Affinage

IGF2R

Cation-independent mannose-6-phosphate receptor · UniProt P11717

Length
2491 aa
Mass
274.4 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IGF2R (CI-MPR/CD222) is a multifunctional type I transmembrane receptor that serves dual roles as a clearance receptor for IGF-II and as a transporter of mannose 6-phosphate (M6P)-tagged lysosomal enzymes from the TGN to lysosomes. Genetic epistasis in mice demonstrates that IGF2R sequesters IGF-II for lysosomal degradation, limiting IGF1R-mediated growth signaling—loss of maternal Igf2r causes overgrowth and perinatal lethality rescued by elimination of IGF-II or IGF1R (PMID:8806828, PMID:8076514)—while its M6P-binding function independently prevents pericellular cathepsin accumulation and ECM invasion (PMID:22521359, PMID:31748500). Crystal structures reveal that IGF-II binds a hydrophobic pocket in extracellular domain 11, with domain 13 modulating flexibility, and the same binding surface is convergently recognized by IGF-binding proteins (PMID:18046459, PMID:11867533). Igf2r is subject to genomic imprinting controlled by a maternally methylated intronic CpG island (DMR2/region 2) that drives paternal-allele expression of the Airn lncRNA; Airn silences paternal Igf2r through transcriptional overlap of its promoter, interfering with RNA Pol II recruitment, and continuous Airn expression is required until somatic DNA methylation consolidates silencing (PMID:23239737, PMID:9338788, PMID:23444351).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1993 High

    Identification of two differentially methylated regions at the Igf2r locus—including a maternally methylated intronic CpG island (region 2) inherited from the oocyte—established the candidate imprinting control element and framed the question of how allele-specific expression is regulated.

    Evidence Genomic cloning and allele-specific methylation analysis in mouse embryos and gametes

    PMID:8462104

    Open questions at the time
    • Identity of trans-acting factors recognizing region 2 was unknown
    • Functional necessity of region 2 for imprinting was not yet tested
  2. 1993 High

    Genetic rescue of Igf2r-deficient (Tme) embryonic lethality by removing Igf2 demonstrated that IGF2R functions as a negative regulator of IGF-II bioavailability in vivo, answering the question of whether IGF2R's growth-suppressive role operates through IGF-II clearance.

    Evidence Genetic epistasis crossing Igf2 null with Thp (Igf2r locus) deletion mice

    PMID:8076514

    Open questions at the time
    • Whether M6P-mediated lysosomal enzyme trafficking contributes independently to lethality was unresolved
    • Mechanism of IGF-II internalization and degradation not biochemically defined
  3. 1996 High

    Triple and double mutant mouse crosses placed IGF2R upstream of IGF1R signaling and demonstrated that M6P-mediated lysosomal enzyme trafficking is independently essential for postnatal survival, separating the two major functions of the receptor.

    Evidence Igf2r × Igf2, Igf2r × Igf1r, and Igf2r × Igf2 × Igf1r null mouse crosses

    PMID:8806828

    Open questions at the time
    • Structural basis for IGF-II versus M6P binding discrimination unknown
    • Whether IGF2R signals independently of IGF-II clearance was unaddressed
  4. 1997 High

    YAC transgene experiments with region 2 deletion proved that the intronic CpG island is necessary for imprinted monoallelic Igf2r expression and serves as the promoter for a paternal-allele antisense RNA, answering how the imprinting control element functions.

    Evidence YAC transgenes with region 2 deletion; allele-specific expression and methylation analysis

    PMID:9338788

    Open questions at the time
    • Mechanism by which the antisense RNA silences Igf2r was unknown
    • Minimal cis-elements within region 2 were undefined
  5. 1999 High

    Fine-mapping of a 113-bp methylation imprinting box within DMR2 identified separable de novo methylation and allele-discrimination signals, defining the minimal regulatory architecture for differential methylation.

    Evidence Deletion mapping and protein-binding analysis in transgenic mice

    PMID:9892358

    Open questions at the time
    • Identity of proteins binding the allele-discrimination signal remained unknown
    • How these elements coordinate with chromatin modifications was unresolved
  6. 2001 High

    Biallelic Igf2r expression (via paternal region 2 deletion) caused growth restriction and rescued Tme lethality, demonstrating that the biological purpose of Igf2r imprinting is to limit receptor dosage and thereby increase birth weight.

    Evidence Gene targeting of region 2 on paternal allele in ES cells; weight phenotyping and Tme rescue

    PMID:11311167

    Open questions at the time
    • Whether imprinting-dependent dosage regulation operates in all tissues was untested
    • Postnatal physiological consequences of biallelic expression were incompletely characterized
  7. 2002 High

    The first crystal structure of IGF2R domain 11 revealed a flattened β-barrel fold with the IGF-II binding site at one end, providing the structural framework for understanding ligand recognition.

    Evidence X-ray crystallography at 1.4 Å resolution using anomalous sulfur scattering

    PMID:11867533

    Open questions at the time
    • Atomic details of the IGF-II:domain 11 interface were lacking
    • Role of neighboring domains in binding was unknown
  8. 2003 Medium

    Allele-specific ChIP established a histone code for Igf2r/Airn imprinting—active alleles carry H3K9-Ac and H3K4-Me while silent alleles carry deacetylated, unmethylated histones—and showed that biallelic Igf2r in neurons correlates with biallelic active marks despite maintained Airn expression.

    Evidence Allele-specific ChIP in interspecific crosses; pharmacological inhibitor treatments

    PMID:12975326

    Open questions at the time
    • Causal relationship between histone marks and silencing was not demonstrated
    • Mechanism of neuron-specific escape from imprinting was unexplained
  9. 2003 High

    Demonstration that Airn silences flanking genes Slc22a2/Slc22a3 independently of transcriptional overlap with the Igf2r promoter revealed that Airn has cis-silencing activity beyond simple transcriptional interference, raising the question of distinct silencing mechanisms at different targets.

    Evidence Igf2r promoter replacement/deletion in mice with allele-specific expression of Slc22a2/Slc22a3

    PMID:12853484

    Open questions at the time
    • Mechanism of Airn-mediated silencing of flanking genes was undefined
    • Whether Airn RNA product or transcription act mediates silencing at flanking loci was unclear
  10. 2006 High

    Discovery of the PACS-1/GGA3/CK2 phosphorylation cascade defined how CI-MPR is sorted between TGN and endosomes: CK2 phosphorylation of GGA3 releases CI-MPR at endosomes while CK2 phosphorylation of PACS-1 promotes endosome-to-TGN retrieval.

    Evidence Co-immunoprecipitation, kinase assays, RNAi, dominant-negative and phospho-mutant constructs

    PMID:16977309

    Open questions at the time
    • Whether additional kinases or adaptors regulate CI-MPR trafficking was unaddressed
    • In vivo relevance of the PACS-1 phosphorylation cascade was not tested
  11. 2006 Medium

    Igf2r transgene overexpression delayed mammary tumor onset in Igf2-overexpressing mice, providing direct in vivo evidence that IGF2R functions as a tumor suppressor through IGF-II degradation.

    Evidence Igf2r transgenic crossed with Igf2-overexpressing mammary tumor mice

    PMID:16452186

    Open questions at the time
    • Whether M6P-dependent cathepsin trafficking also contributes to tumor suppression was untested
    • Human tumor relevance was not directly addressed
  12. 2007 High

    Crystal structures of multi-domain IGF2R complexes with IGF-II resolved the binding interface: domain 11 engages IGF-II via a hydrophobic pocket contacting Phe19 and Leu53, while domain 13 modulates binding site flexibility, and mutagenesis confirmed this hotspot is shared with IGF-binding proteins.

    Evidence X-ray crystallography of domain 11–14 constructs ± IGF-II; site-directed mutagenesis; NMR-based docking

    PMID:17850746 PMID:18046459

    Open questions at the time
    • Full-length ectodomain structure was unavailable
    • pH-dependent conformational changes governing ligand release were not structurally characterized
  13. 2007 Medium

    CI-MPR was shown to bind enzymatically active heparanase at the cell surface in an M6P-independent manner, expanding the receptor's extracellular functions to include tethering of ECM-degrading enzymes.

    Evidence Binding assays in CI-MPR-transfected cells; M6P competition; ECM degradation assays

    PMID:18073203

    Open questions at the time
    • Heparanase binding site on IGF2R was not mapped
    • Physiological significance in vivo was not established
  14. 2009 Medium

    Kinetic allele-specific analysis during ES cell differentiation showed that Airn generates an expression bias (up to 10-fold maternal upregulation) rather than absolute paternal silencing, reframing the imprinting mechanism as dosage modulation.

    Evidence In vitro ES cell differentiation with allele-specific quantitative expression and ChIP

    PMID:19141673

    Open questions at the time
    • Whether this expression bias model applies in all tissues in vivo was untested
    • Factors driving maternal allele upregulation were unidentified
  15. 2011 Medium

    Identification of TACE/ADAM-17 as the sheddase generating soluble IGF2R revealed a new anti-angiogenic mechanism: shed sIGF2R binds plasminogen, preventing plasminogen activation and thereby inhibiting angiogenesis and tumor invasion.

    Evidence TACE inhibitors and RNAi; plasminogen binding assays; in vitro invasion and in vivo tumor models

    PMID:21273553

    Open questions at the time
    • Regulation of TACE-mediated shedding of IGF2R was not characterized
    • Relative contribution of sIGF2R versus membrane-bound IGF2R to anti-angiogenic activity was unclear
  16. 2012 High

    Endogenous truncation of Airn demonstrated that transcriptional overlap with the Igf2r promoter—not the Airn RNA product—is necessary and sufficient for paternal Igf2r silencing, resolving a long-standing mechanistic debate about whether the lncRNA or the act of transcription mediates silencing.

    Evidence Gene targeting to truncate Airn at different lengths; RNA Pol II ChIP; allele-specific expression

    PMID:23239737

    Open questions at the time
    • How transcriptional overlap blocks Pol II recruitment mechanistically was unresolved
    • Whether chromatin remodelers are recruited during the interference was unknown
  17. 2012 High

    Reconstitution of IGF2R in receptor-deficient liver cells showed that M6P-binding (not IGF-II binding) is required to prevent cathepsin hypersecretion and ECM invasion, establishing the M6P-trafficking function as the mechanism of IGF2R's anti-invasive activity in liver.

    Evidence Wild-type vs. M6P-binding mutant IGF2R reconstitution; cathepsin secretion and ECM invasion assays

    PMID:22521359

    Open questions at the time
    • Whether this mechanism operates in other cancer types was not tested
    • Specific M6P-tagged cathepsins responsible for invasion were not individually identified
  18. 2012 Medium

    Comparative binding analysis across species revealed that IGF2 binding by IGF2R originated through an exon splice enhancer in domain 11's CD loop in monotremes, with subsequent structural evolution of binding loops in therians improving affinity—linking splicing constraints to receptor evolution.

    Evidence ESE splicing assays; cross-species SPR binding measurements; structural loop comparisons

    PMID:23197533

    Open questions at the time
    • Whether imprinting truly accelerated affinity maturation is speculative
    • Ancestral IGF2R structure in non-mammalian vertebrates was not determined
  19. 2013 High

    Inducible Airn experiments showed that continuous Airn expression is required until somatic DNA methylation consolidates paternal Igf2r silencing, after which Airn becomes dispensable, defining a two-phase silencing model (Airn-dependent initiation → methylation-dependent maintenance).

    Evidence Inducible Airn on/off system in ES cells during differentiation; allele-specific expression and methylation

    PMID:23444351

    Open questions at the time
    • Identity of DNA methyltransferase(s) consolidating somatic methylation at Igf2r was not determined
    • Timing of the transition in vivo was not established
  20. 2014 Medium

    CD222/IGF2R was shown to control Lck spatial distribution and activity in T cells—knockdown traps Lck in the cytosol with inhibitory phosphorylation—revealing a previously unrecognized role for IGF2R in TCR signaling.

    Evidence siRNA knockdown with rescue; Lck localization by immunofluorescence; phospho-Lck blotting; T cell functional assays

    PMID:25127865

    Open questions at the time
    • Direct physical interaction between IGF2R and Lck was not demonstrated
    • Whether IGF2R trafficking of Lck is M6P-dependent was untested
  21. 2016 High

    Engineered domain 11 variants with 100-fold improved IGF2 affinity validated the structural basis of binding (AB-CD and FG-FG interloop contacts) and demonstrated therapeutic potential as IGF2 traps depleting pathological IGF2 isoforms in vivo.

    Evidence Yeast surface display; SPR; NMR; in vivo IGF2 depletion

    PMID:27140600

    Open questions at the time
    • Pharmacokinetics and long-term safety of domain 11 traps were not characterized
    • Selectivity over IGF1 binding was not fully profiled
  22. 2019 Medium

    IGF2R depletion in cancer cells disrupted Golgi-to-lysosome cathepsin transport, causing autophagy and mitophagy dysfunction with ROS accumulation, separating the M6P-trafficking contribution from IGF-II clearance in maintaining lysosomal homeostasis.

    Evidence siRNA knockdown; cathepsin trafficking, lysosomal activity, autophagy/mitophagy marker assays

    PMID:31748500

    Open questions at the time
    • Whether autophagy dysfunction is a direct or secondary consequence of cathepsin mistrafficking was unclear
    • Generalizability beyond cervical cancer cells was untested
  23. 2019 Medium

    Identification of an IGF2R–CD20 complex in myoblasts, where IGF2R blockade activates the calcineurin/NFAT pathway and promotes muscle regeneration in dystrophic mice, revealed a signaling axis linking IGF2R to calcium homeostasis and myogenesis.

    Evidence Co-immunoprecipitation; anti-IGF2R antibody; NFAT/calcineurin analysis; SERCA assay; mdx mouse model

    PMID:31793167

    Open questions at the time
    • Whether IGF2R–CD20 interaction is direct or mediated by adaptor proteins was not resolved
    • Mechanism linking IGF2R blockade to CD20 phosphorylation was not defined
  24. 2020 Medium

    IGF2R nuclear translocation upon low-dose IGF2 stimulation was shown to activate GSK3α/β and Dnmt3a-mediated methylation, suppressing v-ATPase expression and redirecting protons to mitochondria to sustain oxidative phosphorylation in macrophages, revealing an unexpected nuclear signaling role.

    Evidence Nuclear translocation imaging; GSK3 inhibition; Dnmt3a ChIP; v-ATPase assembly and mitochondrial proton flux assays; colitis mouse model

    PMID:33239287

    Open questions at the time
    • Mechanism of IGF2R nuclear import is unknown
    • Whether nuclear IGF2R retains receptor function or acts as a transcriptional co-regulator was not distinguished
  25. 2021 Medium

    Soluble CD22 was identified as an IGF2R ligand on myeloid cells that disrupts lysosomal trafficking, and blocking this interaction rescued lysosome dysfunction in NPC1-mutant microglia, establishing IGF2R as a node in neuroinflammatory lysosomal pathology.

    Evidence Unbiased proteomic screens; IGF2R domain truncation; lysosomal trafficking in iPSC-derived microglia

    PMID:34851695

    Open questions at the time
    • Precise IGF2R domains mediating sCD22 binding were not fully resolved
    • In vivo relevance in NPC1 disease models was not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the full-length ectodomain structure of IGF2R, the mechanism of IGF2R nuclear translocation and its nuclear targets, the molecular basis for tissue-specific escape from imprinting (e.g., neurons), and whether IGF2R's diverse signaling roles (Lck regulation, calcineurin/NFAT activation, macrophage metabolic reprogramming) operate through a unified trafficking mechanism or distinct receptor pools.
  • No full-length IGF2R ectodomain structure exists
  • Nuclear import mechanism undefined
  • Tissue-specific imprinting escape mechanism unknown
  • Integration of trafficking versus signaling functions not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005764 lysosome 3 GO:0005794 Golgi apparatus 3 GO:0005768 endosome 2 GO:0005886 plasma membrane 2 GO:0005576 extracellular region 1 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-9609507 Protein localization 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
CD22CSNK2A1GGA3IGF2MS4A1PACS1RAB9A

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 The mouse Igf2r locus contains two differentially methylated regions: region 1 (promoter, methylated on the silent paternal chromosome after fertilization) and region 2 (intron 2 CpG island, methylated only on the expressed maternal chromosome and inherited from the female gamete), identifying the maternally methylated intronic region as a candidate imprinting signal required for maternal-allele expression. Cloning of 130 kb genomic locus, methylation analysis of parental alleles in embryos and gametes Cell High 8462104
1997 Imprinted expression of mouse Igf2r depends on the intronic CpG island (region 2): YAC transgenes reproducing the full Igf2r locus show parental-specific methylation and monoallelic expression, but deletion of region 2 abolishes imprinting and restores biallelic expression. Region 2 also serves as the promoter for a paternal-allele antisense RNA whose production depends on region 2. YAC transgene experiments with region 2 deletion, allele-specific expression and methylation analysis Nature High 9338788
1996 IGF2R functions as a clearance receptor for IGF-II: mice lacking Igf2r (maternally inherited null allele) show elevated serum and tissue IGF-II, overgrowth, and perinatal lethality. Lethality is completely rescued by additional elimination of either IGF-II or IGF1R, placing IGF2R upstream of IGF1R-mediated signaling in growth control. Mannose 6-phosphate-mediated lysosomal enzyme trafficking is separately essential, as CD-MPR/CI-MPR double knockouts die postnatally even in an IGF-II null background. Genetic epistasis via double and triple mutant mouse crosses (Igf2r×Igf2, Igf2r×Igf1r, Igf2r×Igf2×Igf1r null backgrounds) Developmental biology High 8806828
1993 Genetic rescue of the T-associated maternal effect (Tme) lethal phenotype by removing Igf2 in Igf2r-deficient embryos demonstrates that the Tme lethality results from excess IGF-II signaling when IGF2R-mediated degradation is absent, establishing IGF2R as a negative regulator of IGF-II bioavailability in vivo. Genetic epistasis: crossing Igf2 null mice with Thp (Igf2r locus) deletion mice, rescue analysis at birth Development (Cambridge, England) High 8076514
1999 A 113-bp sequence within the Igf2r DMR2 constitutes a methylation imprinting box containing two cis-acting elements: a de novo methylation signal and an allele-discrimination signal that bind specific proteins, establishing the regulatory system for differential methylation at the Igf2r locus. Deletion mapping and protein-binding analysis of DMR2 sub-sequences in transgenic mouse system Nature High 9892358
2001 Biallelic expression of Igf2r (achieved by deleting region 2 from the paternal allele, creating a non-imprinted R2Δ allele) causes a 20% reduction in embryonic and adult weight, and rescues the Tme lethal phenotype, demonstrating that the biological function of Igf2r imprinting is to increase birth weight by restricting Igf2r expression to the maternal allele. Gene targeting in ES cells to delete region 2 on paternal allele; phenotypic analysis of R2Δ transgenic mice including weight measurements and rescue of Tme Development (Cambridge, England) High 11311167
2002 Crystal structure of IGF2R domain 11 at 1.4 Å resolution (solved by anomalous sulfur scattering) reveals two crossed beta-sheets forming a flattened beta-barrel, with the putative IGF-II binding site at one end of the barrel, providing the first structural basis for IGF-II binding by IGF2R. X-ray crystallography at 1.4 Å resolution using anomalous scattering of sulfur The EMBO journal High 11867533
2007 Crystal structures of IGF2R domains 11–12, 11–12–13–14, and the domain 11–12–13/IGF-II complex reveal that domain 11 directly binds IGF-II via a hydrophobic pocket engaging Phe19 and Leu53 of IGF-II, while domain 13 modulates binding site flexibility. Mutagenesis confirms this binding hotspot and shows that IGF-binding proteins and IGF2R have converged on the same high-affinity binding surface on IGF-II. X-ray crystallography of IGF2R domain complexes plus site-directed mutagenesis of binding interface residues The EMBO journal High 18046459
2007 NMR-based modeling of the IGF2/IGF2R domain 11 complex reveals that the interaction is driven by critical hydrophobic residues on both IGF2 and domain 11 of IGF2R, with a ring of flexible charged residues on IGF2R modulating binding affinity. Heteronuclear NMR combined with HADDOCK docking and existing mutagenesis data Structure (London, England : 1993) Medium 17850746
2012 Airn lncRNA silences Igf2r on the paternal allele through transcriptional overlap of the Igf2r promoter (interfering with RNA Pol II recruitment), not through its spliced or unspliced RNA products, nuclear size, or location. Shortening the Airn transcript demonstrated that only overlap with the Igf2r promoter is required for silencing. Endogenous truncation of Airn to different lengths by gene targeting; RNA Pol II ChIP; allele-specific expression analysis Science (New York, N.Y.) High 23239737
2003 Imprinted silencing of Slc22a2 and Slc22a3 (flanking Igf2r) by the Airn RNA does not require transcriptional overlap between Airn and Igf2r or the Igf2r promoter itself, indicating that Airn has intrinsic cis-silencing properties independent of transcriptional interference at Igf2r. Replacement of Igf2r promoter with thymidine kinase promoter and Igf2r promoter deletion in mice; allele-specific expression analysis of Slc22a2/Slc22a3 The EMBO journal High 12853484
2013 Continuous Airn lncRNA expression is required to maintain Igf2r silencing until the paternal Igf2r promoter acquires somatic DNA methylation; once methylated, Airn expression is dispensable. Airn-mediated initiation of Igf2r silencing is not restricted to a developmental window and can be maintained without DNA methylation, showing that Airn is both necessary and sufficient for silencing throughout ES cell differentiation. Inducible Airn expression system in ES cells; conditional Airn on/off during differentiation; allele-specific expression and methylation analysis Development (Cambridge, England) High 23444351
2006 A PACS-1/GGA3/CK2 complex regulates CI-MPR (IGF2R) sorting: PACS-1 links GGA3 to CK2; CK2 phosphorylates GGA3 to release it from CI-MPR at early endosomes, and phosphorylates PACS-1 Ser278 to promote PACS-1 binding to CI-MPR for endosome-to-TGN retrieval, constituting a phosphorylation cascade that coordinates opposing TGN export and endosomal retrieval of CI-MPR. Co-immunoprecipitation, kinase assays, RNA interference, dominant-negative and phospho-mutant constructs, subcellular fractionation The EMBO journal High 16977309
2016 Rab9 mediates delivery of CI-MPR (IGF2R) to the endosomal pathway at the early-to-late endosome transition (Rab5-positive to Rab7a-positive stage); constitutively active Rab9Q66L disperses CI-MPR from the Golgi without affecting retrograde transport; CI-MPR transiently localizes to distinct domains on maturing endosomes with rapid vesicle attachment/detachment. Live confocal imaging, Rab9 constitutively active mutant expression, colocalization and trafficking analysis in HeLa cells Traffic (Copenhagen, Denmark) Medium 26663757
2008 IGF2 promotes endothelial progenitor cell (EPC) homing predominantly through IGF2R-linked Gi protein signaling requiring intracellular Ca2+ mobilization via PLCβ2, not IGF1R. High-dose IGF2 shifts signaling to IGF1R. IGF2R activation enhances multiple steps of EPC homing in vitro and EPC recruitment and neovascularization in vivo. Receptor-specific antibody blockade, Gi inhibition with pertussis toxin, PLCβ2 knockdown, Ca2+ mobilization assays, in vitro homing assays, in vivo angiogenesis models Blood Medium 18832656
2007 Cell surface CI-MPR (IGF2R/CD222) binds enzymatically active heparanase in a mannose 6-phosphate-independent manner; binding is optimal at slightly acidic pH and tethers heparanase to the cell surface to promote extracellular matrix degradation. The cation-dependent MPR does not bind heparanase. Binding assays using transfected mouse L cells expressing human CIMPR, competition with mannose 6-phosphate, ECM degradation assays The Journal of biological chemistry Medium 18073203
2011 TACE (ADAM-17) mediates ectodomain shedding of M6P/IGF2R from human endothelial cells to generate soluble M6P/IGF2R (sM6P/IGF2R), which binds plasminogen, prevents plasminogen binding to the cell surface and uPA, thereby inhibiting plasminogen activation and blocking angiogenesis and tumor cell invasion in vitro and in vivo. TACE-specific inhibitors and RNAi; plasminogen binding assays; in vitro cell invasion assays; in vivo tumor growth model Circulation research Medium 21273553
2014 CD222 (CI-MPR/IGF2R) controls the spatial distribution and activity of Lck in T cells: CD222 knockdown causes Lck retention in the cytosol, prevents Lck recruitment to CD45 at the cell surface, and results in abundant inhibitory phosphorylation of Lck at steady state, thereby impairing TCR-induced signaling and T cell effector functions. CD222 siRNA knockdown; CD222 reconstitution rescue; Lck localization by immunofluorescence; phospho-Lck western blotting; T cell functional assays Journal of immunology (Baltimore, Md. : 1950) Medium 25127865
2012 M6P/IGF2R restricts liver cell invasion by preventing pericellular action of M6P-modified cathepsins: M6P/IGF2R-deficient fetal rat liver cells hypersecrete lysosomal cathepsins and invade ECM in a cathepsin-dependent manner; forced expression of wild-type IGF2R restores intracellular cathepsin transport and reduces invasion. Functional M6P-binding sites (not IGF-II binding capacity) are required for this anti-invasive activity. Reconstitution of M6P/IGF2R in receptor-deficient cells; RNAi knockdown in receptor-positive hepatocytes; cathepsin secretion assays; ECM invasion assays; wild-type vs. M6P-binding mutant IGF2R comparison Journal of hepatology High 22521359
2019 IGF2R and the store-operated Ca2+ channel CD20 share a common hydrophobic binding motif stabilizing their association; IGF2R blockade by neutralizing antibody increases myoblast proliferation and differentiation via the calmodulin/calcineurin/NFAT pathway, induces CD20 phosphorylation activating SERCA and removing intracellular Ca2+, and stimulates muscle regeneration in dystrophic mdx mice. Co-immunoprecipitation of IGF2R-CD20 complex; anti-IGF2R neutralizing antibody treatment; NFAT/calcineurin pathway analysis; SERCA activity assay; in vivo mdx mouse model EMBO molecular medicine Medium 31793167
2020 IGF2R activation by low-dose IGF2 triggers nucleus translocation of IGF2R, which promotes Dnmt3a-mediated DNA methylation via GSK3α/β activation, leading to impaired vacuolar-type H+-ATPase (v-ATPase) expression; sequestrated v-ATPase assembly inhibits proton channeling to lysosomes and redirects protons to mitochondria to sustain oxidative phosphorylation, thereby promoting an anti-inflammatory macrophage phenotype. IGF2R nuclear translocation imaging; GSK3α/β inhibition; Dnmt3a ChIP; v-ATPase assembly assays; mitochondrial proton flux measurements; IGF2R-specific IGF2 mutant; colitis mouse model Science advances Medium 33239287
2021 Soluble CD22 (sCD22) binds to IGF2R on human myeloid cells near the critical mannose 6-phosphate-binding domains (identified by targeted IGF2R truncation and proteomic screens), disrupting lysosomal protein trafficking. Blocking the sCD22-IGF2R interaction with CD22 antibodies ameliorates lysosome dysfunction in NPC1-mutant human microglia-like cells. Unbiased genetic and proteomic screens for CD22 binding partners; IGF2R domain truncation; flow cytometry; lysosomal trafficking assays in iPSC-derived microglia Science translational medicine Medium 34851695
2019 IGF2R depletion in cervical cancer cells disrupts Golgi-to-lysosome transport of M6P-tagged cathepsins, causing decreased lysosomal activity, abnormal cathepsin accumulation, and dysfunction of both autophagy and mitophagy leading to misfolded protein accumulation and ROS production; this is the M6P-receptor function of IGF2R rather than IGF1R signaling antagonism. IGF2R siRNA knockdown; cathepsin trafficking assays; lysosomal activity assays; autophagy/mitophagy markers; apoptosis assays Cell death & disease Medium 31748500
2006 Overexpression of Igf2r transgene in mice delays mammary tumor onset and decreases tumor multiplicity caused by Igf2 overexpression, providing in vivo genetic evidence that IGF2R tumor suppressor activity operates at least in part through degradation of IGF-II. Igf2r transgenic mice crossed with Igf2-overexpressing mammary tumor mice; tumor onset and multiplicity analysis Cancer research Medium 16452186
2012 An exon splice enhancer (ESE) encoded within the DNA sequence of the CD loop of IGF2R domain 11 in monotremes provided the initial fortuitous acquisition of IGF2 binding by M6P/IGF2R. Structural evolution of additional binding site loops (AB, HI, FG) in therians then improved IGF2 affinity, and the subsequent imprinting of IGF2R may have accelerated affinity maturation through parental conflict. ESE mapping by splicing assays; species comparison of IGF2:domain 11 binding by surface plasmon resonance; structural analysis of binding loops Science (New York, N.Y.) Medium 23197533
2016 Yeast surface display selection identified novel mutations in IGF2R domain 11 binding loops (AB, CD, FG, HI) that collectively achieve a 100-fold improvement in IGF2 binding affinity and twofold reduction in koff; the structural basis is improved shape complementarity through interloop (AB-CD) and intraloop (FG-FG) side chain interactions confirmed by NMR. High-affinity domain 11 Fc fusion proteins act as IGF2 traps that deplete pathological IGF2 isoforms and abrogate IGF2-dependent signaling in vivo. Yeast surface display selection; surface plasmon resonance; NMR structural analysis; in vivo IGF2 depletion assay Proceedings of the National Academy of Sciences of the United States of America High 27140600
2003 Active alleles of both Igf2r and Air are associated with acetylated histones H3/H4, H3K9-Ac, and H3K4-Me, while silenced alleles are associated with methylated DNA, deacetylated H3K9, and unmethylated H3K4. In neurons, biallelic Igf2r expression correlates with biallelic histone acetylation and H3K4 methylation at DMR1, despite maintained imprinted Air expression, establishing a histone code for Igf2r/Air imprinting. Chromatin immunoprecipitation (ChIP) with allele-specific analysis in Mus musculus × Mus spretus interspecific mice; 5-aza-deoxycytidine and TSA treatment experiments Endocrinology Medium 12975326
2009 During in vitro ES cell differentiation, Airn ncRNA expression leads to gain of repressive epigenetic marks on the paternal Igf2r promoter but does not silence the paternal Igf2r promoter per se; instead, Airn generates an expression bias by allowing up to 10-fold increase of maternal Igf2r expression while paternal expression remains constant, indicating imprinting arises from allele-specific expression bias rather than direct paternal silencing. In vitro ES cell differentiation; allele-specific quantitative expression analysis of Igf2r and Airn; ChIP for repressive histone marks on paternal Igf2r promoter Development (Cambridge, England) Medium 19141673

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture. Nature genetics 606 11175780
1993 Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell 540 8462104
1997 Imprinted expression of the Igf2r gene depends on an intronic CpG island. Nature 476 9338788
2012 Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science (New York, N.Y.) 407 23239737
1996 Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. Developmental biology 384 8806828
1995 M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nature genetics 323 7493029
2000 The imprinted antisense RNA at the Igf2r locus overlaps but does not imprint Mas1. Nature genetics 219 10802648
1993 Functional polymorphism in the parental imprinting of the human IGF2R gene. Biochemical and biophysical research communications 204 8267611
2000 M6P/IGF2R imprinting evolution in mammals. Molecular cell 202 10882106
2001 Bidirectional action of the Igf2r imprint control element on upstream and downstream imprinted genes. Genes & development 146 11562346
2008 Endothelial progenitor cell homing: prominent role of the IGF2-IGF2R-PLCbeta2 axis. Blood 128 18832656
1993 Rescue of the T-associated maternal effect in mice carrying null mutations in Igf-2 and Igf2r, two reciprocally imprinted genes. Development (Cambridge, England) 124 8076514
1999 The imprinting box of the mouse Igf2r gene. Nature 110 9892358
1995 Conservation of a maternal-specific methylation signal at the human IGF2R locus. Human molecular genetics 105 8595419
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