{"gene":"IGF2R","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1993,"finding":"The mouse Igf2r locus contains two differentially methylated regions: region 1 (promoter, methylated on the silent paternal chromosome) and region 2 (intron 2 CpG island, methylated only on the expressed maternal chromosome). Region 2 methylation is inherited from the female gamete, whereas region 1 methylation is acquired post-fertilization, identifying the expressed maternal allele as carrying the imprinting signal.","method":"Cloning of 130 kb genomic locus; bisulfite/methylation analysis of parental-specific CpG methylation patterns","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct methylation mapping across entire locus in multiple tissues, foundational paper widely replicated","pmids":["8462104"],"is_preprint":false},{"year":1997,"finding":"Imprinted expression of mouse Igf2r depends on the intronic CpG island (region 2) in intron 2: deletion of region 2 from YAC transgenes abolishes imprinting and restores biallelic Igf2r expression. Region 2 also serves as the promoter for an antisense RNA expressed from the paternal allele, whose production depends on region 2.","method":"YAC transgene experiments with region 2 deletion; allele-specific expression analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional deletion in transgenic mice with direct allelic expression readout, independently replicated","pmids":["9338788"],"is_preprint":false},{"year":2012,"finding":"Silencing of Igf2r by Airn requires transcriptional overlap of Airn with the Igf2r promoter, which interferes with RNA Polymerase II recruitment. Spliced and unspliced Airn lncRNA products, nuclear size, and location are dispensable; only the act of transcription overlapping the Igf2r promoter is required.","method":"Endogenous truncation of Airn to different lengths in mice; RNA Pol II ChIP; allele-specific expression assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple endogenous truncation alleles with mechanistic ChIP readout, published in high-tier journal","pmids":["23239737"],"is_preprint":false},{"year":1996,"finding":"IGF2R/CI-MPR serves to clear IGF-II by targeting it for lysosomal degradation, thereby limiting IGF1R-mediated growth signaling. Genetic epistasis shows that Igf2r null-induced overgrowth and lethality are fully rescued by loss of either Igf2 or Igf1r.","method":"Mouse genetics: double and triple knockout epistasis (Igf2r/Igf2, Igf2r/Igf1r, Igf2r/Igf2/Igf1r null combinations); birthweight and survival analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis with multiple double/triple mutant combinations, definitive pathway placement","pmids":["8806828"],"is_preprint":false},{"year":2007,"finding":"Crystal structures of IGF2R domains 11-12, 11-12-13-14, and the domains 11-12-13/IGF-II complex reveal that domain 11 directly contacts IGF-II and domain 13 modulates binding-site flexibility. Phe19 and Leu53 of IGF-II lock into a hydrophobic pocket unique to domain 11 of mammalian IGF2Rs. Mutagenesis confirms this hydrophobic 'binding-hotspot' and shows convergent evolution with IGF-binding proteins.","method":"X-ray crystallography of domain complexes; site-directed mutagenesis of IGF-II and IGF2R; binding assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus binding assays in one study","pmids":["18046459"],"is_preprint":false},{"year":2007,"finding":"NMR-based models of the IGF2R domain 11/IGF-II interaction show that the interaction is driven by critical hydrophobic residues on both partners, with a ring of flexible charged residues on IGF2R modulating binding.","method":"Heteronuclear NMR combined with existing mutagenesis data; HADDOCK docking","journal":"Structure","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — solution NMR structure but computational docking model, single study","pmids":["17850746"],"is_preprint":false},{"year":2012,"finding":"The DNA sequence encoding the IGF2-binding CD loop of monotreme IGF2R functions as an exon splice enhancer (ESE). Structural evolution of additional binding loops (AB, HI, FG) improved therian IGF2 affinity, indicating that ESE evolution drove the fortuitous acquisition of IGF2 binding by M6P/IGF2R, with subsequent imprinting accelerating affinity maturation.","method":"Comparative structural biology; ESE functional assays; surface plasmon resonance binding assays across species","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional ESE assay plus binding kinetics across multiple species, rigorous mechanistic dissection","pmids":["23197533"],"is_preprint":false},{"year":2016,"finding":"Yeast surface display selection combined with structure-guided mutagenesis of domain 11 binding loops (AB, CD, FG, HI) achieved a 100-fold improvement in IGF2 affinity over IGF1, with NMR confirming increased AB-loop rigidity and structural analysis showing improved shape complementarity via interloop side-chain interactions. High-affinity domain 11 Fc fusions depleted pathological IGF2 isoforms from serum and abrogated IGF2-dependent signaling in vivo.","method":"Yeast surface display; surface plasmon resonance; NMR; X-ray crystallography; in vivo IGF2-dependent signaling assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal structural and functional methods, in vivo validation","pmids":["27140600"],"is_preprint":false},{"year":2006,"finding":"A PACS-1/GGA3/CK2 complex regulates CI-MPR (IGF2R) trafficking between endosomes and the TGN. PACS-1 links GGA3 to CK2; CK2-mediated phosphorylation of GGA3 releases it from CI-MPR, while CK2 phosphorylation of PACS-1 Ser278 promotes PACS-1 binding to CI-MPR for TGN retrieval. Both GGA3 and PACS-1 bind an overlapping WLM-containing trafficking motif on CI-MPR.","method":"Co-immunoprecipitation; phosphorylation assays; siRNA knockdown; subcellular trafficking assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro phosphorylation cascade, functional trafficking readout","pmids":["16977309"],"is_preprint":false},{"year":2017,"finding":"Retromer knockdown or knockout does not perturb CI-MPR (IGF2R) endosome-to-TGN transport, but knockdown of the retromer-linked SNX-BAR proteins (SNX1/2 with SNX5/6) causes pronounced CI-MPR transport defects. SNX5 and SNX6 associate with CI-MPR through a specific WLM endosomal sorting motif, coupling sequence-dependent cargo recognition with tubular profile biogenesis required for endosome-to-TGN transport.","method":"Knockout/knockdown of retromer components and SNX-BAR proteins; co-immunoprecipitation; CI-MPR trafficking assays; tubular endosome imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO plus reciprocal Co-IP plus trafficking assays; reappraises retromer dogma with multiple orthogonal methods","pmids":["28935633"],"is_preprint":false},{"year":2020,"finding":"CASP9 localizes to the endosomal membrane and facilitates retrograde transport of IGF2R/CI-MPR from endosomes to the TGN via a non-apoptotic mechanism. CASP9-deficient cells show IGF2R degradation, cathepsin D missorting, and late endosome accumulation. A catalytically inactive CASP9 mutant rescues IGF2R stability. CASP9 interacts with retromer component VPS35 and SNX1-SNX5/SNX2-SNX6 dimers, as well as ESCRT-0 component HGS/HRS and clathrin heavy chain.","method":"CASP9 KO/KD; co-immunoprecipitation with retromer and SNX components; IGF2R trafficking and stability assays; cathepsin D sorting assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with functional rescue by catalytic mutant plus Co-IP with multiple interactors, single lab","pmids":["32397873"],"is_preprint":false},{"year":2016,"finding":"CI-MPR (IGF2R) enters the endosomal pathway with Rab9 at the early-to-late endosome transition (Rab5-to-Rab7a stage), localizes transiently to separate domains on maturing endosomes, and Rab9 constitutively active mutant (Q66L) disperses CI-MPR and TGN46 from the Golgi without affecting retrograde transport of CI-MPR.","method":"Live confocal imaging; Rab9Q66L expression; colocalization studies in HeLa cells","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — live imaging with constitutively active mutant, multiple cell lines, single lab","pmids":["26663757"],"is_preprint":false},{"year":2008,"finding":"IGF2R mediates EPC homing via Gi protein-linked signaling and requires intracellular Ca2+ mobilization induced by phospholipase C beta2 isoform. IGF2-induced hypoxic conditions stimulated EPC migration, recruitment, and neovascular incorporation; all actions were abolished by pertussis toxin (Gi inhibition) or PLCβ2 knockdown.","method":"In vitro EPC homing assays; pertussis toxin and siRNA-based inhibition; Ca2+ mobilization assays; in vivo angiogenesis model","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibition with multiple functional readouts, single lab","pmids":["18832656"],"is_preprint":false},{"year":2020,"finding":"Low-dose IGF2 activates IGF2R, leading to nuclear translocation of IGF2R that promotes Dnmt3a-mediated DNA methylation via GSK3α/β activation, thereby suppressing vacuolar-type H+-ATPase (v-ATPase) expression. Sequestration of v-ATPase assembly inhibits proton channeling to lysosomes and redirects protons to the mitochondrial intermembrane space, enabling sustained oxidative phosphorylation and an anti-inflammatory macrophage phenotype.","method":"Subcellular fractionation; nuclear translocation assay; Dnmt3a ChIP; v-ATPase expression analysis; mitochondrial proton channeling assay; IGF2R-specific IGF2 mutant treatment in colitis model","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays in one study, in vivo validation with selective mutant, single lab","pmids":["33239287"],"is_preprint":false},{"year":2007,"finding":"Cell surface-expressed CI-MPR (IGF2R/CD222) binds enzymatically active heparanase independently of mannose 6-phosphate. Purified heparanase binds CIMPR-expressing mouse L cells (not CDMPR-expressing cells), remains at the cell surface for ~10 minutes, and tethering of heparanase to cell surfaces via CIMPR enhances extracellular matrix degradation.","method":"Binding assays with purified heparanase on transfected L cell lines; competition with M6P; ECM degradation assays; primary T cell activation experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with receptor-expressing vs. non-expressing cell lines plus functional ECM readout, single lab","pmids":["18073203"],"is_preprint":false},{"year":2011,"finding":"Soluble M6P/IGF2R (sM6P/IGF2R) is shed from human endothelial cells by TACE (ADAM-17). The shed ectodomain binds plasminogen, preventing its binding to cell surface and to uPA, thereby inhibiting plasminogen activation and blocking angiogenesis and cancer cell invasion.","method":"Specific TACE inhibitors and siRNA; plasminogen binding assays; in vitro invasion assay; in vivo endothelial invasion and tumor growth assays with M6P/IGF2R-derived peptide","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological plus RNAi inhibition with in vitro and in vivo functional readouts, single lab","pmids":["21273553"],"is_preprint":false},{"year":2014,"finding":"CD222 (IGF2R) controls spatial distribution and activity of Lck in T cells: knockdown of CD222 retains Lck in the cytosol, obstructing its recruitment to CD45 at the cell surface and resulting in predominant inhibitory phosphorylation of Lck (Tyr505), thereby impairing TCR-induced signaling and effector functions.","method":"CD222 siRNA knockdown with reconstitution; Lck localization by imaging/fractionation; Lck phosphorylation status; TCR signaling assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with reconstitution rescue, localization and phosphorylation readouts, single lab","pmids":["25127865"],"is_preprint":false},{"year":2021,"finding":"sCD22 binds to IGF2R on human myeloid cells (microglia-like cells) near critical mannose 6-phosphate-binding domains, disrupting lysosomal protein trafficking. Targeted truncation of IGF2R mapped the sCD22 docking site. Blocking the sCD22-IGF2R interaction with CD22 antibodies ameliorated lysosome dysfunction in NPC1 mutant iPSC-derived microglia-like cells.","method":"Unbiased genetic and proteomic screens; IGF2R truncation mapping; lysosomal trafficking assays; CD22 blocking antibody rescue in iPSC-derived microglia","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased screen plus domain truncation mapping plus functional rescue in human disease model, multiple orthogonal methods","pmids":["34851695"],"is_preprint":false},{"year":2019,"finding":"IGF2R depletion in cervical cancer cells disrupts Golgi-to-lysosome transport of M6P-tagged cathepsins, leading to decreased lysosomal activity, abnormal cathepsin accumulation, dysfunction of autophagy and mitophagy, accumulation of misfolded proteins, and ROS production, ultimately inducing apoptosis. The M6P-binding function (not the IGF1R signaling antagonism) underlies these effects.","method":"siRNA knockdown of IGF2R; lysosomal activity assays; cathepsin localization; autophagy/mitophagy assays; apoptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple mechanistic readouts distinguishing M6P vs. IGF signaling functions, single lab","pmids":["31748500"],"is_preprint":false},{"year":2012,"finding":"M6P/IGF2R restricts liver cell invasion by preventing pericellular action of M6P-modified cathepsins: reconstitution of IGF2R in receptor-deficient FRL14 cells restores intracellular cathepsin transport to lysosomes and reduces invasiveness; knockdown in receptor-positive hepatocytes increases cathepsin secretion and invasiveness. Functional M6P-binding sites, but not the IGF-II-binding capacity, are required for anti-invasive activity.","method":"Wild-type vs. M6P-binding-mutant IGF2R reconstitution in receptor-deficient cells; RNAi knockdown in receptor-positive cells; cathepsin secretion assays; ECM invasion assays","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function reconstitution plus loss-of-function KD, domain-function dissection with mutant receptor, multiple readouts","pmids":["22521359"],"is_preprint":false},{"year":2006,"finding":"Overexpression of Igf2r delays onset and reduces multiplicity of IGF-II-driven mammary tumors in Igf2-transgenic mice, providing in vivo genetic evidence that lysosomal targeting and degradation of IGF-II underlies the tumor suppressor activity of IGF2R.","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 / Moderate — in vivo genetic cross with quantitative tumor phenotype, single lab","pmids":["16452186"],"is_preprint":false},{"year":2001,"finding":"Biallelic expression of Igf2r (via paternal inheritance of region 2-deleted non-imprinted allele) reduces late embryonic weight by ~20% persisting into adulthood, demonstrating that imprinting of Igf2r functions to increase birth weight. The non-imprinted allele also rescues lethality of maternally inherited Igf2r null allele and Tme mutation, establishing Igf2r as the Tme gene.","method":"Gene targeting in mouse ES cells to delete region 2; allele-specific expression analysis; body weight measurement; genetic rescue crosses","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — precise endogenous gene targeting with multiple genetic cross outcomes and quantitative growth phenotypes","pmids":["11311167"],"is_preprint":false},{"year":2001,"finding":"The Igf2r imprint control element (Region2/ICE) acts bidirectionally to regulate not only Igf2r but also two novel imprinted genes, Slc22a2 and Slc22a3, located 110 and 155 kb downstream; these genes are repressed on the paternal allele without being overlapped by the Air transcript, demonstrating ICE-mediated silencing independent of Air transcript overlap.","method":"Allele-specific expression analysis of Slc22a2 and Slc22a3 in mice with targeted region 2 deletions","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct allele-specific expression analysis in targeted deletion mice, definitive cluster organization","pmids":["11562346"],"is_preprint":false},{"year":2013,"finding":"Continuous Airn expression is necessary and sufficient to maintain Igf2r silencing throughout ES cell differentiation, but only until the paternal Igf2r promoter acquires somatic DNA methylation. After methylation is established, Airn expression is no longer required. Airn initiation of silencing is not restricted to a single developmental window.","method":"Inducible Airn expression system in mouse ES cells; allele-specific Igf2r expression; DNA methylation analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible on/off system with temporal dissection of requirement, multiple epigenetic readouts","pmids":["23444351"],"is_preprint":false},{"year":2004,"finding":"Allele-specific histone modifications at the Igf2r and Air promoters correlate with imprinting status across tissues: active alleles show acetylated H3/H4, H3K9-Ac, and H3K4-Me; silenced alleles show deacetylated H3K9 and unmethylated H3K4. Tri-methyl H3K9 (not di-methyl) marks the silenced Air allele. Treatment with 5-aza-dCyd and/or TSA partially reactivates the silenced Igf2r allele with concurrent biallelic histone acetylation.","method":"Allele-specific ChIP in Mus musculus × M. spretus interspecific mice; quantitative PCR; drug treatment (5-azadCyd, TSA)","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — allele-specific ChIP with drug treatment rescue, single lab","pmids":["15294879"],"is_preprint":false},{"year":2019,"finding":"IGF2R and the store-operated Ca2+ channel CD20 share a common hydrophobic binding motif that stabilizes their association. Blockade of IGF2R with neutralizing antibodies increases proliferation and differentiation of myoblasts via the calmodulin/calcineurin/NFAT pathway, induces CD20 phosphorylation leading to SERCA activation, and removes intracellular Ca2+. In dystrophic mdx mice, anti-IGF2R treatment stimulates muscle regeneration and force recovery.","method":"Co-immunoprecipitation of IGF2R and CD20; IGF2R neutralizing antibody; calcineurin/NFAT pathway assays; SERCA activity; in vivo mdx mouse model","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus multiple downstream signaling readouts plus in vivo model, single lab","pmids":["31793167"],"is_preprint":false},{"year":1999,"finding":"A 113-bp sequence within the Igf2r intron 2 DMR constitutes a methylation imprinting box containing two cis-acting elements: a de novo methylation signal and an allele-discrimination signal that bind specific proteins and are involved in establishing differential methylation at the Igf2r DMR.","method":"Deletion mapping and protein-binding assays (gel shift/footprint) of the 113-bp imprinting box; de novo methylation assays","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cis-element deletion mapping with protein-binding assays, single lab but published in Nature","pmids":["9892358"],"is_preprint":false},{"year":2017,"finding":"IGF2R-activated cardiac hypertrophy and apoptosis under high glucose conditions proceed through Gαq-mediated calcineurin-dependent signaling, upregulating ANP and BNP, downregulating p-Akt and p-Bad, and increasing cytochrome c and cleaved caspase-3.","method":"Immunoblotting; TUNEL assay; high-glucose treatment of H9c2 cells and STZ-diabetic rat hearts; expression analysis of calcineurin pathway components","journal":"Biomedicine & pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative pathway analysis without receptor-specific genetic rescue or mutagenesis","pmids":["29136764"],"is_preprint":false}],"current_model":"IGF2R (CI-MPR) is a multifunctional transmembrane receptor that traffics mannose-6-phosphate-tagged lysosomal enzymes from the trans-Golgi network to lysosomes via sequential interactions with GGA3 (TGN export), SNX5/SNX6-containing SNX-BAR complexes (endosomal tubular sorting), and PACS-1 (endosome-to-TGN retrieval, regulated by a CK2 phosphorylation cascade); it concurrently sequesters extracellular IGF-II through a hydrophobic binding pocket in domain 11 (modulated by domain 13), targeting it for lysosomal degradation to suppress IGF1R-mediated growth signaling, a function genetically validated as the mechanism of its tumor suppressor and growth-regulatory activities; its expression is controlled by genomic imprinting through an intronic CpG island (region 2/DMR2) that is maternally methylated and serves as the promoter for the paternal-allele-specific Airn lncRNA, whose transcriptional overlap with the Igf2r promoter (not the lncRNA product itself) silences paternal Igf2r by blocking RNA Pol II recruitment; additionally, IGF2R can signal through Gi/PLCβ2/Ca2+ to promote EPC homing, undergoes nuclear translocation to activate GSK3/Dnmt3a-mediated methylation suppressing v-ATPase in macrophages, and its retrograde endosomal recycling is facilitated by a non-apoptotic endosomal function of CASP9 acting through retromer and SNX-BAR complexes."},"narrative":{"mechanistic_narrative":"IGF2R (the cation-independent mannose-6-phosphate receptor, CI-MPR) is a multifunctional transmembrane receptor that couples lysosomal enzyme trafficking to growth control and tissue homeostasis [PMID:8806828, PMID:31748500]. Through a hydrophobic binding pocket in domain 11, modulated by domain 13, it directly captures extracellular IGF-II via the IGF-II residues Phe19 and Leu53, and routes it for lysosomal degradation, thereby limiting IGF1R-mediated growth signaling [PMID:18046459]; mouse genetics establishes this clearance function as the basis of its growth-regulatory and tumor-suppressor activity, since Igf2r-null overgrowth and lethality are fully rescued by loss of Igf2 or Igf1r, and Igf2r overexpression suppresses IGF-II-driven mammary tumors [PMID:8806828, PMID:16452186]. In parallel, its M6P-binding activity directs newly synthesized cathepsins from the Golgi to lysosomes; loss of this function causes cathepsin missorting, lysosomal and autophagic dysfunction, and increased pericellular cathepsin activity that promotes invasion [PMID:31748500, PMID:22521359]. Receptor recycling between endosomes and the trans-Golgi network is organized by an overlapping WLM-containing trafficking motif recognized by GGA3 and PACS-1 under control of a CK2 phosphorylation cascade, and by SNX1/2–SNX5/6 SNX-BAR complexes that drive tubular endosome-to-TGN transport independently of classical retromer; CASP9 facilitates this retrograde step non-catalytically through VPS35 and SNX-BAR dimers [PMID:16977309, PMID:28935633, PMID:32397873]. Igf2r is subject to genomic imprinting: a maternally methylated intronic CpG island (region 2/DMR2) serves as the promoter for the paternally expressed Airn lncRNA, whose transcriptional overlap with the Igf2r promoter — not the lncRNA product — silences the paternal allele by blocking RNA Pol II recruitment, with somatic DNA methylation later locking in the silent state [PMID:9338788, PMID:23239737, PMID:23444351]. Beyond these core roles, IGF2R has been linked to non-canonical surface and signaling functions including Gi/PLCβ2/Ca2+-dependent endothelial progenitor cell homing, nuclear translocation driving Dnmt3a-mediated v-ATPase suppression in macrophages, and modulation of Lck localization in T cells [PMID:18832656, PMID:33239287, PMID:25127865].","teleology":[{"year":1993,"claim":"Established that the Igf2r locus carries two parental-specific methylation marks and identified which allele bears the gametic imprint, defining the molecular substrate of Igf2r imprinting.","evidence":"Cloning of the genomic locus and bisulfite/methylation mapping of parental CpG patterns","pmids":["8462104"],"confidence":"High","gaps":["Did not establish how region 2 methylation directs allele-specific expression","No identification of trans-acting silencing machinery"]},{"year":1997,"claim":"Demonstrated that the intronic CpG island is functionally required for imprinting and is itself the promoter for a paternal antisense RNA, linking the methylation mark to a transcriptional silencing mechanism.","evidence":"YAC transgene region 2 deletion with allele-specific expression analysis in mice","pmids":["9338788"],"confidence":"High","gaps":["Did not resolve whether the lncRNA product or the act of transcription silences Igf2r","Mechanism of Pol II interference unknown"]},{"year":1999,"claim":"Mapped cis-acting elements within the DMR that establish differential methylation, dissecting the imprinting box into de novo methylation and allele-discrimination signals.","evidence":"Deletion mapping and protein-binding/de novo methylation assays of a 113-bp box","pmids":["9892358"],"confidence":"Medium","gaps":["Bound proteins not definitively identified","Single lab; cis-element function not validated at the endogenous locus"]},{"year":1996,"claim":"Placed IGF2R definitively in the IGF growth axis by showing genetically that its function is to clear IGF-II and antagonize IGF1R signaling.","evidence":"Mouse double/triple knockout epistasis (Igf2r/Igf2/Igf1r) with growth and survival readouts","pmids":["8806828"],"confidence":"High","gaps":["Did not distinguish the IGF-II clearance function from M6P-dependent enzyme trafficking","No structural basis for IGF-II binding"]},{"year":2001,"claim":"Showed in vivo that imprinting of Igf2r functions to control body weight and confirmed Igf2r as the Tme gene, and separately revealed the imprint control element silences neighboring genes independently of antisense overlap.","evidence":"Endogenous region 2 deletion in mice; growth measurement; rescue crosses; allele-specific expression of Slc22a2/Slc22a3","pmids":["11311167","11562346"],"confidence":"High","gaps":["Mechanism of overlap-independent silencing of Slc22a2/3 unresolved","Did not address developmental timing of the silencing requirement"]},{"year":2004,"claim":"Connected imprinting status to a defined chromatin code, showing allele-specific histone modifications accompany silencing and that pharmacological reversal can reactivate the silent allele.","evidence":"Allele-specific ChIP in interspecific mice with 5-aza-dCyd/TSA treatment","pmids":["15294879"],"confidence":"Medium","gaps":["Correlative chromatin marks; causal hierarchy of methylation vs. histone marks unresolved","Single lab"]},{"year":2006,"claim":"Defined the molecular machinery of receptor recycling, showing a PACS-1/GGA3/CK2 phosphorylation cascade governs CI-MPR shuttling between endosomes and the TGN through a shared trafficking motif.","evidence":"Reciprocal Co-IP, in vitro phosphorylation, siRNA, and trafficking assays","pmids":["16977309"],"confidence":"High","gaps":["Did not address the tubular carrier biogenesis step","Relationship to retromer not tested"]},{"year":2006,"claim":"Provided in vivo genetic confirmation that lysosomal targeting of IGF-II underlies IGF2R tumor suppression.","evidence":"Igf2r-transgenic × Igf2-overexpressing mammary tumor mouse cross with tumor onset/multiplicity readout","pmids":["16452186"],"confidence":"Medium","gaps":["Single lab","Did not separate IGF-II degradation from M6P-cargo functions in tumor suppression"]},{"year":2007,"claim":"Resolved the structural basis of IGF-II capture, identifying the domain 11 hydrophobic hotspot and domain 13 modulation that mediate high-affinity, mammal-specific IGF-II binding.","evidence":"X-ray crystallography of domain complexes, NMR/docking, and mutagenesis with binding assays","pmids":["18046459","17850746"],"confidence":"High","gaps":["NMR-based interaction model is computational (docking)","Did not address full-length receptor avidity in membranes"]},{"year":2007,"claim":"Identified an M6P-independent surface function, showing IGF2R tethers active heparanase at the cell surface to enhance extracellular matrix degradation.","evidence":"Heparanase binding on CIMPR- vs CDMPR-expressing L cells with M6P competition and ECM degradation assays","pmids":["18073203"],"confidence":"Medium","gaps":["Single lab","Physiological significance of surface heparanase tethering not established in vivo"]},{"year":2008,"claim":"Revealed an unexpected G-protein signaling role, showing IGF2R drives endothelial progenitor cell homing via Gi/PLCβ2/Ca2+.","evidence":"Pertussis toxin and PLCβ2 siRNA inhibition with EPC homing and Ca2+ assays plus in vivo angiogenesis","pmids":["18832656"],"confidence":"Medium","gaps":["Single lab","Direct coupling of IGF2R to Gi not structurally defined"]},{"year":2011,"claim":"Showed that a TACE-shed IGF2R ectodomain acts in trans, sequestering plasminogen to inhibit its activation and block angiogenesis and invasion.","evidence":"TACE inhibition/siRNA, plasminogen binding, and in vitro/in vivo invasion assays","pmids":["21273553"],"confidence":"Medium","gaps":["Single lab","Relative contribution of soluble vs. membrane receptor in vivo unquantified"]},{"year":2012,"claim":"Settled the imprinting mechanism debate by demonstrating that Airn transcriptional overlap with the Igf2r promoter, not the lncRNA product, silences the paternal allele by interfering with Pol II recruitment.","evidence":"Endogenous Airn truncation alleles with Pol II ChIP and allele-specific expression in mice","pmids":["23239737"],"confidence":"High","gaps":["Did not explain the transition to methylation-locked silencing","Mechanism of Pol II exclusion at the promoter not fully resolved"]},{"year":2012,"claim":"Reconstructed the evolutionary origin of IGF2 binding and dissected the M6P-binding function from IGF-II clearance in cancer cell invasion.","evidence":"Comparative structural biology with ESE assays and SPR across species; IGF2R reconstitution with M6P-binding mutants and cathepsin/invasion assays","pmids":["23197533","22521359"],"confidence":"High","gaps":["Did not link evolutionary affinity changes to disease phenotypes","Invasion study limited to liver cell models"]},{"year":2013,"claim":"Defined the temporal logic of imprinting maintenance, showing Airn is required to initiate and sustain silencing only until somatic DNA methylation of the paternal promoter takes over.","evidence":"Inducible Airn on/off system in ES cells with allele-specific expression and methylation analysis","pmids":["23444351"],"confidence":"High","gaps":["Did not identify the methyltransferase recruitment step","Mechanism converting transcriptional interference to stable methylation unknown"]},{"year":2014,"claim":"Implicated IGF2R in adaptive immune signaling by showing it controls Lck localization and CD45 access required for TCR signaling in T cells.","evidence":"CD222 siRNA knockdown with reconstitution, Lck localization/phosphorylation, and TCR signaling assays","pmids":["25127865"],"confidence":"Medium","gaps":["Single lab","Whether Lck regulation depends on receptor trafficking vs. direct interaction unresolved"]},{"year":2016,"claim":"Located the endosomal entry point of CI-MPR recycling, placing it at the Rab5-to-Rab7a transition with Rab9 involvement.","evidence":"Live confocal imaging and Rab9Q66L expression in HeLa cells","pmids":["26663757"],"confidence":"Medium","gaps":["Single lab","Did not establish functional requirement of Rab9 for retrograde transport"]},{"year":2016,"claim":"Engineered high-affinity domain 11 variants demonstrating that the IGF-II binding module can be repurposed as an IGF2-depleting therapeutic.","evidence":"Yeast surface display, SPR, NMR, crystallography, and in vivo IGF2 signaling assays","pmids":["27140600"],"confidence":"High","gaps":["Engineered reagent; not a statement about endogenous receptor regulation","Long-term in vivo efficacy/safety not addressed"]},{"year":2017,"claim":"Reappraised retrograde transport machinery, showing SNX1/2–SNX5/6 SNX-BAR complexes, not classical retromer, mediate CI-MPR endosome-to-TGN transport via the WLM sorting motif.","evidence":"Retromer and SNX-BAR KO/KD, reciprocal Co-IP, trafficking and tubular endosome imaging","pmids":["28935633"],"confidence":"High","gaps":["Did not define how WLM recognition couples to tubule formation mechanistically","Other accessory factors in tubule scission unidentified"]},{"year":2019,"claim":"Established that the M6P-cargo function of IGF2R, independent of IGF1R antagonism, maintains lysosomal and autophagic integrity, loss of which triggers ROS-driven apoptosis.","evidence":"siRNA knockdown in cervical cancer cells with lysosomal, autophagy/mitophagy, and apoptosis readouts","pmids":["31748500"],"confidence":"Medium","gaps":["Single lab","Cell-type generality of the apoptotic outcome untested"]},{"year":2019,"claim":"Identified IGF2R as a surface partner of the Ca2+ channel CD20 in muscle and a therapeutic target for promoting regeneration in dystrophy.","evidence":"Co-IP, IGF2R neutralizing antibody, calcineurin/NFAT and SERCA assays, and mdx mouse model","pmids":["31793167"],"confidence":"Medium","gaps":["Single lab","Direct IGF2R–CD20 binding interface not structurally mapped"]},{"year":2020,"claim":"Uncovered a non-apoptotic role for CASP9 in IGF2R retrograde recycling, acting through retromer and SNX-BAR components independently of catalytic activity.","evidence":"CASP9 KO/KD with catalytic-mutant rescue, Co-IP with VPS35/SNX/ESCRT components, and trafficking/sorting assays","pmids":["32397873"],"confidence":"Medium","gaps":["Single lab","How CASP9 mechanistically promotes tubular sorting unclear"]},{"year":2020,"claim":"Defined a nuclear signaling branch in which low-dose IGF2-activated IGF2R drives Dnmt3a-mediated v-ATPase suppression to reprogram macrophage metabolism toward an anti-inflammatory phenotype.","evidence":"Subcellular fractionation, nuclear translocation assays, Dnmt3a ChIP, proton channeling assays, and a colitis model with selective IGF2 mutant","pmids":["33239287"],"confidence":"Medium","gaps":["Single lab","Mechanism of IGF2R nuclear translocation and GSK3 activation unresolved"]},{"year":2021,"claim":"Identified sCD22 as an IGF2R ligand that docks near M6P-binding domains and disrupts lysosomal trafficking, providing a druggable axis in lysosomal disease.","evidence":"Unbiased screens, IGF2R truncation mapping, lysosomal trafficking assays, and CD22 blocking antibody rescue in NPC1 iPSC-microglia","pmids":["34851695"],"confidence":"High","gaps":["sCD22 binding interface not structurally resolved","Generality across other lysosomal diseases not established"]},{"year":null,"claim":"How IGF2R integrates its canonical lysosomal-trafficking and IGF-II-clearance roles with its multiple non-canonical surface/nuclear signaling outputs (Gi/PLCβ2, CD20/SERCA, Lck, nuclear Dnmt3a) within a single physiological program remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model connecting trafficking and signaling functions","Most non-canonical functions rest on single-lab evidence without structural mechanism","Tissue-specific switching between functions not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[3,18,19]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[3,4,15]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[12,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[14,15,25]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[8,9,11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[8,9,10,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[8,9,10]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[18,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,12,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,23]}],"complexes":[],"partners":["GGA3","PACS1","SNX5","SNX6","VPS35","CASP9","IGF2"],"other_free_text":[]}},"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":"8462104","id":"PMC_8462104","title":"Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal.","date":"1993","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8462104","citation_count":540,"is_preprint":false},{"pmid":"9338788","id":"PMC_9338788","title":"Imprinted expression of the Igf2r gene depends on an intronic CpG island.","date":"1997","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9338788","citation_count":476,"is_preprint":false},{"pmid":"23239737","id":"PMC_23239737","title":"Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing.","date":"2012","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23239737","citation_count":409,"is_preprint":false},{"pmid":"8806828","id":"PMC_8806828","title":"Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds.","date":"1996","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/8806828","citation_count":384,"is_preprint":false},{"pmid":"7493029","id":"PMC_7493029","title":"M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity.","date":"1995","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7493029","citation_count":323,"is_preprint":false},{"pmid":"7720562","id":"PMC_7720562","title":"Mouse embryonic germ (EG) cell lines: transmission through the germline and differences in the methylation imprint of insulin-like growth factor 2 receptor (Igf2r) gene compared with embryonic stem (ES) cell lines.","date":"1994","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/7720562","citation_count":262,"is_preprint":false},{"pmid":"10802648","id":"PMC_10802648","title":"The imprinted antisense RNA at the Igf2r locus overlaps but does not imprint Mas1.","date":"2000","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10802648","citation_count":219,"is_preprint":false},{"pmid":"8267611","id":"PMC_8267611","title":"Functional polymorphism in the parental imprinting of the human IGF2R gene.","date":"1993","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8267611","citation_count":204,"is_preprint":false},{"pmid":"10882106","id":"PMC_10882106","title":"M6P/IGF2R imprinting evolution in mammals.","date":"2000","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/10882106","citation_count":202,"is_preprint":false},{"pmid":"28935633","id":"PMC_28935633","title":"Sequence-dependent cargo recognition by SNX-BARs mediates retromer-independent transport of CI-MPR.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28935633","citation_count":155,"is_preprint":false},{"pmid":"11562346","id":"PMC_11562346","title":"Bidirectional action of the Igf2r imprint control element on upstream and downstream imprinted genes.","date":"2001","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/11562346","citation_count":146,"is_preprint":false},{"pmid":"18832656","id":"PMC_18832656","title":"Endothelial progenitor cell homing: prominent role of the IGF2-IGF2R-PLCbeta2 axis.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18832656","citation_count":128,"is_preprint":false},{"pmid":"9892358","id":"PMC_9892358","title":"The imprinting box of the mouse Igf2r gene.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9892358","citation_count":110,"is_preprint":false},{"pmid":"8595419","id":"PMC_8595419","title":"Conservation of a maternal-specific methylation signal at the human IGF2R locus.","date":"1995","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8595419","citation_count":106,"is_preprint":false},{"pmid":"11311167","id":"PMC_11311167","title":"Non-imprinted Igf2r expression decreases growth and rescues the Tme mutation in mice.","date":"2001","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11311167","citation_count":101,"is_preprint":false},{"pmid":"18046459","id":"PMC_18046459","title":"Structure and functional analysis of the IGF-II/IGF2R interaction.","date":"2007","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/18046459","citation_count":100,"is_preprint":false},{"pmid":"10734317","id":"PMC_10734317","title":"M6P/IGF2R is mutated in squamous cell carcinoma of the lung.","date":"2000","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10734317","citation_count":98,"is_preprint":false},{"pmid":"9516081","id":"PMC_9516081","title":"The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R), a putative breast tumor suppressor gene.","date":"1998","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/9516081","citation_count":95,"is_preprint":false},{"pmid":"17387467","id":"PMC_17387467","title":"N-Acetyltransferase Mpr1 confers ethanol tolerance on Saccharomyces cerevisiae by reducing reactive oxygen species.","date":"2007","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/17387467","citation_count":87,"is_preprint":false},{"pmid":"14654216","id":"PMC_14654216","title":"Conservation of IGF2-H19 and IGF2R imprinting in sheep: effects of somatic cell nuclear transfer.","date":"2003","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/14654216","citation_count":86,"is_preprint":false},{"pmid":"19796953","id":"PMC_19796953","title":"Keeping IGF-II under control: lessons from the IGF-II-IGF2R crystal structure.","date":"2009","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19796953","citation_count":82,"is_preprint":false},{"pmid":"15308773","id":"PMC_15308773","title":"Role of the yeast acetyltransferase Mpr1 in oxidative stress: regulation of oxygen reactive species caused by a toxic proline catabolism intermediate.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15308773","citation_count":78,"is_preprint":false},{"pmid":"23444351","id":"PMC_23444351","title":"Imprinted Igf2r silencing depends on continuous Airn lncRNA expression and is not restricted to a developmental window.","date":"2013","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23444351","citation_count":78,"is_preprint":false},{"pmid":"16977309","id":"PMC_16977309","title":"A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16977309","citation_count":78,"is_preprint":false},{"pmid":"12853484","id":"PMC_12853484","title":"Imprinted silencing of Slc22a2 and Slc22a3 does not need transcriptional overlap between Igf2r and Air.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12853484","citation_count":73,"is_preprint":false},{"pmid":"12658632","id":"PMC_12658632","title":"Erasure of methylation imprinting of Igf2r during mouse primordial germ-cell development.","date":"2003","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/12658632","citation_count":71,"is_preprint":false},{"pmid":"9763452","id":"PMC_9763452","title":"A mutation in a novel yeast proteasomal gene, RPN11/MPR1, produces a cell cycle arrest, overreplication of nuclear and mitochondrial DNA, and an altered mitochondrial morphology.","date":"1998","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/9763452","citation_count":68,"is_preprint":false},{"pmid":"33239287","id":"PMC_33239287","title":"IGF2R-initiated proton rechanneling dictates an anti-inflammatory property in macrophages.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33239287","citation_count":60,"is_preprint":false},{"pmid":"11455432","id":"PMC_11455432","title":"Imprint status of M6P/IGF2R and IGF2 in chickens.","date":"2001","source":"Development genes and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/11455432","citation_count":59,"is_preprint":false},{"pmid":"15294879","id":"PMC_15294879","title":"Promoter-restricted histone code, not the differentially methylated DNA regions or antisense transcripts, marks the imprinting status of IGF2R in human and mouse.","date":"2004","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15294879","citation_count":59,"is_preprint":false},{"pmid":"8824797","id":"PMC_8824797","title":"Maternal-specific methylation of the human IGF2R gene is not accompanied by allele-specific transcription.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8824797","citation_count":59,"is_preprint":false},{"pmid":"19251056","id":"PMC_19251056","title":"Interactions of IGF-II with the IGF2R/cation-independent mannose-6-phosphate receptor mechanism and biological outcomes.","date":"2009","source":"Vitamins and hormones","url":"https://pubmed.ncbi.nlm.nih.gov/19251056","citation_count":58,"is_preprint":false},{"pmid":"19646808","id":"PMC_19646808","title":"Mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) in carcinogenesis.","date":"2009","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/19646808","citation_count":56,"is_preprint":false},{"pmid":"16037066","id":"PMC_16037066","title":"Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air.","date":"2005","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16037066","citation_count":56,"is_preprint":false},{"pmid":"11981765","id":"PMC_11981765","title":"M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan.","date":"2002","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/11981765","citation_count":55,"is_preprint":false},{"pmid":"18786520","id":"PMC_18786520","title":"Prenatal choline supplementation in rats increases the expression of IGF2 and its receptor IGF2R and enhances IGF2-induced acetylcholine release in hippocampus and frontal cortex.","date":"2008","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/18786520","citation_count":55,"is_preprint":false},{"pmid":"12975326","id":"PMC_12975326","title":"The histone code regulating expression of the imprinted mouse Igf2r gene.","date":"2003","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/12975326","citation_count":54,"is_preprint":false},{"pmid":"19141673","id":"PMC_19141673","title":"An in vitro ES cell imprinting model shows that imprinted expression of the Igf2r gene arises from an allele-specific expression bias.","date":"2009","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19141673","citation_count":54,"is_preprint":false},{"pmid":"31748500","id":"PMC_31748500","title":"Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31748500","citation_count":53,"is_preprint":false},{"pmid":"9076684","id":"PMC_9076684","title":"Paternal repression of the imprinted mouse Igf2r locus occurs during implantation and is stable in all tissues of the post-implantation mouse embryo.","date":"1997","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/9076684","citation_count":53,"is_preprint":false},{"pmid":"12507915","id":"PMC_12507915","title":"Tissue-specific inactivation of murine M6P/IGF2R.","date":"2003","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12507915","citation_count":49,"is_preprint":false},{"pmid":"20550582","id":"PMC_20550582","title":"An antioxidative mechanism mediated by the yeast N-acetyltransferase Mpr1: oxidative stress-induced arginine synthesis and its physiological role.","date":"2010","source":"FEMS yeast research","url":"https://pubmed.ncbi.nlm.nih.gov/20550582","citation_count":47,"is_preprint":false},{"pmid":"18073203","id":"PMC_18073203","title":"Cell surface-expressed cation-independent mannose 6-phosphate receptor (CD222) binds enzymatically active heparanase independently of mannose 6-phosphate to promote extracellular matrix degradation.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18073203","citation_count":46,"is_preprint":false},{"pmid":"18602895","id":"PMC_18602895","title":"Allele-specific targeting of hsa-miR-657 to human IGF2R creates a potential mechanism underlying the association of ACAA-insertion/deletion polymorphism with type 2 diabetes.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18602895","citation_count":45,"is_preprint":false},{"pmid":"16432260","id":"PMC_16432260","title":"High throughput detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer.","date":"2006","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/16432260","citation_count":43,"is_preprint":false},{"pmid":"11350125","id":"PMC_11350125","title":"Allelic IGF2R repression does not correlate with expression of antisense RNA in human extraembryonic tissues.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11350125","citation_count":41,"is_preprint":false},{"pmid":"16272133","id":"PMC_16272133","title":"N-acetyltransferase Mpr1 confers freeze tolerance on Saccharomyces cerevisiae by reducing reactive oxygen species.","date":"2005","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16272133","citation_count":41,"is_preprint":false},{"pmid":"9570384","id":"PMC_9570384","title":"Deletion of the M6P/IGF2r gene in primary hepatocellular carcinoma.","date":"1997","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/9570384","citation_count":40,"is_preprint":false},{"pmid":"32645488","id":"PMC_32645488","title":"Effect of prenatal bisphenol A exposure on early childhood body mass index through epigenetic influence on the insulin-like growth factor 2 receptor (IGF2R) gene.","date":"2020","source":"Environment international","url":"https://pubmed.ncbi.nlm.nih.gov/32645488","citation_count":40,"is_preprint":false},{"pmid":"11805093","id":"PMC_11805093","title":"Unregulated expression of the imprinted genes H19 and Igf2r in mouse uniparental fetuses.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11805093","citation_count":39,"is_preprint":false},{"pmid":"17850746","id":"PMC_17850746","title":"Structural insights into the interaction of insulin-like growth factor 2 with IGF2R domain 11.","date":"2007","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/17850746","citation_count":39,"is_preprint":false},{"pmid":"23197533","id":"PMC_23197533","title":"An exon splice enhancer primes IGF2:IGF2R binding site structure and function evolution.","date":"2012","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23197533","citation_count":38,"is_preprint":false},{"pmid":"34365465","id":"PMC_34365465","title":"Autophagy-associated circular RNA hsa_circ_0007813 modulates human bladder cancer progression via hsa-miR-361-3p/IGF2R regulation.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34365465","citation_count":37,"is_preprint":false},{"pmid":"28713781","id":"PMC_28713781","title":"The Metalloprotease, Mpr1, Engages AnnexinA2 to Promote the Transcytosis of Fungal Cells across the Blood-Brain Barrier.","date":"2017","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28713781","citation_count":36,"is_preprint":false},{"pmid":"34851695","id":"PMC_34851695","title":"The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C.","date":"2021","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34851695","citation_count":35,"is_preprint":false},{"pmid":"9722161","id":"PMC_9722161","title":"Imprinting of the mouse Igf2r gene depends on an intronic CpG island.","date":"1998","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9722161","citation_count":34,"is_preprint":false},{"pmid":"21056085","id":"PMC_21056085","title":"Protein intake during gestation affects postnatal bovine skeletal muscle growth and relative expression of IGF1, IGF1R, IGF2 and IGF2R.","date":"2010","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/21056085","citation_count":34,"is_preprint":false},{"pmid":"16575181","id":"PMC_16575181","title":"Cross-species clues of an epigenetic imprinting regulatory code for the IGF2R gene.","date":"2006","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16575181","citation_count":33,"is_preprint":false},{"pmid":"11474191","id":"PMC_11474191","title":"Sequence polymorphisms, allelic expression status and chromosome locations of the chicken IGF2 and MPR1 genes.","date":"2001","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11474191","citation_count":32,"is_preprint":false},{"pmid":"16452186","id":"PMC_16452186","title":"Delayed onset of Igf2-induced mammary tumors in Igf2r transgenic mice.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16452186","citation_count":32,"is_preprint":false},{"pmid":"26663757","id":"PMC_26663757","title":"Spatiotemporal Resolution of Rab9 and CI-MPR Dynamics in the Endocytic Pathway.","date":"2016","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/26663757","citation_count":32,"is_preprint":false},{"pmid":"9268631","id":"PMC_9268631","title":"Characterization of the C3 YAC contig from proximal mouse chromosome 17 and analysis of allelic expression of genes flanking the imprinted Igf2r gene.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9268631","citation_count":32,"is_preprint":false},{"pmid":"21273553","id":"PMC_21273553","title":"Soluble M6P/IGF2R released by TACE controls angiogenesis via blocking plasminogen activation.","date":"2011","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/21273553","citation_count":31,"is_preprint":false},{"pmid":"10347113","id":"PMC_10347113","title":"Failure to detect genetic alteration of the mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) gene in hepatocellular carcinomas in Japan.","date":"1999","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/10347113","citation_count":31,"is_preprint":false},{"pmid":"34335947","id":"PMC_34335947","title":"Trop2 binding IGF2R induces gefitinib resistance in NSCLC by remodeling the tumor microenvironment.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34335947","citation_count":31,"is_preprint":false},{"pmid":"31793167","id":"PMC_31793167","title":"Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy.","date":"2019","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31793167","citation_count":30,"is_preprint":false},{"pmid":"23227253","id":"PMC_23227253","title":"Quantitative allele-specific expression and DNA methylation analysis of H19, IGF2 and IGF2R in the human placenta across gestation reveals H19 imprinting plasticity.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23227253","citation_count":29,"is_preprint":false},{"pmid":"17150312","id":"PMC_17150312","title":"Igf-2r expression regulated by epigenetic modification and the locus of gene imprinting disrupted in cloned cattle.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/17150312","citation_count":29,"is_preprint":false},{"pmid":"17998818","id":"PMC_17998818","title":"Imprinting of opossum Igf2r in the absence of differential methylation and air.","date":"2006","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/17998818","citation_count":29,"is_preprint":false},{"pmid":"11163495","id":"PMC_11163495","title":"Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor (M6P/IGF2R) locus predisposes patients to radiation-induced lung injury.","date":"2001","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/11163495","citation_count":27,"is_preprint":false},{"pmid":"16777210","id":"PMC_16777210","title":"Zygote donor nitrogen metabolism and in vitro embryo culture perturbs in utero development and IGF2R expression in ovine fetal tissues.","date":"2006","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/16777210","citation_count":27,"is_preprint":false},{"pmid":"34485272","id":"PMC_34485272","title":"CircRNF111 Protects Against Insulin Resistance and Lipid Deposition via Regulating miR-143-3p/IGF2R Axis in Metabolic Syndrome.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34485272","citation_count":27,"is_preprint":false},{"pmid":"22521359","id":"PMC_22521359","title":"M6P/IGF2R modulates the invasiveness of liver cells via its capacity to bind mannose 6-phosphate residues.","date":"2012","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/22521359","citation_count":26,"is_preprint":false},{"pmid":"31391495","id":"PMC_31391495","title":"Detection and targeting insulin growth factor receptor type 2 (IGF2R) in osteosarcoma PDX in mouse models and in canine osteosarcoma tumors.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31391495","citation_count":26,"is_preprint":false},{"pmid":"16204191","id":"PMC_16204191","title":"Long-range DNase I hypersensitivity mapping reveals the imprinted Igf2r and Air promoters share cis-regulatory elements.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16204191","citation_count":26,"is_preprint":false},{"pmid":"24555901","id":"PMC_24555901","title":"Structure and function of MPN (Mpr1/Pad1 N-terminal) domain-containing proteins.","date":"2014","source":"Current protein & peptide science","url":"https://pubmed.ncbi.nlm.nih.gov/24555901","citation_count":25,"is_preprint":false},{"pmid":"11438990","id":"PMC_11438990","title":"Mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) variants in American and Japanese populations.","date":"2001","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/11438990","citation_count":25,"is_preprint":false},{"pmid":"11943459","id":"PMC_11943459","title":"Mitochondrial effects of the pleiotropic proteasomal mutation mpr1/rpn11: uncoupling from cell cycle defects in extragenic revertants.","date":"2002","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11943459","citation_count":24,"is_preprint":false},{"pmid":"12478591","id":"PMC_12478591","title":"Polymorphism of the MPR1 gene required for toxic proline analogue resistance in the Saccharomyces cerevisiae complex species.","date":"2002","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/12478591","citation_count":24,"is_preprint":false},{"pmid":"27744117","id":"PMC_27744117","title":"Targeted therapy of osteosarcoma with radiolabeled monoclonal antibody to an insulin-like growth factor-2 receptor (IGF2R).","date":"2016","source":"Nuclear medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/27744117","citation_count":24,"is_preprint":false},{"pmid":"25127865","id":"PMC_25127865","title":"The late endosomal transporter CD222 directs the spatial distribution and activity of Lck.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25127865","citation_count":23,"is_preprint":false},{"pmid":"25922844","id":"PMC_25922844","title":"The association of soluble IGF2R and IGF2R gene polymorphism with type 2 diabetes.","date":"2015","source":"Journal of diabetes research","url":"https://pubmed.ncbi.nlm.nih.gov/25922844","citation_count":23,"is_preprint":false},{"pmid":"29136764","id":"PMC_29136764","title":"Cardiac apoptosis induced under high glucose condition involves activation of IGF2R signaling in H9c2 cardiomyoblasts and streptozotocin-induced diabetic rat hearts.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/29136764","citation_count":23,"is_preprint":false},{"pmid":"21761181","id":"PMC_21761181","title":"The molecular basis of IGF-II/IGF2R recognition: a combined molecular dynamics simulation, free-energy calculation and computational alanine scanning study.","date":"2011","source":"Journal of molecular modeling","url":"https://pubmed.ncbi.nlm.nih.gov/21761181","citation_count":23,"is_preprint":false},{"pmid":"19208780","id":"PMC_19208780","title":"Structure and function of the human Gly1619Arg polymorphism of M6P/IGF2R domain 11 implicated in IGF2 dependent growth.","date":"2009","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19208780","citation_count":22,"is_preprint":false},{"pmid":"33704916","id":"PMC_33704916","title":"IGF2R circular RNA hsa_circ_0131235 expression in the middle temporal cortex is associated with AD pathology.","date":"2021","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/33704916","citation_count":22,"is_preprint":false},{"pmid":"33424850","id":"PMC_33424850","title":"Environmental Factor-Mediated Transgenerational Inheritance of Igf2r Hypomethylation and Pulmonary Allergic Response via Targeting Dendritic Cells.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33424850","citation_count":22,"is_preprint":false},{"pmid":"23818613","id":"PMC_23818613","title":"Structural and functional analysis of the yeast N-acetyltransferase Mpr1 involved in oxidative stress tolerance via proline metabolism.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23818613","citation_count":21,"is_preprint":false},{"pmid":"24968760","id":"PMC_24968760","title":"Knockdown of IGF2R suppresses proliferation and induces apoptosis in hemangioma cells in vitro and in vivo.","date":"2014","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24968760","citation_count":21,"is_preprint":false},{"pmid":"24613755","id":"PMC_24613755","title":"Effects of a novel SNP of IGF2R gene on growth traits and expression rate of IGF2R and IGF2 genes in gluteus medius muscle of Egyptian buffalo.","date":"2014","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24613755","citation_count":21,"is_preprint":false},{"pmid":"27140600","id":"PMC_27140600","title":"Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27140600","citation_count":21,"is_preprint":false},{"pmid":"24204972","id":"PMC_24204972","title":"Generation of five human lactoferrin transgenic cloned goats using fibroblast cells and their methylation status of putative differential methylation regions of IGF2R and H19 imprinted genes.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24204972","citation_count":21,"is_preprint":false},{"pmid":"17976054","id":"PMC_17976054","title":"Imprinted expression of the canine IGF2R, in the absence of an anti-sense transcript or promoter methylation.","date":"2007","source":"Evolution & development","url":"https://pubmed.ncbi.nlm.nih.gov/17976054","citation_count":20,"is_preprint":false},{"pmid":"20096471","id":"PMC_20096471","title":"Antioxidant N-acetyltransferase Mpr1/2 of industrial baker's yeast enhances fermentation ability after air-drying stress in bread dough.","date":"2010","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20096471","citation_count":20,"is_preprint":false},{"pmid":"16304558","id":"PMC_16304558","title":"Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer.","date":"2006","source":"Prostate cancer and prostatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/16304558","citation_count":19,"is_preprint":false},{"pmid":"30161190","id":"PMC_30161190","title":"The structure-function analysis of the Mpr1 metalloprotease determinants of activity during migration of fungal cells across the blood-brain barrier.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30161190","citation_count":19,"is_preprint":false},{"pmid":"25918552","id":"PMC_25918552","title":"Tissue-specific regulation of Igf2r/Airn imprinting during gastrulation.","date":"2015","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/25918552","citation_count":19,"is_preprint":false},{"pmid":"24014609","id":"PMC_24014609","title":"Epistasis between IGF2R and ADAMTS19 polymorphisms associates with premature ovarian failure.","date":"2013","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24014609","citation_count":19,"is_preprint":false},{"pmid":"32397873","id":"PMC_32397873","title":"Involvement of CASP9 (caspase 9) in IGF2R/CI-MPR endosomal transport.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/32397873","citation_count":18,"is_preprint":false},{"pmid":"24398995","id":"PMC_24398995","title":"Valproic acid substantially downregulated genes folr1, IGF2R, RGS2, COL6A3, EDNRB, KLF6, and pax-3, N-acetylcysteine alleviated most of the induced gene alterations in chicken embryo model.","date":"2013","source":"Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie","url":"https://pubmed.ncbi.nlm.nih.gov/24398995","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49985,"output_tokens":7248,"usd":0.129337,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16417,"output_tokens":6635,"usd":0.12398,"stage2_stop_reason":"end_turn"},"total_usd":0.253317,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"The mouse Igf2r locus contains two differentially methylated regions: region 1 (promoter, methylated on the silent paternal chromosome) and region 2 (intron 2 CpG island, methylated only on the expressed maternal chromosome). Region 2 methylation is inherited from the female gamete, whereas region 1 methylation is acquired post-fertilization, identifying the expressed maternal allele as carrying the imprinting signal.\",\n      \"method\": \"Cloning of 130 kb genomic locus; bisulfite/methylation analysis of parental-specific CpG methylation patterns\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct methylation mapping across entire locus in multiple tissues, foundational paper widely replicated\",\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) in intron 2: deletion of region 2 from YAC transgenes abolishes imprinting and restores biallelic Igf2r expression. Region 2 also serves as the promoter for an antisense RNA expressed from the paternal allele, whose production depends on region 2.\",\n      \"method\": \"YAC transgene experiments with region 2 deletion; allele-specific expression analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional deletion in transgenic mice with direct allelic expression readout, independently replicated\",\n      \"pmids\": [\"9338788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Silencing of Igf2r by Airn requires transcriptional overlap of Airn with the Igf2r promoter, which interferes with RNA Polymerase II recruitment. Spliced and unspliced Airn lncRNA products, nuclear size, and location are dispensable; only the act of transcription overlapping the Igf2r promoter is required.\",\n      \"method\": \"Endogenous truncation of Airn to different lengths in mice; RNA Pol II ChIP; allele-specific expression assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple endogenous truncation alleles with mechanistic ChIP readout, published in high-tier journal\",\n      \"pmids\": [\"23239737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"IGF2R/CI-MPR serves to clear IGF-II by targeting it for lysosomal degradation, thereby limiting IGF1R-mediated growth signaling. Genetic epistasis shows that Igf2r null-induced overgrowth and lethality are fully rescued by loss of either Igf2 or Igf1r.\",\n      \"method\": \"Mouse genetics: double and triple knockout epistasis (Igf2r/Igf2, Igf2r/Igf1r, Igf2r/Igf2/Igf1r null combinations); birthweight and survival analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis with multiple double/triple mutant combinations, definitive pathway placement\",\n      \"pmids\": [\"8806828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structures of IGF2R domains 11-12, 11-12-13-14, and the domains 11-12-13/IGF-II complex reveal that domain 11 directly contacts IGF-II and domain 13 modulates binding-site flexibility. Phe19 and Leu53 of IGF-II lock into a hydrophobic pocket unique to domain 11 of mammalian IGF2Rs. Mutagenesis confirms this hydrophobic 'binding-hotspot' and shows convergent evolution with IGF-binding proteins.\",\n      \"method\": \"X-ray crystallography of domain complexes; site-directed mutagenesis of IGF-II and IGF2R; binding assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus binding assays in one study\",\n      \"pmids\": [\"18046459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NMR-based models of the IGF2R domain 11/IGF-II interaction show that the interaction is driven by critical hydrophobic residues on both partners, with a ring of flexible charged residues on IGF2R modulating binding.\",\n      \"method\": \"Heteronuclear NMR combined with existing mutagenesis data; HADDOCK docking\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — solution NMR structure but computational docking model, single study\",\n      \"pmids\": [\"17850746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The DNA sequence encoding the IGF2-binding CD loop of monotreme IGF2R functions as an exon splice enhancer (ESE). Structural evolution of additional binding loops (AB, HI, FG) improved therian IGF2 affinity, indicating that ESE evolution drove the fortuitous acquisition of IGF2 binding by M6P/IGF2R, with subsequent imprinting accelerating affinity maturation.\",\n      \"method\": \"Comparative structural biology; ESE functional assays; surface plasmon resonance binding assays across species\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional ESE assay plus binding kinetics across multiple species, rigorous mechanistic dissection\",\n      \"pmids\": [\"23197533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Yeast surface display selection combined with structure-guided mutagenesis of domain 11 binding loops (AB, CD, FG, HI) achieved a 100-fold improvement in IGF2 affinity over IGF1, with NMR confirming increased AB-loop rigidity and structural analysis showing improved shape complementarity via interloop side-chain interactions. High-affinity domain 11 Fc fusions depleted pathological IGF2 isoforms from serum and abrogated IGF2-dependent signaling in vivo.\",\n      \"method\": \"Yeast surface display; surface plasmon resonance; NMR; X-ray crystallography; in vivo IGF2-dependent signaling assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal structural and functional methods, in vivo validation\",\n      \"pmids\": [\"27140600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A PACS-1/GGA3/CK2 complex regulates CI-MPR (IGF2R) trafficking between endosomes and the TGN. PACS-1 links GGA3 to CK2; CK2-mediated phosphorylation of GGA3 releases it from CI-MPR, while CK2 phosphorylation of PACS-1 Ser278 promotes PACS-1 binding to CI-MPR for TGN retrieval. Both GGA3 and PACS-1 bind an overlapping WLM-containing trafficking motif on CI-MPR.\",\n      \"method\": \"Co-immunoprecipitation; phosphorylation assays; siRNA knockdown; subcellular trafficking assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro phosphorylation cascade, functional trafficking readout\",\n      \"pmids\": [\"16977309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Retromer knockdown or knockout does not perturb CI-MPR (IGF2R) endosome-to-TGN transport, but knockdown of the retromer-linked SNX-BAR proteins (SNX1/2 with SNX5/6) causes pronounced CI-MPR transport defects. SNX5 and SNX6 associate with CI-MPR through a specific WLM endosomal sorting motif, coupling sequence-dependent cargo recognition with tubular profile biogenesis required for endosome-to-TGN transport.\",\n      \"method\": \"Knockout/knockdown of retromer components and SNX-BAR proteins; co-immunoprecipitation; CI-MPR trafficking assays; tubular endosome imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO plus reciprocal Co-IP plus trafficking assays; reappraises retromer dogma with multiple orthogonal methods\",\n      \"pmids\": [\"28935633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CASP9 localizes to the endosomal membrane and facilitates retrograde transport of IGF2R/CI-MPR from endosomes to the TGN via a non-apoptotic mechanism. CASP9-deficient cells show IGF2R degradation, cathepsin D missorting, and late endosome accumulation. A catalytically inactive CASP9 mutant rescues IGF2R stability. CASP9 interacts with retromer component VPS35 and SNX1-SNX5/SNX2-SNX6 dimers, as well as ESCRT-0 component HGS/HRS and clathrin heavy chain.\",\n      \"method\": \"CASP9 KO/KD; co-immunoprecipitation with retromer and SNX components; IGF2R trafficking and stability assays; cathepsin D sorting assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with functional rescue by catalytic mutant plus Co-IP with multiple interactors, single lab\",\n      \"pmids\": [\"32397873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CI-MPR (IGF2R) enters the endosomal pathway with Rab9 at the early-to-late endosome transition (Rab5-to-Rab7a stage), localizes transiently to separate domains on maturing endosomes, and Rab9 constitutively active mutant (Q66L) disperses CI-MPR and TGN46 from the Golgi without affecting retrograde transport of CI-MPR.\",\n      \"method\": \"Live confocal imaging; Rab9Q66L expression; colocalization studies in HeLa cells\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — live imaging with constitutively active mutant, multiple cell lines, single lab\",\n      \"pmids\": [\"26663757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IGF2R mediates EPC homing via Gi protein-linked signaling and requires intracellular Ca2+ mobilization induced by phospholipase C beta2 isoform. IGF2-induced hypoxic conditions stimulated EPC migration, recruitment, and neovascular incorporation; all actions were abolished by pertussis toxin (Gi inhibition) or PLCβ2 knockdown.\",\n      \"method\": \"In vitro EPC homing assays; pertussis toxin and siRNA-based inhibition; Ca2+ mobilization assays; in vivo angiogenesis model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibition with multiple functional readouts, single lab\",\n      \"pmids\": [\"18832656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Low-dose IGF2 activates IGF2R, leading to nuclear translocation of IGF2R that promotes Dnmt3a-mediated DNA methylation via GSK3α/β activation, thereby suppressing vacuolar-type H+-ATPase (v-ATPase) expression. Sequestration of v-ATPase assembly inhibits proton channeling to lysosomes and redirects protons to the mitochondrial intermembrane space, enabling sustained oxidative phosphorylation and an anti-inflammatory macrophage phenotype.\",\n      \"method\": \"Subcellular fractionation; nuclear translocation assay; Dnmt3a ChIP; v-ATPase expression analysis; mitochondrial proton channeling assay; IGF2R-specific IGF2 mutant treatment in colitis model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays in one study, in vivo validation with selective mutant, single lab\",\n      \"pmids\": [\"33239287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cell surface-expressed CI-MPR (IGF2R/CD222) binds enzymatically active heparanase independently of mannose 6-phosphate. Purified heparanase binds CIMPR-expressing mouse L cells (not CDMPR-expressing cells), remains at the cell surface for ~10 minutes, and tethering of heparanase to cell surfaces via CIMPR enhances extracellular matrix degradation.\",\n      \"method\": \"Binding assays with purified heparanase on transfected L cell lines; competition with M6P; ECM degradation assays; primary T cell activation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with receptor-expressing vs. non-expressing cell lines plus functional ECM readout, single lab\",\n      \"pmids\": [\"18073203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Soluble M6P/IGF2R (sM6P/IGF2R) is shed from human endothelial cells by TACE (ADAM-17). The shed ectodomain binds plasminogen, preventing its binding to cell surface and to uPA, thereby inhibiting plasminogen activation and blocking angiogenesis and cancer cell invasion.\",\n      \"method\": \"Specific TACE inhibitors and siRNA; plasminogen binding assays; in vitro invasion assay; in vivo endothelial invasion and tumor growth assays with M6P/IGF2R-derived peptide\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological plus RNAi inhibition with in vitro and in vivo functional readouts, single lab\",\n      \"pmids\": [\"21273553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD222 (IGF2R) controls spatial distribution and activity of Lck in T cells: knockdown of CD222 retains Lck in the cytosol, obstructing its recruitment to CD45 at the cell surface and resulting in predominant inhibitory phosphorylation of Lck (Tyr505), thereby impairing TCR-induced signaling and effector functions.\",\n      \"method\": \"CD222 siRNA knockdown with reconstitution; Lck localization by imaging/fractionation; Lck phosphorylation status; TCR signaling assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with reconstitution rescue, localization and phosphorylation readouts, single lab\",\n      \"pmids\": [\"25127865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"sCD22 binds to IGF2R on human myeloid cells (microglia-like cells) near critical mannose 6-phosphate-binding domains, disrupting lysosomal protein trafficking. Targeted truncation of IGF2R mapped the sCD22 docking site. Blocking the sCD22-IGF2R interaction with CD22 antibodies ameliorated lysosome dysfunction in NPC1 mutant iPSC-derived microglia-like cells.\",\n      \"method\": \"Unbiased genetic and proteomic screens; IGF2R truncation mapping; lysosomal trafficking assays; CD22 blocking antibody rescue in iPSC-derived microglia\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased screen plus domain truncation mapping plus functional rescue in human disease model, multiple orthogonal methods\",\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, leading to decreased lysosomal activity, abnormal cathepsin accumulation, dysfunction of autophagy and mitophagy, accumulation of misfolded proteins, and ROS production, ultimately inducing apoptosis. The M6P-binding function (not the IGF1R signaling antagonism) underlies these effects.\",\n      \"method\": \"siRNA knockdown of IGF2R; lysosomal activity assays; cathepsin localization; autophagy/mitophagy assays; apoptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple mechanistic readouts distinguishing M6P vs. IGF signaling functions, single lab\",\n      \"pmids\": [\"31748500\"],\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: reconstitution of IGF2R in receptor-deficient FRL14 cells restores intracellular cathepsin transport to lysosomes and reduces invasiveness; knockdown in receptor-positive hepatocytes increases cathepsin secretion and invasiveness. Functional M6P-binding sites, but not the IGF-II-binding capacity, are required for anti-invasive activity.\",\n      \"method\": \"Wild-type vs. M6P-binding-mutant IGF2R reconstitution in receptor-deficient cells; RNAi knockdown in receptor-positive cells; cathepsin secretion assays; ECM invasion assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function reconstitution plus loss-of-function KD, domain-function dissection with mutant receptor, multiple readouts\",\n      \"pmids\": [\"22521359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpression of Igf2r delays onset and reduces multiplicity of IGF-II-driven mammary tumors in Igf2-transgenic mice, providing in vivo genetic evidence that lysosomal targeting and degradation of IGF-II underlies the tumor suppressor activity of IGF2R.\",\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 / Moderate — in vivo genetic cross with quantitative tumor phenotype, single lab\",\n      \"pmids\": [\"16452186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Biallelic expression of Igf2r (via paternal inheritance of region 2-deleted non-imprinted allele) reduces late embryonic weight by ~20% persisting into adulthood, demonstrating that imprinting of Igf2r functions to increase birth weight. The non-imprinted allele also rescues lethality of maternally inherited Igf2r null allele and Tme mutation, establishing Igf2r as the Tme gene.\",\n      \"method\": \"Gene targeting in mouse ES cells to delete region 2; allele-specific expression analysis; body weight measurement; genetic rescue crosses\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precise endogenous gene targeting with multiple genetic cross outcomes and quantitative growth phenotypes\",\n      \"pmids\": [\"11311167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The Igf2r imprint control element (Region2/ICE) acts bidirectionally to regulate not only Igf2r but also two novel imprinted genes, Slc22a2 and Slc22a3, located 110 and 155 kb downstream; these genes are repressed on the paternal allele without being overlapped by the Air transcript, demonstrating ICE-mediated silencing independent of Air transcript overlap.\",\n      \"method\": \"Allele-specific expression analysis of Slc22a2 and Slc22a3 in mice with targeted region 2 deletions\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct allele-specific expression analysis in targeted deletion mice, definitive cluster organization\",\n      \"pmids\": [\"11562346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Continuous Airn expression is necessary and sufficient to maintain Igf2r silencing throughout ES cell differentiation, but only until the paternal Igf2r promoter acquires somatic DNA methylation. After methylation is established, Airn expression is no longer required. Airn initiation of silencing is not restricted to a single developmental window.\",\n      \"method\": \"Inducible Airn expression system in mouse ES cells; allele-specific Igf2r expression; DNA methylation analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible on/off system with temporal dissection of requirement, multiple epigenetic readouts\",\n      \"pmids\": [\"23444351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Allele-specific histone modifications at the Igf2r and Air promoters correlate with imprinting status across tissues: active alleles show acetylated H3/H4, H3K9-Ac, and H3K4-Me; silenced alleles show deacetylated H3K9 and unmethylated H3K4. Tri-methyl H3K9 (not di-methyl) marks the silenced Air allele. Treatment with 5-aza-dCyd and/or TSA partially reactivates the silenced Igf2r allele with concurrent biallelic histone acetylation.\",\n      \"method\": \"Allele-specific ChIP in Mus musculus × M. spretus interspecific mice; quantitative PCR; drug treatment (5-azadCyd, TSA)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — allele-specific ChIP with drug treatment rescue, single lab\",\n      \"pmids\": [\"15294879\"],\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 that stabilizes their association. Blockade of IGF2R with neutralizing antibodies increases proliferation and differentiation of myoblasts via the calmodulin/calcineurin/NFAT pathway, induces CD20 phosphorylation leading to SERCA activation, and removes intracellular Ca2+. In dystrophic mdx mice, anti-IGF2R treatment stimulates muscle regeneration and force recovery.\",\n      \"method\": \"Co-immunoprecipitation of IGF2R and CD20; IGF2R neutralizing antibody; calcineurin/NFAT pathway assays; SERCA activity; in vivo mdx mouse model\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus multiple downstream signaling readouts plus in vivo model, single lab\",\n      \"pmids\": [\"31793167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A 113-bp sequence within the Igf2r intron 2 DMR constitutes a methylation imprinting box containing two cis-acting elements: a de novo methylation signal and an allele-discrimination signal that bind specific proteins and are involved in establishing differential methylation at the Igf2r DMR.\",\n      \"method\": \"Deletion mapping and protein-binding assays (gel shift/footprint) of the 113-bp imprinting box; de novo methylation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cis-element deletion mapping with protein-binding assays, single lab but published in Nature\",\n      \"pmids\": [\"9892358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IGF2R-activated cardiac hypertrophy and apoptosis under high glucose conditions proceed through Gαq-mediated calcineurin-dependent signaling, upregulating ANP and BNP, downregulating p-Akt and p-Bad, and increasing cytochrome c and cleaved caspase-3.\",\n      \"method\": \"Immunoblotting; TUNEL assay; high-glucose treatment of H9c2 cells and STZ-diabetic rat hearts; expression analysis of calcineurin pathway components\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative pathway analysis without receptor-specific genetic rescue or mutagenesis\",\n      \"pmids\": [\"29136764\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGF2R (CI-MPR) is a multifunctional transmembrane receptor that traffics mannose-6-phosphate-tagged lysosomal enzymes from the trans-Golgi network to lysosomes via sequential interactions with GGA3 (TGN export), SNX5/SNX6-containing SNX-BAR complexes (endosomal tubular sorting), and PACS-1 (endosome-to-TGN retrieval, regulated by a CK2 phosphorylation cascade); it concurrently sequesters extracellular IGF-II through a hydrophobic binding pocket in domain 11 (modulated by domain 13), targeting it for lysosomal degradation to suppress IGF1R-mediated growth signaling, a function genetically validated as the mechanism of its tumor suppressor and growth-regulatory activities; its expression is controlled by genomic imprinting through an intronic CpG island (region 2/DMR2) that is maternally methylated and serves as the promoter for the paternal-allele-specific Airn lncRNA, whose transcriptional overlap with the Igf2r promoter (not the lncRNA product itself) silences paternal Igf2r by blocking RNA Pol II recruitment; additionally, IGF2R can signal through Gi/PLCβ2/Ca2+ to promote EPC homing, undergoes nuclear translocation to activate GSK3/Dnmt3a-mediated methylation suppressing v-ATPase in macrophages, and its retrograde endosomal recycling is facilitated by a non-apoptotic endosomal function of CASP9 acting through retromer and SNX-BAR complexes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IGF2R (the cation-independent mannose-6-phosphate receptor, CI-MPR) is a multifunctional transmembrane receptor that couples lysosomal enzyme trafficking to growth control and tissue homeostasis [#3, #18]. Through a hydrophobic binding pocket in domain 11, modulated by domain 13, it directly captures extracellular IGF-II via the IGF-II residues Phe19 and Leu53, and routes it for lysosomal degradation, thereby limiting IGF1R-mediated growth signaling [#4]; mouse genetics establishes this clearance function as the basis of its growth-regulatory and tumor-suppressor activity, since Igf2r-null overgrowth and lethality are fully rescued by loss of Igf2 or Igf1r, and Igf2r overexpression suppresses IGF-II-driven mammary tumors [#3, #20]. In parallel, its M6P-binding activity directs newly synthesized cathepsins from the Golgi to lysosomes; loss of this function causes cathepsin missorting, lysosomal and autophagic dysfunction, and increased pericellular cathepsin activity that promotes invasion [#18, #19]. Receptor recycling between endosomes and the trans-Golgi network is organized by an overlapping WLM-containing trafficking motif recognized by GGA3 and PACS-1 under control of a CK2 phosphorylation cascade, and by SNX1/2–SNX5/6 SNX-BAR complexes that drive tubular endosome-to-TGN transport independently of classical retromer; CASP9 facilitates this retrograde step non-catalytically through VPS35 and SNX-BAR dimers [#8, #9, #10]. Igf2r is subject to genomic imprinting: a maternally methylated intronic CpG island (region 2/DMR2) serves as the promoter for the paternally expressed Airn lncRNA, whose transcriptional overlap with the Igf2r promoter — not the lncRNA product — silences the paternal allele by blocking RNA Pol II recruitment, with somatic DNA methylation later locking in the silent state [#1, #2, #23]. Beyond these core roles, IGF2R has been linked to non-canonical surface and signaling functions including Gi/PLCβ2/Ca2+-dependent endothelial progenitor cell homing, nuclear translocation driving Dnmt3a-mediated v-ATPase suppression in macrophages, and modulation of Lck localization in T cells [#12, #13, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that the Igf2r locus carries two parental-specific methylation marks and identified which allele bears the gametic imprint, defining the molecular substrate of Igf2r imprinting.\",\n      \"evidence\": \"Cloning of the genomic locus and bisulfite/methylation mapping of parental CpG patterns\",\n      \"pmids\": [\"8462104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how region 2 methylation directs allele-specific expression\", \"No identification of trans-acting silencing machinery\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated that the intronic CpG island is functionally required for imprinting and is itself the promoter for a paternal antisense RNA, linking the methylation mark to a transcriptional silencing mechanism.\",\n      \"evidence\": \"YAC transgene region 2 deletion with allele-specific expression analysis in mice\",\n      \"pmids\": [\"9338788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether the lncRNA product or the act of transcription silences Igf2r\", \"Mechanism of Pol II interference unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapped cis-acting elements within the DMR that establish differential methylation, dissecting the imprinting box into de novo methylation and allele-discrimination signals.\",\n      \"evidence\": \"Deletion mapping and protein-binding/de novo methylation assays of a 113-bp box\",\n      \"pmids\": [\"9892358\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Bound proteins not definitively identified\", \"Single lab; cis-element function not validated at the endogenous locus\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Placed IGF2R definitively in the IGF growth axis by showing genetically that its function is to clear IGF-II and antagonize IGF1R signaling.\",\n      \"evidence\": \"Mouse double/triple knockout epistasis (Igf2r/Igf2/Igf1r) with growth and survival readouts\",\n      \"pmids\": [\"8806828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish the IGF-II clearance function from M6P-dependent enzyme trafficking\", \"No structural basis for IGF-II binding\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed in vivo that imprinting of Igf2r functions to control body weight and confirmed Igf2r as the Tme gene, and separately revealed the imprint control element silences neighboring genes independently of antisense overlap.\",\n      \"evidence\": \"Endogenous region 2 deletion in mice; growth measurement; rescue crosses; allele-specific expression of Slc22a2/Slc22a3\",\n      \"pmids\": [\"11311167\", \"11562346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of overlap-independent silencing of Slc22a2/3 unresolved\", \"Did not address developmental timing of the silencing requirement\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected imprinting status to a defined chromatin code, showing allele-specific histone modifications accompany silencing and that pharmacological reversal can reactivate the silent allele.\",\n      \"evidence\": \"Allele-specific ChIP in interspecific mice with 5-aza-dCyd/TSA treatment\",\n      \"pmids\": [\"15294879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative chromatin marks; causal hierarchy of methylation vs. histone marks unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the molecular machinery of receptor recycling, showing a PACS-1/GGA3/CK2 phosphorylation cascade governs CI-MPR shuttling between endosomes and the TGN through a shared trafficking motif.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro phosphorylation, siRNA, and trafficking assays\",\n      \"pmids\": [\"16977309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address the tubular carrier biogenesis step\", \"Relationship to retromer not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided in vivo genetic confirmation that lysosomal targeting of IGF-II underlies IGF2R tumor suppression.\",\n      \"evidence\": \"Igf2r-transgenic × Igf2-overexpressing mammary tumor mouse cross with tumor onset/multiplicity readout\",\n      \"pmids\": [\"16452186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not separate IGF-II degradation from M6P-cargo functions in tumor suppression\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the structural basis of IGF-II capture, identifying the domain 11 hydrophobic hotspot and domain 13 modulation that mediate high-affinity, mammal-specific IGF-II binding.\",\n      \"evidence\": \"X-ray crystallography of domain complexes, NMR/docking, and mutagenesis with binding assays\",\n      \"pmids\": [\"18046459\", \"17850746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NMR-based interaction model is computational (docking)\", \"Did not address full-length receptor avidity in membranes\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified an M6P-independent surface function, showing IGF2R tethers active heparanase at the cell surface to enhance extracellular matrix degradation.\",\n      \"evidence\": \"Heparanase binding on CIMPR- vs CDMPR-expressing L cells with M6P competition and ECM degradation assays\",\n      \"pmids\": [\"18073203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological significance of surface heparanase tethering not established in vivo\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed an unexpected G-protein signaling role, showing IGF2R drives endothelial progenitor cell homing via Gi/PLCβ2/Ca2+.\",\n      \"evidence\": \"Pertussis toxin and PLCβ2 siRNA inhibition with EPC homing and Ca2+ assays plus in vivo angiogenesis\",\n      \"pmids\": [\"18832656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct coupling of IGF2R to Gi not structurally defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that a TACE-shed IGF2R ectodomain acts in trans, sequestering plasminogen to inhibit its activation and block angiogenesis and invasion.\",\n      \"evidence\": \"TACE inhibition/siRNA, plasminogen binding, and in vitro/in vivo invasion assays\",\n      \"pmids\": [\"21273553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Relative contribution of soluble vs. membrane receptor in vivo unquantified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Settled the imprinting mechanism debate by demonstrating that Airn transcriptional overlap with the Igf2r promoter, not the lncRNA product, silences the paternal allele by interfering with Pol II recruitment.\",\n      \"evidence\": \"Endogenous Airn truncation alleles with Pol II ChIP and allele-specific expression in mice\",\n      \"pmids\": [\"23239737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain the transition to methylation-locked silencing\", \"Mechanism of Pol II exclusion at the promoter not fully resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reconstructed the evolutionary origin of IGF2 binding and dissected the M6P-binding function from IGF-II clearance in cancer cell invasion.\",\n      \"evidence\": \"Comparative structural biology with ESE assays and SPR across species; IGF2R reconstitution with M6P-binding mutants and cathepsin/invasion assays\",\n      \"pmids\": [\"23197533\", \"22521359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link evolutionary affinity changes to disease phenotypes\", \"Invasion study limited to liver cell models\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the temporal logic of imprinting maintenance, showing Airn is required to initiate and sustain silencing only until somatic DNA methylation of the paternal promoter takes over.\",\n      \"evidence\": \"Inducible Airn on/off system in ES cells with allele-specific expression and methylation analysis\",\n      \"pmids\": [\"23444351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the methyltransferase recruitment step\", \"Mechanism converting transcriptional interference to stable methylation unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Implicated IGF2R in adaptive immune signaling by showing it controls Lck localization and CD45 access required for TCR signaling in T cells.\",\n      \"evidence\": \"CD222 siRNA knockdown with reconstitution, Lck localization/phosphorylation, and TCR signaling assays\",\n      \"pmids\": [\"25127865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether Lck regulation depends on receptor trafficking vs. direct interaction unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Located the endosomal entry point of CI-MPR recycling, placing it at the Rab5-to-Rab7a transition with Rab9 involvement.\",\n      \"evidence\": \"Live confocal imaging and Rab9Q66L expression in HeLa cells\",\n      \"pmids\": [\"26663757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not establish functional requirement of Rab9 for retrograde transport\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Engineered high-affinity domain 11 variants demonstrating that the IGF-II binding module can be repurposed as an IGF2-depleting therapeutic.\",\n      \"evidence\": \"Yeast surface display, SPR, NMR, crystallography, and in vivo IGF2 signaling assays\",\n      \"pmids\": [\"27140600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Engineered reagent; not a statement about endogenous receptor regulation\", \"Long-term in vivo efficacy/safety not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reappraised retrograde transport machinery, showing SNX1/2–SNX5/6 SNX-BAR complexes, not classical retromer, mediate CI-MPR endosome-to-TGN transport via the WLM sorting motif.\",\n      \"evidence\": \"Retromer and SNX-BAR KO/KD, reciprocal Co-IP, trafficking and tubular endosome imaging\",\n      \"pmids\": [\"28935633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how WLM recognition couples to tubule formation mechanistically\", \"Other accessory factors in tubule scission unidentified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that the M6P-cargo function of IGF2R, independent of IGF1R antagonism, maintains lysosomal and autophagic integrity, loss of which triggers ROS-driven apoptosis.\",\n      \"evidence\": \"siRNA knockdown in cervical cancer cells with lysosomal, autophagy/mitophagy, and apoptosis readouts\",\n      \"pmids\": [\"31748500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Cell-type generality of the apoptotic outcome untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified IGF2R as a surface partner of the Ca2+ channel CD20 in muscle and a therapeutic target for promoting regeneration in dystrophy.\",\n      \"evidence\": \"Co-IP, IGF2R neutralizing antibody, calcineurin/NFAT and SERCA assays, and mdx mouse model\",\n      \"pmids\": [\"31793167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct IGF2R–CD20 binding interface not structurally mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Uncovered a non-apoptotic role for CASP9 in IGF2R retrograde recycling, acting through retromer and SNX-BAR components independently of catalytic activity.\",\n      \"evidence\": \"CASP9 KO/KD with catalytic-mutant rescue, Co-IP with VPS35/SNX/ESCRT components, and trafficking/sorting assays\",\n      \"pmids\": [\"32397873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How CASP9 mechanistically promotes tubular sorting unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a nuclear signaling branch in which low-dose IGF2-activated IGF2R drives Dnmt3a-mediated v-ATPase suppression to reprogram macrophage metabolism toward an anti-inflammatory phenotype.\",\n      \"evidence\": \"Subcellular fractionation, nuclear translocation assays, Dnmt3a ChIP, proton channeling assays, and a colitis model with selective IGF2 mutant\",\n      \"pmids\": [\"33239287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of IGF2R nuclear translocation and GSK3 activation unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified sCD22 as an IGF2R ligand that docks near M6P-binding domains and disrupts lysosomal trafficking, providing a druggable axis in lysosomal disease.\",\n      \"evidence\": \"Unbiased screens, IGF2R truncation mapping, lysosomal trafficking assays, and CD22 blocking antibody rescue in NPC1 iPSC-microglia\",\n      \"pmids\": [\"34851695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"sCD22 binding interface not structurally resolved\", \"Generality across other lysosomal diseases not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IGF2R integrates its canonical lysosomal-trafficking and IGF-II-clearance roles with its multiple non-canonical surface/nuclear signaling outputs (Gi/PLCβ2, CD20/SERCA, Lck, nuclear Dnmt3a) within a single physiological program remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model connecting trafficking and signaling functions\", \"Most non-canonical functions rest on single-lab evidence without structural mechanism\", \"Tissue-specific switching between functions not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [3, 18, 19]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [3, 4, 15]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [12, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [14, 15, 25]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [8, 9, 11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [8, 9, 10, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [8, 9, 10]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [18, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 12, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 23]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GGA3\", \"PACS1\", \"SNX5\", \"SNX6\", \"VPS35\", \"CASP9\", \"IGF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}