{"gene":"IGF2R","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1993,"finding":"The mouse Igf2r locus contains two differentially methylated regions: region 1 (promoter, methylated on the silent paternal chromosome after fertilization) and region 2 (intron 2 CpG island, methylated only on the expressed maternal chromosome and inherited from the female gamete), identifying the maternally methylated intronic region as a candidate imprinting signal required for maternal-allele expression.","method":"Cloning of 130 kb genomic locus, methylation analysis of parental alleles in embryos and gametes","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — foundational molecular mapping with allele-specific methylation analysis, replicated across subsequent studies","pmids":["8462104"],"is_preprint":false},{"year":1997,"finding":"Imprinted expression of mouse Igf2r depends on the intronic CpG island (region 2): YAC transgenes reproducing the full Igf2r locus show parental-specific methylation and monoallelic expression, but deletion of region 2 abolishes imprinting and restores biallelic expression. Region 2 also serves as the promoter for a paternal-allele antisense RNA whose production depends on region 2.","method":"YAC transgene experiments with region 2 deletion, allele-specific expression and methylation analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — direct genetic deletion in transgenic mice with functional readout, replicated by multiple labs","pmids":["9338788"],"is_preprint":false},{"year":1996,"finding":"IGF2R functions as a clearance receptor for IGF-II: mice lacking Igf2r (maternally inherited null allele) show elevated serum and tissue IGF-II, overgrowth, and perinatal lethality. Lethality is completely rescued by additional elimination of either IGF-II or IGF1R, placing IGF2R upstream of IGF1R-mediated signaling in growth control. Mannose 6-phosphate-mediated lysosomal enzyme trafficking is separately essential, as CD-MPR/CI-MPR double knockouts die postnatally even in an IGF-II null background.","method":"Genetic epistasis via double and triple mutant mouse crosses (Igf2r×Igf2, Igf2r×Igf1r, Igf2r×Igf2×Igf1r null backgrounds)","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — rigorous in vivo genetic epistasis with multiple double/triple mutant combinations","pmids":["8806828"],"is_preprint":false},{"year":1993,"finding":"Genetic rescue of the T-associated maternal effect (Tme) lethal phenotype by removing Igf2 in Igf2r-deficient embryos demonstrates that the Tme lethality results from excess IGF-II signaling when IGF2R-mediated degradation is absent, establishing IGF2R as a negative regulator of IGF-II bioavailability in vivo.","method":"Genetic epistasis: crossing Igf2 null mice with Thp (Igf2r locus) deletion mice, rescue analysis at birth","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — in vivo epistasis rescue experiment, corroborated by Ludwig et al. 1996","pmids":["8076514"],"is_preprint":false},{"year":1999,"finding":"A 113-bp sequence within the Igf2r DMR2 constitutes a methylation imprinting box containing two cis-acting elements: a de novo methylation signal and an allele-discrimination signal that bind specific proteins, establishing the regulatory system for differential methylation at the Igf2r locus.","method":"Deletion mapping and protein-binding analysis of DMR2 sub-sequences in transgenic mouse system","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — functional dissection of imprinting element with defined sub-sequences, published in high-impact journal","pmids":["9892358"],"is_preprint":false},{"year":2001,"finding":"Biallelic expression of Igf2r (achieved by deleting region 2 from the paternal allele, creating a non-imprinted R2Δ allele) causes a 20% reduction in embryonic and adult weight, and rescues the Tme lethal phenotype, demonstrating that the biological function of Igf2r imprinting is to increase birth weight by restricting Igf2r expression to the maternal allele.","method":"Gene targeting in ES cells to delete region 2 on paternal allele; phenotypic analysis of R2Δ transgenic mice including weight measurements and rescue of Tme","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1–2 — targeted allele manipulation with quantitative phenotypic readout and epistasis rescue","pmids":["11311167"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of IGF2R domain 11 at 1.4 Å resolution (solved by anomalous sulfur scattering) reveals two crossed beta-sheets forming a flattened beta-barrel, with the putative IGF-II binding site at one end of the barrel, providing the first structural basis for IGF-II binding by IGF2R.","method":"X-ray crystallography at 1.4 Å resolution using anomalous scattering of sulfur","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with defined resolution, deposited in PDB","pmids":["11867533"],"is_preprint":false},{"year":2007,"finding":"Crystal structures of IGF2R domains 11–12, 11–12–13–14, and the domain 11–12–13/IGF-II complex reveal that domain 11 directly binds IGF-II via a hydrophobic pocket engaging Phe19 and Leu53 of IGF-II, while domain 13 modulates binding site flexibility. Mutagenesis confirms this binding hotspot and shows that IGF-binding proteins and IGF2R have converged on the same high-affinity binding surface on IGF-II.","method":"X-ray crystallography of IGF2R domain complexes plus site-directed mutagenesis of binding interface residues","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with mutagenesis validation in a single study","pmids":["18046459"],"is_preprint":false},{"year":2007,"finding":"NMR-based modeling of the IGF2/IGF2R domain 11 complex reveals that the interaction is driven by critical hydrophobic residues on both IGF2 and domain 11 of IGF2R, with a ring of flexible charged residues on IGF2R modulating binding affinity.","method":"Heteronuclear NMR combined with HADDOCK docking and existing mutagenesis data","journal":"Structure (London, England : 1993)","confidence":"Medium","confidence_rationale":"Tier 1 method (NMR) but computational docking model rather than experimental structure","pmids":["17850746"],"is_preprint":false},{"year":2012,"finding":"Airn lncRNA silences Igf2r on the paternal allele through transcriptional overlap of the Igf2r promoter (interfering with RNA Pol II recruitment), not through its spliced or unspliced RNA products, nuclear size, or location. Shortening the Airn transcript demonstrated that only overlap with the Igf2r promoter is required for silencing.","method":"Endogenous truncation of Airn to different lengths by gene targeting; RNA Pol II ChIP; allele-specific expression analysis","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 — multiple endogenous truncation alleles with mechanistic ChIP readout, published in Science","pmids":["23239737"],"is_preprint":false},{"year":2003,"finding":"Imprinted silencing of Slc22a2 and Slc22a3 (flanking Igf2r) by the Airn RNA does not require transcriptional overlap between Airn and Igf2r or the Igf2r promoter itself, indicating that Airn has intrinsic cis-silencing properties independent of transcriptional interference at Igf2r.","method":"Replacement of Igf2r promoter with thymidine kinase promoter and Igf2r promoter deletion in mice; allele-specific expression analysis of Slc22a2/Slc22a3","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — targeted promoter replacement and deletion with allele-specific readouts","pmids":["12853484"],"is_preprint":false},{"year":2013,"finding":"Continuous Airn lncRNA expression is required to maintain Igf2r silencing until the paternal Igf2r promoter acquires somatic DNA methylation; once methylated, Airn expression is dispensable. Airn-mediated initiation of Igf2r silencing is not restricted to a developmental window and can be maintained without DNA methylation, showing that Airn is both necessary and sufficient for silencing throughout ES cell differentiation.","method":"Inducible Airn expression system in ES cells; conditional Airn on/off during differentiation; allele-specific expression and methylation analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — inducible genetic system with temporal control and allele-specific readouts","pmids":["23444351"],"is_preprint":false},{"year":2006,"finding":"A PACS-1/GGA3/CK2 complex regulates CI-MPR (IGF2R) sorting: PACS-1 links GGA3 to CK2; CK2 phosphorylates GGA3 to release it from CI-MPR at early endosomes, and phosphorylates PACS-1 Ser278 to promote PACS-1 binding to CI-MPR for endosome-to-TGN retrieval, constituting a phosphorylation cascade that coordinates opposing TGN export and endosomal retrieval of CI-MPR.","method":"Co-immunoprecipitation, kinase assays, RNA interference, dominant-negative and phospho-mutant constructs, subcellular fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical and cell biological methods in one study","pmids":["16977309"],"is_preprint":false},{"year":2016,"finding":"Rab9 mediates delivery of CI-MPR (IGF2R) to the endosomal pathway at the early-to-late endosome transition (Rab5-positive to Rab7a-positive stage); constitutively active Rab9Q66L disperses CI-MPR from the Golgi without affecting retrograde transport; CI-MPR transiently localizes to distinct domains on maturing endosomes with rapid vesicle attachment/detachment.","method":"Live confocal imaging, Rab9 constitutively active mutant expression, colocalization and trafficking analysis in HeLa cells","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging with functional mutants, but single lab study","pmids":["26663757"],"is_preprint":false},{"year":2008,"finding":"IGF2 promotes endothelial progenitor cell (EPC) homing predominantly through IGF2R-linked Gi protein signaling requiring intracellular Ca2+ mobilization via PLCβ2, not IGF1R. High-dose IGF2 shifts signaling to IGF1R. IGF2R activation enhances multiple steps of EPC homing in vitro and EPC recruitment and neovascularization in vivo.","method":"Receptor-specific antibody blockade, Gi inhibition with pertussis toxin, PLCβ2 knockdown, Ca2+ mobilization assays, in vitro homing assays, in vivo angiogenesis models","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pharmacological and genetic interventions with in vitro and in vivo readouts, single lab","pmids":["18832656"],"is_preprint":false},{"year":2007,"finding":"Cell surface CI-MPR (IGF2R/CD222) binds enzymatically active heparanase in a mannose 6-phosphate-independent manner; binding is optimal at slightly acidic pH and tethers heparanase to the cell surface to promote extracellular matrix degradation. The cation-dependent MPR does not bind heparanase.","method":"Binding assays using transfected mouse L cells expressing human CIMPR, competition with mannose 6-phosphate, ECM degradation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct binding assay with receptor-expressing transfectants and functional ECM degradation readout","pmids":["18073203"],"is_preprint":false},{"year":2011,"finding":"TACE (ADAM-17) mediates ectodomain shedding of M6P/IGF2R from human endothelial cells to generate soluble M6P/IGF2R (sM6P/IGF2R), which binds plasminogen, prevents plasminogen binding to the cell surface and uPA, thereby inhibiting plasminogen activation and blocking angiogenesis and tumor cell invasion in vitro and in vivo.","method":"TACE-specific inhibitors and RNAi; plasminogen binding assays; in vitro cell invasion assays; in vivo tumor growth model","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and RNAi identification of sheddase, with direct binding and functional invasion assays","pmids":["21273553"],"is_preprint":false},{"year":2014,"finding":"CD222 (CI-MPR/IGF2R) controls the spatial distribution and activity of Lck in T cells: CD222 knockdown causes Lck retention in the cytosol, prevents Lck recruitment to CD45 at the cell surface, and results in abundant inhibitory phosphorylation of Lck at steady state, thereby impairing TCR-induced signaling and T cell effector functions.","method":"CD222 siRNA knockdown; CD222 reconstitution rescue; Lck localization by immunofluorescence; phospho-Lck western blotting; T cell functional assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 — knockdown with rescue, defined molecular readout and functional consequence","pmids":["25127865"],"is_preprint":false},{"year":2012,"finding":"M6P/IGF2R restricts liver cell invasion by preventing pericellular action of M6P-modified cathepsins: M6P/IGF2R-deficient fetal rat liver cells hypersecrete lysosomal cathepsins and invade ECM in a cathepsin-dependent manner; forced expression of wild-type IGF2R restores intracellular cathepsin transport and reduces invasion. Functional M6P-binding sites (not IGF-II binding capacity) are required for this anti-invasive activity.","method":"Reconstitution of M6P/IGF2R in receptor-deficient cells; RNAi knockdown in receptor-positive hepatocytes; cathepsin secretion assays; ECM invasion assays; wild-type vs. M6P-binding mutant IGF2R comparison","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution experiment with domain-specific mutants and multiple functional readouts","pmids":["22521359"],"is_preprint":false},{"year":2019,"finding":"IGF2R and the store-operated Ca2+ channel CD20 share a common hydrophobic binding motif stabilizing their association; IGF2R blockade by neutralizing antibody increases myoblast proliferation and differentiation via the calmodulin/calcineurin/NFAT pathway, induces CD20 phosphorylation activating SERCA and removing intracellular Ca2+, and stimulates muscle regeneration in dystrophic mdx mice.","method":"Co-immunoprecipitation of IGF2R-CD20 complex; anti-IGF2R neutralizing antibody treatment; NFAT/calcineurin pathway analysis; SERCA activity assay; in vivo mdx mouse model","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical complex identification plus in vitro and in vivo functional validation","pmids":["31793167"],"is_preprint":false},{"year":2020,"finding":"IGF2R activation by low-dose IGF2 triggers nucleus translocation of IGF2R, which promotes Dnmt3a-mediated DNA methylation via GSK3α/β activation, leading to impaired vacuolar-type H+-ATPase (v-ATPase) expression; sequestrated v-ATPase assembly inhibits proton channeling to lysosomes and redirects protons to mitochondria to sustain oxidative phosphorylation, thereby promoting an anti-inflammatory macrophage phenotype.","method":"IGF2R nuclear translocation imaging; GSK3α/β inhibition; Dnmt3a ChIP; v-ATPase assembly assays; mitochondrial proton flux measurements; IGF2R-specific IGF2 mutant; colitis mouse model","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mechanistic assays in one study with in vivo validation, but single lab","pmids":["33239287"],"is_preprint":false},{"year":2021,"finding":"Soluble CD22 (sCD22) binds to IGF2R on human myeloid cells near the critical mannose 6-phosphate-binding domains (identified by targeted IGF2R truncation and proteomic screens), disrupting lysosomal protein trafficking. Blocking the sCD22-IGF2R interaction with CD22 antibodies ameliorates lysosome dysfunction in NPC1-mutant human microglia-like cells.","method":"Unbiased genetic and proteomic screens for CD22 binding partners; IGF2R domain truncation; flow cytometry; lysosomal trafficking assays in iPSC-derived microglia","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — unbiased proteomic identification plus domain truncation with functional lysosomal readout","pmids":["34851695"],"is_preprint":false},{"year":2019,"finding":"IGF2R depletion in cervical cancer cells disrupts Golgi-to-lysosome transport of M6P-tagged cathepsins, causing decreased lysosomal activity, abnormal cathepsin accumulation, and dysfunction of both autophagy and mitophagy leading to misfolded protein accumulation and ROS production; this is the M6P-receptor function of IGF2R rather than IGF1R signaling antagonism.","method":"IGF2R siRNA knockdown; cathepsin trafficking assays; lysosomal activity assays; autophagy/mitophagy markers; apoptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific mechanistic pathway readouts, single lab","pmids":["31748500"],"is_preprint":false},{"year":2006,"finding":"Overexpression of Igf2r transgene in mice delays mammary tumor onset and decreases tumor multiplicity caused by Igf2 overexpression, providing in vivo genetic evidence that IGF2R tumor suppressor activity operates at least in part through degradation of IGF-II.","method":"Igf2r transgenic mice crossed with Igf2-overexpressing mammary tumor mice; tumor onset and multiplicity analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic test of IGF2R tumor suppressor mechanism via IGF-II degradation","pmids":["16452186"],"is_preprint":false},{"year":2012,"finding":"An exon splice enhancer (ESE) encoded within the DNA sequence of the CD loop of IGF2R domain 11 in monotremes provided the initial fortuitous acquisition of IGF2 binding by M6P/IGF2R. Structural evolution of additional binding site loops (AB, HI, FG) in therians then improved IGF2 affinity, and the subsequent imprinting of IGF2R may have accelerated affinity maturation through parental conflict.","method":"ESE mapping by splicing assays; species comparison of IGF2:domain 11 binding by surface plasmon resonance; structural analysis of binding loops","journal":"Science (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 — comparative functional biochemistry with SPR binding measurements and ESE functional assays","pmids":["23197533"],"is_preprint":false},{"year":2016,"finding":"Yeast surface display selection identified novel mutations in IGF2R domain 11 binding loops (AB, CD, FG, HI) that collectively achieve a 100-fold improvement in IGF2 binding affinity and twofold reduction in koff; the structural basis is improved shape complementarity through interloop (AB-CD) and intraloop (FG-FG) side chain interactions confirmed by NMR. High-affinity domain 11 Fc fusion proteins act as IGF2 traps that deplete pathological IGF2 isoforms and abrogate IGF2-dependent signaling in vivo.","method":"Yeast surface display selection; surface plasmon resonance; NMR structural analysis; in vivo IGF2 depletion assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — structure + mutagenesis + in vivo functional validation in a single study","pmids":["27140600"],"is_preprint":false},{"year":2003,"finding":"Active alleles of both Igf2r and Air are associated with acetylated histones H3/H4, H3K9-Ac, and H3K4-Me, while silenced alleles are associated with methylated DNA, deacetylated H3K9, and unmethylated H3K4. In neurons, biallelic Igf2r expression correlates with biallelic histone acetylation and H3K4 methylation at DMR1, despite maintained imprinted Air expression, establishing a histone code for Igf2r/Air imprinting.","method":"Chromatin immunoprecipitation (ChIP) with allele-specific analysis in Mus musculus × Mus spretus interspecific mice; 5-aza-deoxycytidine and TSA treatment experiments","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — allele-specific ChIP with pharmacological validation, single lab","pmids":["12975326"],"is_preprint":false},{"year":2009,"finding":"During in vitro ES cell differentiation, Airn ncRNA expression leads to gain of repressive epigenetic marks on the paternal Igf2r promoter but does not silence the paternal Igf2r promoter per se; instead, Airn generates an expression bias by allowing up to 10-fold increase of maternal Igf2r expression while paternal expression remains constant, indicating imprinting arises from allele-specific expression bias rather than direct paternal silencing.","method":"In vitro ES cell differentiation; allele-specific quantitative expression analysis of Igf2r and Airn; ChIP for repressive histone marks on paternal Igf2r promoter","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 — allele-specific expression kinetics with epigenetic marks in an ES cell differentiation model, single lab","pmids":["19141673"],"is_preprint":false}],"current_model":"IGF2R/CI-MPR is a multifunctional transmembrane receptor that (1) sequesters and targets IGF-II to lysosomes for degradation, limiting IGF1R-mediated growth signaling, with IGF-II binding mediated by a hydrophobic pocket in extracellular domain 11 (domains 13 modulating flexibility) as defined by crystal structures and mutagenesis; (2) traffics M6P-tagged lysosomal enzymes from the TGN to lysosomes, regulated by a PACS-1/GGA3/CK2 phosphorylation cascade and Rab9-mediated endosomal delivery; (3) undergoes TACE-mediated ectodomain shedding to generate a soluble form that inhibits plasminogen activation and angiogenesis; (4) is subject to genomic imprinting on the maternal allele controlled by an intronic CpG island (DMR2/region 2) that acts as an imprinting control element driving paternal-allele expression of the Airn lncRNA, which silences paternal Igf2r through transcriptional overlap of its promoter and generates an expression bias favoring the maternal allele; and (5) additionally modulates T cell Lck localization, macrophage metabolic reprogramming via IGF2R nuclear translocation and v-ATPase regulation, and muscle differentiation via CD20 and calcineurin/NFAT pathways."},"narrative":{"teleology":[{"year":1993,"claim":"Identification of two differentially methylated regions at the Igf2r locus—including a maternally methylated intronic CpG island (region 2) inherited from the oocyte—established the candidate imprinting control element and framed the question of how allele-specific expression is regulated.","evidence":"Genomic cloning and allele-specific methylation analysis in mouse embryos and gametes","pmids":["8462104"],"confidence":"High","gaps":["Identity of trans-acting factors recognizing region 2 was unknown","Functional necessity of region 2 for imprinting was not yet tested"]},{"year":1993,"claim":"Genetic rescue of Igf2r-deficient (Tme) embryonic lethality by removing Igf2 demonstrated that IGF2R functions as a negative regulator of IGF-II bioavailability in vivo, answering the question of whether IGF2R's growth-suppressive role operates through IGF-II clearance.","evidence":"Genetic epistasis crossing Igf2 null with Thp (Igf2r locus) deletion mice","pmids":["8076514"],"confidence":"High","gaps":["Whether M6P-mediated lysosomal enzyme trafficking contributes independently to lethality was unresolved","Mechanism of IGF-II internalization and degradation not biochemically defined"]},{"year":1996,"claim":"Triple and double mutant mouse crosses placed IGF2R upstream of IGF1R signaling and demonstrated that M6P-mediated lysosomal enzyme trafficking is independently essential for postnatal survival, separating the two major functions of the receptor.","evidence":"Igf2r × Igf2, Igf2r × Igf1r, and Igf2r × Igf2 × Igf1r null mouse crosses","pmids":["8806828"],"confidence":"High","gaps":["Structural basis for IGF-II versus M6P binding discrimination unknown","Whether IGF2R signals independently of IGF-II clearance was unaddressed"]},{"year":1997,"claim":"YAC transgene experiments with region 2 deletion proved that the intronic CpG island is necessary for imprinted monoallelic Igf2r expression and serves as the promoter for a paternal-allele antisense RNA, answering how the imprinting control element functions.","evidence":"YAC transgenes with region 2 deletion; allele-specific expression and methylation analysis","pmids":["9338788"],"confidence":"High","gaps":["Mechanism by which the antisense RNA silences Igf2r was unknown","Minimal cis-elements within region 2 were undefined"]},{"year":1999,"claim":"Fine-mapping of a 113-bp methylation imprinting box within DMR2 identified separable de novo methylation and allele-discrimination signals, defining the minimal regulatory architecture for differential methylation.","evidence":"Deletion mapping and protein-binding analysis in transgenic mice","pmids":["9892358"],"confidence":"High","gaps":["Identity of proteins binding the allele-discrimination signal remained unknown","How these elements coordinate with chromatin modifications was unresolved"]},{"year":2001,"claim":"Biallelic Igf2r expression (via paternal region 2 deletion) caused growth restriction and rescued Tme lethality, demonstrating that the biological purpose of Igf2r imprinting is to limit receptor dosage and thereby increase birth weight.","evidence":"Gene targeting of region 2 on paternal allele in ES cells; weight phenotyping and Tme rescue","pmids":["11311167"],"confidence":"High","gaps":["Whether imprinting-dependent dosage regulation operates in all tissues was untested","Postnatal physiological consequences of biallelic expression were incompletely characterized"]},{"year":2002,"claim":"The first crystal structure of IGF2R domain 11 revealed a flattened β-barrel fold with the IGF-II binding site at one end, providing the structural framework for understanding ligand recognition.","evidence":"X-ray crystallography at 1.4 Å resolution using anomalous sulfur scattering","pmids":["11867533"],"confidence":"High","gaps":["Atomic details of the IGF-II:domain 11 interface were lacking","Role of neighboring domains in binding was unknown"]},{"year":2003,"claim":"Allele-specific ChIP established a histone code for Igf2r/Airn imprinting—active alleles carry H3K9-Ac and H3K4-Me while silent alleles carry deacetylated, unmethylated histones—and showed that biallelic Igf2r in neurons correlates with biallelic active marks despite maintained Airn expression.","evidence":"Allele-specific ChIP in interspecific crosses; pharmacological inhibitor treatments","pmids":["12975326"],"confidence":"Medium","gaps":["Causal relationship between histone marks and silencing was not demonstrated","Mechanism of neuron-specific escape from imprinting was unexplained"]},{"year":2003,"claim":"Demonstration that Airn silences flanking genes Slc22a2/Slc22a3 independently of transcriptional overlap with the Igf2r promoter revealed that Airn has cis-silencing activity beyond simple transcriptional interference, raising the question of distinct silencing mechanisms at different targets.","evidence":"Igf2r promoter replacement/deletion in mice with allele-specific expression of Slc22a2/Slc22a3","pmids":["12853484"],"confidence":"High","gaps":["Mechanism of Airn-mediated silencing of flanking genes was undefined","Whether Airn RNA product or transcription act mediates silencing at flanking loci was unclear"]},{"year":2006,"claim":"Discovery of the PACS-1/GGA3/CK2 phosphorylation cascade defined how CI-MPR is sorted between TGN and endosomes: CK2 phosphorylation of GGA3 releases CI-MPR at endosomes while CK2 phosphorylation of PACS-1 promotes endosome-to-TGN retrieval.","evidence":"Co-immunoprecipitation, kinase assays, RNAi, dominant-negative and phospho-mutant constructs","pmids":["16977309"],"confidence":"High","gaps":["Whether additional kinases or adaptors regulate CI-MPR trafficking was unaddressed","In vivo relevance of the PACS-1 phosphorylation cascade was not tested"]},{"year":2006,"claim":"Igf2r transgene overexpression delayed mammary tumor onset in Igf2-overexpressing mice, providing direct in vivo evidence that IGF2R functions as a tumor suppressor through IGF-II degradation.","evidence":"Igf2r transgenic crossed with Igf2-overexpressing mammary tumor mice","pmids":["16452186"],"confidence":"Medium","gaps":["Whether M6P-dependent cathepsin trafficking also contributes to tumor suppression was untested","Human tumor relevance was not directly addressed"]},{"year":2007,"claim":"Crystal structures of multi-domain IGF2R complexes with IGF-II resolved the binding interface: domain 11 engages IGF-II via a hydrophobic pocket contacting Phe19 and Leu53, while domain 13 modulates binding site flexibility, and mutagenesis confirmed this hotspot is shared with IGF-binding proteins.","evidence":"X-ray crystallography of domain 11–14 constructs ± IGF-II; site-directed mutagenesis; NMR-based docking","pmids":["18046459","17850746"],"confidence":"High","gaps":["Full-length ectodomain structure was unavailable","pH-dependent conformational changes governing ligand release were not structurally characterized"]},{"year":2007,"claim":"CI-MPR was shown to bind enzymatically active heparanase at the cell surface in an M6P-independent manner, expanding the receptor's extracellular functions to include tethering of ECM-degrading enzymes.","evidence":"Binding assays in CI-MPR-transfected cells; M6P competition; ECM degradation assays","pmids":["18073203"],"confidence":"Medium","gaps":["Heparanase binding site on IGF2R was not mapped","Physiological significance in vivo was not established"]},{"year":2009,"claim":"Kinetic allele-specific analysis during ES cell differentiation showed that Airn generates an expression bias (up to 10-fold maternal upregulation) rather than absolute paternal silencing, reframing the imprinting mechanism as dosage modulation.","evidence":"In vitro ES cell differentiation with allele-specific quantitative expression and ChIP","pmids":["19141673"],"confidence":"Medium","gaps":["Whether this expression bias model applies in all tissues in vivo was untested","Factors driving maternal allele upregulation were unidentified"]},{"year":2011,"claim":"Identification of TACE/ADAM-17 as the sheddase generating soluble IGF2R revealed a new anti-angiogenic mechanism: shed sIGF2R binds plasminogen, preventing plasminogen activation and thereby inhibiting angiogenesis and tumor invasion.","evidence":"TACE inhibitors and RNAi; plasminogen binding assays; in vitro invasion and in vivo tumor models","pmids":["21273553"],"confidence":"Medium","gaps":["Regulation of TACE-mediated shedding of IGF2R was not characterized","Relative contribution of sIGF2R versus membrane-bound IGF2R to anti-angiogenic activity was unclear"]},{"year":2012,"claim":"Endogenous truncation of Airn demonstrated that transcriptional overlap with the Igf2r promoter—not the Airn RNA product—is necessary and sufficient for paternal Igf2r silencing, resolving a long-standing mechanistic debate about whether the lncRNA or the act of transcription mediates silencing.","evidence":"Gene targeting to truncate Airn at different lengths; RNA Pol II ChIP; allele-specific expression","pmids":["23239737"],"confidence":"High","gaps":["How transcriptional overlap blocks Pol II recruitment mechanistically was unresolved","Whether chromatin remodelers are recruited during the interference was unknown"]},{"year":2012,"claim":"Reconstitution of IGF2R in receptor-deficient liver cells showed that M6P-binding (not IGF-II binding) is required to prevent cathepsin hypersecretion and ECM invasion, establishing the M6P-trafficking function as the mechanism of IGF2R's anti-invasive activity in liver.","evidence":"Wild-type vs. M6P-binding mutant IGF2R reconstitution; cathepsin secretion and ECM invasion assays","pmids":["22521359"],"confidence":"High","gaps":["Whether this mechanism operates in other cancer types was not tested","Specific M6P-tagged cathepsins responsible for invasion were not individually identified"]},{"year":2012,"claim":"Comparative binding analysis across species revealed that IGF2 binding by IGF2R originated through an exon splice enhancer in domain 11's CD loop in monotremes, with subsequent structural evolution of binding loops in therians improving affinity—linking splicing constraints to receptor evolution.","evidence":"ESE splicing assays; cross-species SPR binding measurements; structural loop comparisons","pmids":["23197533"],"confidence":"Medium","gaps":["Whether imprinting truly accelerated affinity maturation is speculative","Ancestral IGF2R structure in non-mammalian vertebrates was not determined"]},{"year":2013,"claim":"Inducible Airn experiments showed that continuous Airn expression is required until somatic DNA methylation consolidates paternal Igf2r silencing, after which Airn becomes dispensable, defining a two-phase silencing model (Airn-dependent initiation → methylation-dependent maintenance).","evidence":"Inducible Airn on/off system in ES cells during differentiation; allele-specific expression and methylation","pmids":["23444351"],"confidence":"High","gaps":["Identity of DNA methyltransferase(s) consolidating somatic methylation at Igf2r was not determined","Timing of the transition in vivo was not established"]},{"year":2014,"claim":"CD222/IGF2R was shown to control Lck spatial distribution and activity in T cells—knockdown traps Lck in the cytosol with inhibitory phosphorylation—revealing a previously unrecognized role for IGF2R in TCR signaling.","evidence":"siRNA knockdown with rescue; Lck localization by immunofluorescence; phospho-Lck blotting; T cell functional assays","pmids":["25127865"],"confidence":"Medium","gaps":["Direct physical interaction between IGF2R and Lck was not demonstrated","Whether IGF2R trafficking of Lck is M6P-dependent was untested"]},{"year":2016,"claim":"Engineered domain 11 variants with 100-fold improved IGF2 affinity validated the structural basis of binding (AB-CD and FG-FG interloop contacts) and demonstrated therapeutic potential as IGF2 traps depleting pathological IGF2 isoforms in vivo.","evidence":"Yeast surface display; SPR; NMR; in vivo IGF2 depletion","pmids":["27140600"],"confidence":"High","gaps":["Pharmacokinetics and long-term safety of domain 11 traps were not characterized","Selectivity over IGF1 binding was not fully profiled"]},{"year":2019,"claim":"IGF2R depletion in cancer cells disrupted Golgi-to-lysosome cathepsin transport, causing autophagy and mitophagy dysfunction with ROS accumulation, separating the M6P-trafficking contribution from IGF-II clearance in maintaining lysosomal homeostasis.","evidence":"siRNA knockdown; cathepsin trafficking, lysosomal activity, autophagy/mitophagy marker assays","pmids":["31748500"],"confidence":"Medium","gaps":["Whether autophagy dysfunction is a direct or secondary consequence of cathepsin mistrafficking was unclear","Generalizability beyond cervical cancer cells was untested"]},{"year":2019,"claim":"Identification of an IGF2R–CD20 complex in myoblasts, where IGF2R blockade activates the calcineurin/NFAT pathway and promotes muscle regeneration in dystrophic mice, revealed a signaling axis linking IGF2R to calcium homeostasis and myogenesis.","evidence":"Co-immunoprecipitation; anti-IGF2R antibody; NFAT/calcineurin analysis; SERCA assay; mdx mouse model","pmids":["31793167"],"confidence":"Medium","gaps":["Whether IGF2R–CD20 interaction is direct or mediated by adaptor proteins was not resolved","Mechanism linking IGF2R blockade to CD20 phosphorylation was not defined"]},{"year":2020,"claim":"IGF2R nuclear translocation upon low-dose IGF2 stimulation was shown to activate GSK3α/β and Dnmt3a-mediated methylation, suppressing v-ATPase expression and redirecting protons to mitochondria to sustain oxidative phosphorylation in macrophages, revealing an unexpected nuclear signaling role.","evidence":"Nuclear translocation imaging; GSK3 inhibition; Dnmt3a ChIP; v-ATPase assembly and mitochondrial proton flux assays; colitis mouse model","pmids":["33239287"],"confidence":"Medium","gaps":["Mechanism of IGF2R nuclear import is unknown","Whether nuclear IGF2R retains receptor function or acts as a transcriptional co-regulator was not distinguished"]},{"year":2021,"claim":"Soluble CD22 was identified as an IGF2R ligand on myeloid cells that disrupts lysosomal trafficking, and blocking this interaction rescued lysosome dysfunction in NPC1-mutant microglia, establishing IGF2R as a node in neuroinflammatory lysosomal pathology.","evidence":"Unbiased proteomic screens; IGF2R domain truncation; lysosomal trafficking in iPSC-derived microglia","pmids":["34851695"],"confidence":"Medium","gaps":["Precise IGF2R domains mediating sCD22 binding were not fully resolved","In vivo relevance in NPC1 disease models was not tested"]},{"year":null,"claim":"Major unresolved questions include the full-length ectodomain structure of IGF2R, the mechanism of IGF2R nuclear translocation and its nuclear targets, the molecular basis for tissue-specific escape from imprinting (e.g., neurons), and whether IGF2R's diverse signaling roles (Lck regulation, calcineurin/NFAT activation, macrophage metabolic reprogramming) operate through a unified trafficking mechanism or distinct receptor pools.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length IGF2R ectodomain structure exists","Nuclear import mechanism undefined","Tissue-specific imprinting escape mechanism unknown","Integration of trafficking versus signaling functions not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[2,3,7,18,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,23,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[15,17]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[12,13,22]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[12,13]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2,18,22]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[12,13,18,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,14,17,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,5,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,21]}],"complexes":[],"partners":["IGF2","PACS1","GGA3","CSNK2A1","RAB9A","MS4A1","CD22"],"other_free_text":[]},"mechanistic_narrative":"IGF2R (CI-MPR/CD222) is a multifunctional type I transmembrane receptor that serves dual roles as a clearance receptor for IGF-II and as a transporter of mannose 6-phosphate (M6P)-tagged lysosomal enzymes from the TGN to lysosomes. Genetic epistasis in mice demonstrates that IGF2R sequesters IGF-II for lysosomal degradation, limiting IGF1R-mediated growth signaling—loss of maternal Igf2r causes overgrowth and perinatal lethality rescued by elimination of IGF-II or IGF1R [PMID:8806828, PMID:8076514]—while its M6P-binding function independently prevents pericellular cathepsin accumulation and ECM invasion [PMID:22521359, PMID:31748500]. Crystal structures reveal that IGF-II binds a hydrophobic pocket in extracellular domain 11, with domain 13 modulating flexibility, and the same binding surface is convergently recognized by IGF-binding proteins [PMID:18046459, PMID:11867533]. Igf2r is subject to genomic imprinting controlled by a maternally methylated intronic CpG island (DMR2/region 2) that drives paternal-allele expression of the Airn lncRNA; Airn silences paternal Igf2r through transcriptional overlap of its promoter, interfering with RNA Pol II recruitment, and continuous Airn expression is required until somatic DNA methylation consolidates silencing [PMID:23239737, PMID:9338788, PMID:23444351]."},"prefetch_data":{"uniprot":{"accession":"P11717","full_name":"Cation-independent mannose-6-phosphate receptor","aliases":["300 kDa mannose 6-phosphate receptor","MPR 300","Insulin-like growth factor 2 receptor","Insulin-like growth factor II receptor","IGF-II receptor","M6P/IGF2 receptor","M6P/IGF2R"],"length_aa":2491,"mass_kda":274.4,"function":"Mediates the transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes (PubMed:18817523, PubMed:2963003). Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate receptors in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelysosomal compartment where the low pH mediates the dissociation of the complex (PubMed:18817523, PubMed:2963003). The receptor is then recycled back to the Golgi for another round of trafficking through its binding to the retromer (PubMed:18817523). This receptor also binds IGF2 (PubMed:18046459). Acts as a positive regulator of T-cell coactivation by binding DPP4 (PubMed:10900005)","subcellular_location":"Golgi apparatus membrane; Endosome membrane","url":"https://www.uniprot.org/uniprotkb/P11717/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IGF2R","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"CLTB","stoichiometry":0.2},{"gene":"STX12","stoichiometry":0.2},{"gene":"STX7","stoichiometry":0.2},{"gene":"VAMP3","stoichiometry":0.2},{"gene":"VTI1A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IGF2R","total_profiled":1310},"omim":[{"mim_id":"621073","title":"SORTING NEXIN 32; SNX32","url":"https://www.omim.org/entry/621073"},{"mim_id":"619811","title":"UHRF1-BINDING PROTEIN 1-LIKE; UHRF1BP1L","url":"https://www.omim.org/entry/619811"},{"mim_id":"618606","title":"PONTOCEREBELLAR HYPOPLASIA, TYPE 13; PCH13","url":"https://www.omim.org/entry/618606"},{"mim_id":"616186","title":"H19/IGF2-IMPRINTING CONTROL REGION","url":"https://www.omim.org/entry/616186"},{"mim_id":"615850","title":"VPS53 SUBUNIT OF GARP COMPLEX; VPS53","url":"https://www.omim.org/entry/615850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IGF2R"},"hgnc":{"alias_symbol":["CD222","MPRI","MPR1","CIMPR","M6P-R","CI-M6PR","CI-MPR","MPR300"],"prev_symbol":[]},"alphafold":{"accession":"P11717","domains":[{"cath_id":"2.70.130.10","chopping":"47-173_365-375_395-462","consensus_level":"medium","plddt":77.2817,"start":47,"end":462},{"cath_id":"2.70.130.10","chopping":"174-323","consensus_level":"medium","plddt":76.3731,"start":174,"end":323},{"cath_id":"2.70.130.10","chopping":"475-621","consensus_level":"medium","plddt":77.5518,"start":475,"end":621},{"cath_id":"2.70.130.10","chopping":"1093-1214","consensus_level":"medium","plddt":77.4103,"start":1093,"end":1214},{"cath_id":"2.70.130.10","chopping":"1223-1334_1343-1361","consensus_level":"high","plddt":81.1114,"start":1223,"end":1361},{"cath_id":"2.70.130.10","chopping":"1371-1410_1424-1506","consensus_level":"medium","plddt":79.7972,"start":1371,"end":1506},{"cath_id":"2.70.130.10","chopping":"1520-1580_1596-1647","consensus_level":"medium","plddt":76.9862,"start":1520,"end":1647},{"cath_id":"2.70.130.10","chopping":"1661-1790","consensus_level":"medium","plddt":73.261,"start":1661,"end":1790},{"cath_id":"2.70.130.10","chopping":"1819-1892_1948-1988","consensus_level":"medium","plddt":79.6634,"start":1819,"end":1988},{"cath_id":"2.10.10.10","chopping":"1895-1945","consensus_level":"medium","plddt":84.1488,"start":1895,"end":1945},{"cath_id":"2.70.130.10","chopping":"1992-2128","consensus_level":"medium","plddt":78.6909,"start":1992,"end":2128},{"cath_id":"2.70.130.10","chopping":"2131-2281","consensus_level":"high","plddt":73.391,"start":2131,"end":2281}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P11717","model_url":"https://alphafold.ebi.ac.uk/files/AF-P11717-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P11717-F1-predicted_aligned_error_v6.png","plddt_mean":73.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IGF2R","jax_strain_url":"https://www.jax.org/strain/search?query=IGF2R"},"sequence":{"accession":"P11717","fasta_url":"https://rest.uniprot.org/uniprotkb/P11717.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P11717/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P11717"}},"corpus_meta":[{"pmid":"11175780","id":"PMC_11175780","title":"Epigenetic 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\"method\": \"Cloning of 130 kb genomic locus, methylation analysis of parental alleles in embryos and gametes\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational molecular mapping with allele-specific methylation analysis, replicated across subsequent studies\",\n      \"pmids\": [\"8462104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Imprinted expression of mouse Igf2r depends on the intronic CpG island (region 2): YAC transgenes reproducing the full Igf2r locus show parental-specific methylation and monoallelic expression, but deletion of region 2 abolishes imprinting and restores biallelic expression. Region 2 also serves as the promoter for a paternal-allele antisense RNA whose production depends on region 2.\",\n      \"method\": \"YAC transgene experiments with region 2 deletion, allele-specific expression and methylation analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct genetic deletion in transgenic mice with functional readout, replicated by multiple labs\",\n      \"pmids\": [\"9338788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"IGF2R functions as a clearance receptor for IGF-II: mice lacking Igf2r (maternally inherited null allele) show elevated serum and tissue IGF-II, overgrowth, and perinatal lethality. Lethality is completely rescued by additional elimination of either IGF-II or IGF1R, placing IGF2R upstream of IGF1R-mediated signaling in growth control. Mannose 6-phosphate-mediated lysosomal enzyme trafficking is separately essential, as CD-MPR/CI-MPR double knockouts die postnatally even in an IGF-II null background.\",\n      \"method\": \"Genetic epistasis via double and triple mutant mouse crosses (Igf2r×Igf2, Igf2r×Igf1r, Igf2r×Igf2×Igf1r null backgrounds)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous in vivo genetic epistasis with multiple double/triple mutant combinations\",\n      \"pmids\": [\"8806828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Genetic rescue of the T-associated maternal effect (Tme) lethal phenotype by removing Igf2 in Igf2r-deficient embryos demonstrates that the Tme lethality results from excess IGF-II signaling when IGF2R-mediated degradation is absent, establishing IGF2R as a negative regulator of IGF-II bioavailability in vivo.\",\n      \"method\": \"Genetic epistasis: crossing Igf2 null mice with Thp (Igf2r locus) deletion mice, rescue analysis at birth\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo epistasis rescue experiment, corroborated by Ludwig et al. 1996\",\n      \"pmids\": [\"8076514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A 113-bp sequence within the Igf2r DMR2 constitutes a methylation imprinting box containing two cis-acting elements: a de novo methylation signal and an allele-discrimination signal that bind specific proteins, establishing the regulatory system for differential methylation at the Igf2r locus.\",\n      \"method\": \"Deletion mapping and protein-binding analysis of DMR2 sub-sequences in transgenic mouse system\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional dissection of imprinting element with defined sub-sequences, published in high-impact journal\",\n      \"pmids\": [\"9892358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Biallelic expression of Igf2r (achieved by deleting region 2 from the paternal allele, creating a non-imprinted R2Δ allele) causes a 20% reduction in embryonic and adult weight, and rescues the Tme lethal phenotype, demonstrating that the biological function of Igf2r imprinting is to increase birth weight by restricting Igf2r expression to the maternal allele.\",\n      \"method\": \"Gene targeting in ES cells to delete region 2 on paternal allele; phenotypic analysis of R2Δ transgenic mice including weight measurements and rescue of Tme\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — targeted allele manipulation with quantitative phenotypic readout and epistasis rescue\",\n      \"pmids\": [\"11311167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of IGF2R domain 11 at 1.4 Å resolution (solved by anomalous sulfur scattering) reveals two crossed beta-sheets forming a flattened beta-barrel, with the putative IGF-II binding site at one end of the barrel, providing the first structural basis for IGF-II binding by IGF2R.\",\n      \"method\": \"X-ray crystallography at 1.4 Å resolution using anomalous scattering of sulfur\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with defined resolution, deposited in PDB\",\n      \"pmids\": [\"11867533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structures of IGF2R domains 11–12, 11–12–13–14, and the domain 11–12–13/IGF-II complex reveal that domain 11 directly binds IGF-II via a hydrophobic pocket engaging Phe19 and Leu53 of IGF-II, while domain 13 modulates binding site flexibility. Mutagenesis confirms this binding hotspot and shows that IGF-binding proteins and IGF2R have converged on the same high-affinity binding surface on IGF-II.\",\n      \"method\": \"X-ray crystallography of IGF2R domain complexes plus site-directed mutagenesis of binding interface residues\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with mutagenesis validation in a single study\",\n      \"pmids\": [\"18046459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NMR-based modeling of the IGF2/IGF2R domain 11 complex reveals that the interaction is driven by critical hydrophobic residues on both IGF2 and domain 11 of IGF2R, with a ring of flexible charged residues on IGF2R modulating binding affinity.\",\n      \"method\": \"Heteronuclear NMR combined with HADDOCK docking and existing mutagenesis data\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 method (NMR) but computational docking model rather than experimental structure\",\n      \"pmids\": [\"17850746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Airn lncRNA silences Igf2r on the paternal allele through transcriptional overlap of the Igf2r promoter (interfering with RNA Pol II recruitment), not through its spliced or unspliced RNA products, nuclear size, or location. Shortening the Airn transcript demonstrated that only overlap with the Igf2r promoter is required for silencing.\",\n      \"method\": \"Endogenous truncation of Airn to different lengths by gene targeting; RNA Pol II ChIP; allele-specific expression analysis\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple endogenous truncation alleles with mechanistic ChIP readout, published in Science\",\n      \"pmids\": [\"23239737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Imprinted silencing of Slc22a2 and Slc22a3 (flanking Igf2r) by the Airn RNA does not require transcriptional overlap between Airn and Igf2r or the Igf2r promoter itself, indicating that Airn has intrinsic cis-silencing properties independent of transcriptional interference at Igf2r.\",\n      \"method\": \"Replacement of Igf2r promoter with thymidine kinase promoter and Igf2r promoter deletion in mice; allele-specific expression analysis of Slc22a2/Slc22a3\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — targeted promoter replacement and deletion with allele-specific readouts\",\n      \"pmids\": [\"12853484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Continuous Airn lncRNA expression is required to maintain Igf2r silencing until the paternal Igf2r promoter acquires somatic DNA methylation; once methylated, Airn expression is dispensable. Airn-mediated initiation of Igf2r silencing is not restricted to a developmental window and can be maintained without DNA methylation, showing that Airn is both necessary and sufficient for silencing throughout ES cell differentiation.\",\n      \"method\": \"Inducible Airn expression system in ES cells; conditional Airn on/off during differentiation; allele-specific expression and methylation analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — inducible genetic system with temporal control and allele-specific readouts\",\n      \"pmids\": [\"23444351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A PACS-1/GGA3/CK2 complex regulates CI-MPR (IGF2R) sorting: PACS-1 links GGA3 to CK2; CK2 phosphorylates GGA3 to release it from CI-MPR at early endosomes, and phosphorylates PACS-1 Ser278 to promote PACS-1 binding to CI-MPR for endosome-to-TGN retrieval, constituting a phosphorylation cascade that coordinates opposing TGN export and endosomal retrieval of CI-MPR.\",\n      \"method\": \"Co-immunoprecipitation, kinase assays, RNA interference, dominant-negative and phospho-mutant constructs, subcellular fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical and cell biological methods in one study\",\n      \"pmids\": [\"16977309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab9 mediates delivery of CI-MPR (IGF2R) to the endosomal pathway at the early-to-late endosome transition (Rab5-positive to Rab7a-positive stage); constitutively active Rab9Q66L disperses CI-MPR from the Golgi without affecting retrograde transport; CI-MPR transiently localizes to distinct domains on maturing endosomes with rapid vesicle attachment/detachment.\",\n      \"method\": \"Live confocal imaging, Rab9 constitutively active mutant expression, colocalization and trafficking analysis in HeLa cells\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging with functional mutants, but single lab study\",\n      \"pmids\": [\"26663757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IGF2 promotes endothelial progenitor cell (EPC) homing predominantly through IGF2R-linked Gi protein signaling requiring intracellular Ca2+ mobilization via PLCβ2, not IGF1R. High-dose IGF2 shifts signaling to IGF1R. IGF2R activation enhances multiple steps of EPC homing in vitro and EPC recruitment and neovascularization in vivo.\",\n      \"method\": \"Receptor-specific antibody blockade, Gi inhibition with pertussis toxin, PLCβ2 knockdown, Ca2+ mobilization assays, in vitro homing assays, in vivo angiogenesis models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological and genetic interventions with in vitro and in vivo readouts, single lab\",\n      \"pmids\": [\"18832656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cell surface CI-MPR (IGF2R/CD222) binds enzymatically active heparanase in a mannose 6-phosphate-independent manner; binding is optimal at slightly acidic pH and tethers heparanase to the cell surface to promote extracellular matrix degradation. The cation-dependent MPR does not bind heparanase.\",\n      \"method\": \"Binding assays using transfected mouse L cells expressing human CIMPR, competition with mannose 6-phosphate, ECM degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct binding assay with receptor-expressing transfectants and functional ECM degradation readout\",\n      \"pmids\": [\"18073203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TACE (ADAM-17) mediates ectodomain shedding of M6P/IGF2R from human endothelial cells to generate soluble M6P/IGF2R (sM6P/IGF2R), which binds plasminogen, prevents plasminogen binding to the cell surface and uPA, thereby inhibiting plasminogen activation and blocking angiogenesis and tumor cell invasion in vitro and in vivo.\",\n      \"method\": \"TACE-specific inhibitors and RNAi; plasminogen binding assays; in vitro cell invasion assays; in vivo tumor growth model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and RNAi identification of sheddase, with direct binding and functional invasion assays\",\n      \"pmids\": [\"21273553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD222 (CI-MPR/IGF2R) controls the spatial distribution and activity of Lck in T cells: CD222 knockdown causes Lck retention in the cytosol, prevents Lck recruitment to CD45 at the cell surface, and results in abundant inhibitory phosphorylation of Lck at steady state, thereby impairing TCR-induced signaling and T cell effector functions.\",\n      \"method\": \"CD222 siRNA knockdown; CD222 reconstitution rescue; Lck localization by immunofluorescence; phospho-Lck western blotting; T cell functional assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knockdown with rescue, defined molecular readout and functional consequence\",\n      \"pmids\": [\"25127865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"M6P/IGF2R restricts liver cell invasion by preventing pericellular action of M6P-modified cathepsins: M6P/IGF2R-deficient fetal rat liver cells hypersecrete lysosomal cathepsins and invade ECM in a cathepsin-dependent manner; forced expression of wild-type IGF2R restores intracellular cathepsin transport and reduces invasion. Functional M6P-binding sites (not IGF-II binding capacity) are required for this anti-invasive activity.\",\n      \"method\": \"Reconstitution of M6P/IGF2R in receptor-deficient cells; RNAi knockdown in receptor-positive hepatocytes; cathepsin secretion assays; ECM invasion assays; wild-type vs. M6P-binding mutant IGF2R comparison\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution experiment with domain-specific mutants and multiple functional readouts\",\n      \"pmids\": [\"22521359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IGF2R and the store-operated Ca2+ channel CD20 share a common hydrophobic binding motif stabilizing their association; IGF2R blockade by neutralizing antibody increases myoblast proliferation and differentiation via the calmodulin/calcineurin/NFAT pathway, induces CD20 phosphorylation activating SERCA and removing intracellular Ca2+, and stimulates muscle regeneration in dystrophic mdx mice.\",\n      \"method\": \"Co-immunoprecipitation of IGF2R-CD20 complex; anti-IGF2R neutralizing antibody treatment; NFAT/calcineurin pathway analysis; SERCA activity assay; in vivo mdx mouse model\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical complex identification plus in vitro and in vivo functional validation\",\n      \"pmids\": [\"31793167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IGF2R activation by low-dose IGF2 triggers nucleus translocation of IGF2R, which promotes Dnmt3a-mediated DNA methylation via GSK3α/β activation, leading to impaired vacuolar-type H+-ATPase (v-ATPase) expression; sequestrated v-ATPase assembly inhibits proton channeling to lysosomes and redirects protons to mitochondria to sustain oxidative phosphorylation, thereby promoting an anti-inflammatory macrophage phenotype.\",\n      \"method\": \"IGF2R nuclear translocation imaging; GSK3α/β inhibition; Dnmt3a ChIP; v-ATPase assembly assays; mitochondrial proton flux measurements; IGF2R-specific IGF2 mutant; colitis mouse model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic assays in one study with in vivo validation, but single lab\",\n      \"pmids\": [\"33239287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Soluble CD22 (sCD22) binds to IGF2R on human myeloid cells near the critical mannose 6-phosphate-binding domains (identified by targeted IGF2R truncation and proteomic screens), disrupting lysosomal protein trafficking. Blocking the sCD22-IGF2R interaction with CD22 antibodies ameliorates lysosome dysfunction in NPC1-mutant human microglia-like cells.\",\n      \"method\": \"Unbiased genetic and proteomic screens for CD22 binding partners; IGF2R domain truncation; flow cytometry; lysosomal trafficking assays in iPSC-derived microglia\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased proteomic identification plus domain truncation with functional lysosomal readout\",\n      \"pmids\": [\"34851695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IGF2R depletion in cervical cancer cells disrupts Golgi-to-lysosome transport of M6P-tagged cathepsins, causing decreased lysosomal activity, abnormal cathepsin accumulation, and dysfunction of both autophagy and mitophagy leading to misfolded protein accumulation and ROS production; this is the M6P-receptor function of IGF2R rather than IGF1R signaling antagonism.\",\n      \"method\": \"IGF2R siRNA knockdown; cathepsin trafficking assays; lysosomal activity assays; autophagy/mitophagy markers; apoptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific mechanistic pathway readouts, single lab\",\n      \"pmids\": [\"31748500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpression of Igf2r transgene in mice delays mammary tumor onset and decreases tumor multiplicity caused by Igf2 overexpression, providing in vivo genetic evidence that IGF2R tumor suppressor activity operates at least in part through degradation of IGF-II.\",\n      \"method\": \"Igf2r transgenic mice crossed with Igf2-overexpressing mammary tumor mice; tumor onset and multiplicity analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic test of IGF2R tumor suppressor mechanism via IGF-II degradation\",\n      \"pmids\": [\"16452186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"An exon splice enhancer (ESE) encoded within the DNA sequence of the CD loop of IGF2R domain 11 in monotremes provided the initial fortuitous acquisition of IGF2 binding by M6P/IGF2R. Structural evolution of additional binding site loops (AB, HI, FG) in therians then improved IGF2 affinity, and the subsequent imprinting of IGF2R may have accelerated affinity maturation through parental conflict.\",\n      \"method\": \"ESE mapping by splicing assays; species comparison of IGF2:domain 11 binding by surface plasmon resonance; structural analysis of binding loops\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — comparative functional biochemistry with SPR binding measurements and ESE functional assays\",\n      \"pmids\": [\"23197533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Yeast surface display selection identified novel mutations in IGF2R domain 11 binding loops (AB, CD, FG, HI) that collectively achieve a 100-fold improvement in IGF2 binding affinity and twofold reduction in koff; the structural basis is improved shape complementarity through interloop (AB-CD) and intraloop (FG-FG) side chain interactions confirmed by NMR. High-affinity domain 11 Fc fusion proteins act as IGF2 traps that deplete pathological IGF2 isoforms and abrogate IGF2-dependent signaling in vivo.\",\n      \"method\": \"Yeast surface display selection; surface plasmon resonance; NMR structural analysis; in vivo IGF2 depletion assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure + mutagenesis + in vivo functional validation in a single study\",\n      \"pmids\": [\"27140600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Active alleles of both Igf2r and Air are associated with acetylated histones H3/H4, H3K9-Ac, and H3K4-Me, while silenced alleles are associated with methylated DNA, deacetylated H3K9, and unmethylated H3K4. In neurons, biallelic Igf2r expression correlates with biallelic histone acetylation and H3K4 methylation at DMR1, despite maintained imprinted Air expression, establishing a histone code for Igf2r/Air imprinting.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) with allele-specific analysis in Mus musculus × Mus spretus interspecific mice; 5-aza-deoxycytidine and TSA treatment experiments\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — allele-specific ChIP with pharmacological validation, single lab\",\n      \"pmids\": [\"12975326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"During in vitro ES cell differentiation, Airn ncRNA expression leads to gain of repressive epigenetic marks on the paternal Igf2r promoter but does not silence the paternal Igf2r promoter per se; instead, Airn generates an expression bias by allowing up to 10-fold increase of maternal Igf2r expression while paternal expression remains constant, indicating imprinting arises from allele-specific expression bias rather than direct paternal silencing.\",\n      \"method\": \"In vitro ES cell differentiation; allele-specific quantitative expression analysis of Igf2r and Airn; ChIP for repressive histone marks on paternal Igf2r promoter\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — allele-specific expression kinetics with epigenetic marks in an ES cell differentiation model, single lab\",\n      \"pmids\": [\"19141673\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGF2R/CI-MPR is a multifunctional transmembrane receptor that (1) sequesters and targets IGF-II to lysosomes for degradation, limiting IGF1R-mediated growth signaling, with IGF-II binding mediated by a hydrophobic pocket in extracellular domain 11 (domains 13 modulating flexibility) as defined by crystal structures and mutagenesis; (2) traffics M6P-tagged lysosomal enzymes from the TGN to lysosomes, regulated by a PACS-1/GGA3/CK2 phosphorylation cascade and Rab9-mediated endosomal delivery; (3) undergoes TACE-mediated ectodomain shedding to generate a soluble form that inhibits plasminogen activation and angiogenesis; (4) is subject to genomic imprinting on the maternal allele controlled by an intronic CpG island (DMR2/region 2) that acts as an imprinting control element driving paternal-allele expression of the Airn lncRNA, which silences paternal Igf2r through transcriptional overlap of its promoter and generates an expression bias favoring the maternal allele; and (5) additionally modulates T cell Lck localization, macrophage metabolic reprogramming via IGF2R nuclear translocation and v-ATPase regulation, and muscle differentiation via CD20 and calcineurin/NFAT pathways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IGF2R (CI-MPR/CD222) is a multifunctional type I transmembrane receptor that serves dual roles as a clearance receptor for IGF-II and as a transporter of mannose 6-phosphate (M6P)-tagged lysosomal enzymes from the TGN to lysosomes. Genetic epistasis in mice demonstrates that IGF2R sequesters IGF-II for lysosomal degradation, limiting IGF1R-mediated growth signaling—loss of maternal Igf2r causes overgrowth and perinatal lethality rescued by elimination of IGF-II or IGF1R [PMID:8806828, PMID:8076514]—while its M6P-binding function independently prevents pericellular cathepsin accumulation and ECM invasion [PMID:22521359, PMID:31748500]. Crystal structures reveal that IGF-II binds a hydrophobic pocket in extracellular domain 11, with domain 13 modulating flexibility, and the same binding surface is convergently recognized by IGF-binding proteins [PMID:18046459, PMID:11867533]. Igf2r is subject to genomic imprinting controlled by a maternally methylated intronic CpG island (DMR2/region 2) that drives paternal-allele expression of the Airn lncRNA; Airn silences paternal Igf2r through transcriptional overlap of its promoter, interfering with RNA Pol II recruitment, and continuous Airn expression is required until somatic DNA methylation consolidates silencing [PMID:23239737, PMID:9338788, PMID:23444351].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Identification of two differentially methylated regions at the Igf2r locus—including a maternally methylated intronic CpG island (region 2) inherited from the oocyte—established the candidate imprinting control element and framed the question of how allele-specific expression is regulated.\",\n      \"evidence\": \"Genomic cloning and allele-specific methylation analysis in mouse embryos and gametes\",\n      \"pmids\": [\"8462104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of trans-acting factors recognizing region 2 was unknown\", \"Functional necessity of region 2 for imprinting was not yet tested\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Genetic rescue of Igf2r-deficient (Tme) embryonic lethality by removing Igf2 demonstrated that IGF2R functions as a negative regulator of IGF-II bioavailability in vivo, answering the question of whether IGF2R's growth-suppressive role operates through IGF-II clearance.\",\n      \"evidence\": \"Genetic epistasis crossing Igf2 null with Thp (Igf2r locus) deletion mice\",\n      \"pmids\": [\"8076514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether M6P-mediated lysosomal enzyme trafficking contributes independently to lethality was unresolved\", \"Mechanism of IGF-II internalization and degradation not biochemically defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Triple and double mutant mouse crosses placed IGF2R upstream of IGF1R signaling and demonstrated that M6P-mediated lysosomal enzyme trafficking is independently essential for postnatal survival, separating the two major functions of the receptor.\",\n      \"evidence\": \"Igf2r × Igf2, Igf2r × Igf1r, and Igf2r × Igf2 × Igf1r null mouse crosses\",\n      \"pmids\": [\"8806828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for IGF-II versus M6P binding discrimination unknown\", \"Whether IGF2R signals independently of IGF-II clearance was unaddressed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"YAC transgene experiments with region 2 deletion proved that the intronic CpG island is necessary for imprinted monoallelic Igf2r expression and serves as the promoter for a paternal-allele antisense RNA, answering how the imprinting control element functions.\",\n      \"evidence\": \"YAC transgenes with region 2 deletion; allele-specific expression and methylation analysis\",\n      \"pmids\": [\"9338788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the antisense RNA silences Igf2r was unknown\", \"Minimal cis-elements within region 2 were undefined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Fine-mapping of a 113-bp methylation imprinting box within DMR2 identified separable de novo methylation and allele-discrimination signals, defining the minimal regulatory architecture for differential methylation.\",\n      \"evidence\": \"Deletion mapping and protein-binding analysis in transgenic mice\",\n      \"pmids\": [\"9892358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of proteins binding the allele-discrimination signal remained unknown\", \"How these elements coordinate with chromatin modifications was unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Biallelic Igf2r expression (via paternal region 2 deletion) caused growth restriction and rescued Tme lethality, demonstrating that the biological purpose of Igf2r imprinting is to limit receptor dosage and thereby increase birth weight.\",\n      \"evidence\": \"Gene targeting of region 2 on paternal allele in ES cells; weight phenotyping and Tme rescue\",\n      \"pmids\": [\"11311167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether imprinting-dependent dosage regulation operates in all tissues was untested\", \"Postnatal physiological consequences of biallelic expression were incompletely characterized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The first crystal structure of IGF2R domain 11 revealed a flattened β-barrel fold with the IGF-II binding site at one end, providing the structural framework for understanding ligand recognition.\",\n      \"evidence\": \"X-ray crystallography at 1.4 Å resolution using anomalous sulfur scattering\",\n      \"pmids\": [\"11867533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic details of the IGF-II:domain 11 interface were lacking\", \"Role of neighboring domains in binding was unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Allele-specific ChIP established a histone code for Igf2r/Airn imprinting—active alleles carry H3K9-Ac and H3K4-Me while silent alleles carry deacetylated, unmethylated histones—and showed that biallelic Igf2r in neurons correlates with biallelic active marks despite maintained Airn expression.\",\n      \"evidence\": \"Allele-specific ChIP in interspecific crosses; pharmacological inhibitor treatments\",\n      \"pmids\": [\"12975326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal relationship between histone marks and silencing was not demonstrated\", \"Mechanism of neuron-specific escape from imprinting was unexplained\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstration that Airn silences flanking genes Slc22a2/Slc22a3 independently of transcriptional overlap with the Igf2r promoter revealed that Airn has cis-silencing activity beyond simple transcriptional interference, raising the question of distinct silencing mechanisms at different targets.\",\n      \"evidence\": \"Igf2r promoter replacement/deletion in mice with allele-specific expression of Slc22a2/Slc22a3\",\n      \"pmids\": [\"12853484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Airn-mediated silencing of flanking genes was undefined\", \"Whether Airn RNA product or transcription act mediates silencing at flanking loci was unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery of the PACS-1/GGA3/CK2 phosphorylation cascade defined how CI-MPR is sorted between TGN and endosomes: CK2 phosphorylation of GGA3 releases CI-MPR at endosomes while CK2 phosphorylation of PACS-1 promotes endosome-to-TGN retrieval.\",\n      \"evidence\": \"Co-immunoprecipitation, kinase assays, RNAi, dominant-negative and phospho-mutant constructs\",\n      \"pmids\": [\"16977309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional kinases or adaptors regulate CI-MPR trafficking was unaddressed\", \"In vivo relevance of the PACS-1 phosphorylation cascade was not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Igf2r transgene overexpression delayed mammary tumor onset in Igf2-overexpressing mice, providing direct in vivo evidence that IGF2R functions as a tumor suppressor through IGF-II degradation.\",\n      \"evidence\": \"Igf2r transgenic crossed with Igf2-overexpressing mammary tumor mice\",\n      \"pmids\": [\"16452186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether M6P-dependent cathepsin trafficking also contributes to tumor suppression was untested\", \"Human tumor relevance was not directly addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Crystal structures of multi-domain IGF2R complexes with IGF-II resolved the binding interface: domain 11 engages IGF-II via a hydrophobic pocket contacting Phe19 and Leu53, while domain 13 modulates binding site flexibility, and mutagenesis confirmed this hotspot is shared with IGF-binding proteins.\",\n      \"evidence\": \"X-ray crystallography of domain 11–14 constructs ± IGF-II; site-directed mutagenesis; NMR-based docking\",\n      \"pmids\": [\"18046459\", \"17850746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length ectodomain structure was unavailable\", \"pH-dependent conformational changes governing ligand release were not structurally characterized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"CI-MPR was shown to bind enzymatically active heparanase at the cell surface in an M6P-independent manner, expanding the receptor's extracellular functions to include tethering of ECM-degrading enzymes.\",\n      \"evidence\": \"Binding assays in CI-MPR-transfected cells; M6P competition; ECM degradation assays\",\n      \"pmids\": [\"18073203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heparanase binding site on IGF2R was not mapped\", \"Physiological significance in vivo was not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Kinetic allele-specific analysis during ES cell differentiation showed that Airn generates an expression bias (up to 10-fold maternal upregulation) rather than absolute paternal silencing, reframing the imprinting mechanism as dosage modulation.\",\n      \"evidence\": \"In vitro ES cell differentiation with allele-specific quantitative expression and ChIP\",\n      \"pmids\": [\"19141673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this expression bias model applies in all tissues in vivo was untested\", \"Factors driving maternal allele upregulation were unidentified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of TACE/ADAM-17 as the sheddase generating soluble IGF2R revealed a new anti-angiogenic mechanism: shed sIGF2R binds plasminogen, preventing plasminogen activation and thereby inhibiting angiogenesis and tumor invasion.\",\n      \"evidence\": \"TACE inhibitors and RNAi; plasminogen binding assays; in vitro invasion and in vivo tumor models\",\n      \"pmids\": [\"21273553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulation of TACE-mediated shedding of IGF2R was not characterized\", \"Relative contribution of sIGF2R versus membrane-bound IGF2R to anti-angiogenic activity was unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Endogenous truncation of Airn demonstrated that transcriptional overlap with the Igf2r promoter—not the Airn RNA product—is necessary and sufficient for paternal Igf2r silencing, resolving a long-standing mechanistic debate about whether the lncRNA or the act of transcription mediates silencing.\",\n      \"evidence\": \"Gene targeting to truncate Airn at different lengths; RNA Pol II ChIP; allele-specific expression\",\n      \"pmids\": [\"23239737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How transcriptional overlap blocks Pol II recruitment mechanistically was unresolved\", \"Whether chromatin remodelers are recruited during the interference was unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reconstitution of IGF2R in receptor-deficient liver cells showed that M6P-binding (not IGF-II binding) is required to prevent cathepsin hypersecretion and ECM invasion, establishing the M6P-trafficking function as the mechanism of IGF2R's anti-invasive activity in liver.\",\n      \"evidence\": \"Wild-type vs. M6P-binding mutant IGF2R reconstitution; cathepsin secretion and ECM invasion assays\",\n      \"pmids\": [\"22521359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this mechanism operates in other cancer types was not tested\", \"Specific M6P-tagged cathepsins responsible for invasion were not individually identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Comparative binding analysis across species revealed that IGF2 binding by IGF2R originated through an exon splice enhancer in domain 11's CD loop in monotremes, with subsequent structural evolution of binding loops in therians improving affinity—linking splicing constraints to receptor evolution.\",\n      \"evidence\": \"ESE splicing assays; cross-species SPR binding measurements; structural loop comparisons\",\n      \"pmids\": [\"23197533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether imprinting truly accelerated affinity maturation is speculative\", \"Ancestral IGF2R structure in non-mammalian vertebrates was not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Inducible Airn experiments showed that continuous Airn expression is required until somatic DNA methylation consolidates paternal Igf2r silencing, after which Airn becomes dispensable, defining a two-phase silencing model (Airn-dependent initiation → methylation-dependent maintenance).\",\n      \"evidence\": \"Inducible Airn on/off system in ES cells during differentiation; allele-specific expression and methylation\",\n      \"pmids\": [\"23444351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of DNA methyltransferase(s) consolidating somatic methylation at Igf2r was not determined\", \"Timing of the transition in vivo was not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CD222/IGF2R was shown to control Lck spatial distribution and activity in T cells—knockdown traps Lck in the cytosol with inhibitory phosphorylation—revealing a previously unrecognized role for IGF2R in TCR signaling.\",\n      \"evidence\": \"siRNA knockdown with rescue; Lck localization by immunofluorescence; phospho-Lck blotting; T cell functional assays\",\n      \"pmids\": [\"25127865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between IGF2R and Lck was not demonstrated\", \"Whether IGF2R trafficking of Lck is M6P-dependent was untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Engineered domain 11 variants with 100-fold improved IGF2 affinity validated the structural basis of binding (AB-CD and FG-FG interloop contacts) and demonstrated therapeutic potential as IGF2 traps depleting pathological IGF2 isoforms in vivo.\",\n      \"evidence\": \"Yeast surface display; SPR; NMR; in vivo IGF2 depletion\",\n      \"pmids\": [\"27140600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pharmacokinetics and long-term safety of domain 11 traps were not characterized\", \"Selectivity over IGF1 binding was not fully profiled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"IGF2R depletion in cancer cells disrupted Golgi-to-lysosome cathepsin transport, causing autophagy and mitophagy dysfunction with ROS accumulation, separating the M6P-trafficking contribution from IGF-II clearance in maintaining lysosomal homeostasis.\",\n      \"evidence\": \"siRNA knockdown; cathepsin trafficking, lysosomal activity, autophagy/mitophagy marker assays\",\n      \"pmids\": [\"31748500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether autophagy dysfunction is a direct or secondary consequence of cathepsin mistrafficking was unclear\", \"Generalizability beyond cervical cancer cells was untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of an IGF2R–CD20 complex in myoblasts, where IGF2R blockade activates the calcineurin/NFAT pathway and promotes muscle regeneration in dystrophic mice, revealed a signaling axis linking IGF2R to calcium homeostasis and myogenesis.\",\n      \"evidence\": \"Co-immunoprecipitation; anti-IGF2R antibody; NFAT/calcineurin analysis; SERCA assay; mdx mouse model\",\n      \"pmids\": [\"31793167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IGF2R–CD20 interaction is direct or mediated by adaptor proteins was not resolved\", \"Mechanism linking IGF2R blockade to CD20 phosphorylation was not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"IGF2R nuclear translocation upon low-dose IGF2 stimulation was shown to activate GSK3α/β and Dnmt3a-mediated methylation, suppressing v-ATPase expression and redirecting protons to mitochondria to sustain oxidative phosphorylation in macrophages, revealing an unexpected nuclear signaling role.\",\n      \"evidence\": \"Nuclear translocation imaging; GSK3 inhibition; Dnmt3a ChIP; v-ATPase assembly and mitochondrial proton flux assays; colitis mouse model\",\n      \"pmids\": [\"33239287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of IGF2R nuclear import is unknown\", \"Whether nuclear IGF2R retains receptor function or acts as a transcriptional co-regulator was not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Soluble CD22 was identified as an IGF2R ligand on myeloid cells that disrupts lysosomal trafficking, and blocking this interaction rescued lysosome dysfunction in NPC1-mutant microglia, establishing IGF2R as a node in neuroinflammatory lysosomal pathology.\",\n      \"evidence\": \"Unbiased proteomic screens; IGF2R domain truncation; lysosomal trafficking in iPSC-derived microglia\",\n      \"pmids\": [\"34851695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise IGF2R domains mediating sCD22 binding were not fully resolved\", \"In vivo relevance in NPC1 disease models was not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the full-length ectodomain structure of IGF2R, the mechanism of IGF2R nuclear translocation and its nuclear targets, the molecular basis for tissue-specific escape from imprinting (e.g., neurons), and whether IGF2R's diverse signaling roles (Lck regulation, calcineurin/NFAT activation, macrophage metabolic reprogramming) operate through a unified trafficking mechanism or distinct receptor pools.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length IGF2R ectodomain structure exists\", \"Nuclear import mechanism undefined\", \"Tissue-specific imprinting escape mechanism unknown\", \"Integration of trafficking versus signaling functions not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [2, 3, 7, 18, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 23, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [15, 17]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [12, 13, 22]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 18, 22]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [12, 13, 18, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 14, 17, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 5, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IGF2\",\n      \"PACS1\",\n      \"GGA3\",\n      \"CSNK2A1\",\n      \"RAB9A\",\n      \"MS4A1\",\n      \"CD22\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}