmids\": [\"37492741\", \"33324588\", \"37778229\", \"37511044\", \"35389768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Convergence of these multiple downstream pathways onto one mechanism not unified\", \"ER stress link rests on expression changes without direct mechanistic demonstration\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed LRP1B governs ferroptosis sensitivity and immunotherapy response via STAT3-driven SLC7A11 control, linking the receptor to redox/immune vulnerability.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter, ferroptosis flow cytometry, and in vivo anti-PD-1 experiments in NSCLC\",\n      \"pmids\": [\"39660409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a surface receptor controls STAT3 phosphorylation not mechanistically defined\", \"IL-6-JAK-STAT3 secretory link to ferroptosis only partially connected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified DNMT3B as a direct epigenetic silencer of LRP1B, closing the loop on how the tumor suppressor is inactivated.\",\n      \"evidence\": \"ChIP, luciferase reporter, shRNA, rescue/epistasis, and in vivo transplantation in pheochromocytoma\",\n      \"pmids\": [\"40346661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signals driving DNMT3B recruitment unknown\", \"Generality across other tumor types not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the single endocytic/scavenging activity of LRP1B mechanistically gives rise to its many reported downstream signaling outputs (Wnt, PI3K/AKT, STAT3, AMPK, RhoA), and whether these reflect a common cargo-clearance mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying biochemical model linking receptor endocytosis to the diverse pathway effects\", \"Structural basis of ligand and partner selectivity undetermined\", \"In vivo physiological function of full-length receptor largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 7, 9]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 12, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 12, 14, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 12, 14, 19]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 7, 9]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"uPAR\", \"PDGFRB\", \"PICK1\", \"PKCalpha\", \"DVL2\", \"NCSTN\", \"fibrinogen\", \"PSD-95\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}