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Showing IGF2R — CI-M6PR is a alias.

IGF2R

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

Length
2491 aa
Mass
274.4 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1993 High

    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

    PMID:8462104

    Open questions at the time
    • Did not establish how region 2 methylation directs allele-specific expression
    • No identification of trans-acting silencing machinery
  2. 1997 High

    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

    PMID:9338788

    Open questions at the time
    • Did not resolve whether the lncRNA product or the act of transcription silences Igf2r
    • Mechanism of Pol II interference unknown
  3. 1999 Medium

    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

    PMID:9892358

    Open questions at the time
    • Bound proteins not definitively identified
    • Single lab; cis-element function not validated at the endogenous locus
  4. 1996 High

    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

    PMID:8806828

    Open questions at the time
    • Did not distinguish the IGF-II clearance function from M6P-dependent enzyme trafficking
    • No structural basis for IGF-II binding
  5. 2001 High

    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

    PMID:11311167 PMID:11562346

    Open questions at the time
    • Mechanism of overlap-independent silencing of Slc22a2/3 unresolved
    • Did not address developmental timing of the silencing requirement
  6. 2004 Medium

    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

    PMID:15294879

    Open questions at the time
    • Correlative chromatin marks; causal hierarchy of methylation vs. histone marks unresolved
    • Single lab
  7. 2006 High

    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

    PMID:16977309

    Open questions at the time
    • Did not address the tubular carrier biogenesis step
    • Relationship to retromer not tested
  8. 2006 Medium

    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

    PMID:16452186

    Open questions at the time
    • Single lab
    • Did not separate IGF-II degradation from M6P-cargo functions in tumor suppression
  9. 2007 High

    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

    PMID:17850746 PMID:18046459

    Open questions at the time
    • NMR-based interaction model is computational (docking)
    • Did not address full-length receptor avidity in membranes
  10. 2007 Medium

    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

    PMID:18073203

    Open questions at the time
    • Single lab
    • Physiological significance of surface heparanase tethering not established in vivo
  11. 2008 Medium

    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

    PMID:18832656

    Open questions at the time
    • Single lab
    • Direct coupling of IGF2R to Gi not structurally defined
  12. 2011 Medium

    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

    PMID:21273553

    Open questions at the time
    • Single lab
    • Relative contribution of soluble vs. membrane receptor in vivo unquantified
  13. 2012 High

    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

    PMID:23239737

    Open questions at the time
    • Did not explain the transition to methylation-locked silencing
    • Mechanism of Pol II exclusion at the promoter not fully resolved
  14. 2012 High

    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

    PMID:22521359 PMID:23197533

    Open questions at the time
    • Did not link evolutionary affinity changes to disease phenotypes
    • Invasion study limited to liver cell models
  15. 2013 High

    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

    PMID:23444351

    Open questions at the time
    • Did not identify the methyltransferase recruitment step
    • Mechanism converting transcriptional interference to stable methylation unknown
  16. 2014 Medium

    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

    PMID:25127865

    Open questions at the time
    • Single lab
    • Whether Lck regulation depends on receptor trafficking vs. direct interaction unresolved
  17. 2016 Medium

    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

    PMID:26663757

    Open questions at the time
    • Single lab
    • Did not establish functional requirement of Rab9 for retrograde transport
  18. 2016 High

    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

    PMID:27140600

    Open questions at the time
    • Engineered reagent; not a statement about endogenous receptor regulation
    • Long-term in vivo efficacy/safety not addressed
  19. 2017 High

    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

    PMID:28935633

    Open questions at the time
    • Did not define how WLM recognition couples to tubule formation mechanistically
    • Other accessory factors in tubule scission unidentified
  20. 2019 Medium

    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

    PMID:31748500

    Open questions at the time
    • Single lab
    • Cell-type generality of the apoptotic outcome untested
  21. 2019 Medium

    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

    PMID:31793167

    Open questions at the time
    • Single lab
    • Direct IGF2R–CD20 binding interface not structurally mapped
  22. 2020 Medium

    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

    PMID:32397873

    Open questions at the time
    • Single lab
    • How CASP9 mechanistically promotes tubular sorting unclear
  23. 2020 Medium

    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

    PMID:33239287

    Open questions at the time
    • Single lab
    • Mechanism of IGF2R nuclear translocation and GSK3 activation unresolved
  24. 2021 High

    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

    PMID:34851695

    Open questions at the time
    • sCD22 binding interface not structurally resolved
    • Generality across other lysosomal diseases not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 3 GO:0140313 molecular sequestering activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005768 endosome 4 GO:0005794 Golgi apparatus 3 GO:0005886 plasma membrane 3 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9609507 Protein localization 2
Partners
CASP9GGA3IGF2PACS1SNX5SNX6VPS35

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) 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. Cloning of 130 kb genomic locus; bisulfite/methylation analysis of parental-specific CpG methylation patterns Cell High 8462104
1997 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. YAC transgene experiments with region 2 deletion; allele-specific expression analysis Nature High 9338788
2012 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. Endogenous truncation of Airn to different lengths in mice; RNA Pol II ChIP; allele-specific expression assays Science High 23239737
1996 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. Mouse genetics: double and triple knockout epistasis (Igf2r/Igf2, Igf2r/Igf1r, Igf2r/Igf2/Igf1r null combinations); birthweight and survival analysis Developmental biology High 8806828
2007 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. X-ray crystallography of domain complexes; site-directed mutagenesis of IGF-II and IGF2R; binding assays The EMBO journal High 18046459
2007 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. Heteronuclear NMR combined with existing mutagenesis data; HADDOCK docking Structure Medium 17850746
2012 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. Comparative structural biology; ESE functional assays; surface plasmon resonance binding assays across species Science High 23197533
2016 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. Yeast surface display; surface plasmon resonance; NMR; X-ray crystallography; in vivo IGF2-dependent signaling assay Proceedings of the National Academy of Sciences of the United States of America High 27140600
2006 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. Co-immunoprecipitation; phosphorylation assays; siRNA knockdown; subcellular trafficking assays The EMBO journal High 16977309
2017 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. Knockout/knockdown of retromer components and SNX-BAR proteins; co-immunoprecipitation; CI-MPR trafficking assays; tubular endosome imaging The Journal of cell biology High 28935633
2020 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. CASP9 KO/KD; co-immunoprecipitation with retromer and SNX components; IGF2R trafficking and stability assays; cathepsin D sorting assays Autophagy Medium 32397873
2016 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. Live confocal imaging; Rab9Q66L expression; colocalization studies in HeLa cells Traffic Medium 26663757
2008 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. In vitro EPC homing assays; pertussis toxin and siRNA-based inhibition; Ca2+ mobilization assays; in vivo angiogenesis model Blood Medium 18832656
2020 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. Subcellular fractionation; nuclear translocation assay; Dnmt3a ChIP; v-ATPase expression analysis; mitochondrial proton channeling assay; IGF2R-specific IGF2 mutant treatment in colitis model Science advances Medium 33239287
2007 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. Binding assays with purified heparanase on transfected L cell lines; competition with M6P; ECM degradation assays; primary T cell activation experiments The Journal of biological chemistry Medium 18073203
2011 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. 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 Circulation research Medium 21273553
2014 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. CD222 siRNA knockdown with reconstitution; Lck localization by imaging/fractionation; Lck phosphorylation status; TCR signaling assays Journal of immunology Medium 25127865
2021 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. Unbiased genetic and proteomic screens; IGF2R truncation mapping; lysosomal trafficking assays; CD22 blocking antibody rescue in iPSC-derived microglia Science translational medicine High 34851695
2019 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. siRNA knockdown of IGF2R; lysosomal activity assays; cathepsin localization; autophagy/mitophagy assays; apoptosis assays Cell death & disease Medium 31748500
2012 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. 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 of hepatology High 22521359
2006 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. Igf2r transgenic mice crossed with Igf2-overexpressing mammary tumor mice; tumor onset and multiplicity analysis Cancer research Medium 16452186
2001 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. Gene targeting in mouse ES cells to delete region 2; allele-specific expression analysis; body weight measurement; genetic rescue crosses Development High 11311167
2001 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. Allele-specific expression analysis of Slc22a2 and Slc22a3 in mice with targeted region 2 deletions Genes & development High 11562346
2013 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. Inducible Airn expression system in mouse ES cells; allele-specific Igf2r expression; DNA methylation analysis Development High 23444351
2004 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. Allele-specific ChIP in Mus musculus × M. spretus interspecific mice; quantitative PCR; drug treatment (5-azadCyd, TSA) Human molecular genetics Medium 15294879
2019 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. Co-immunoprecipitation of IGF2R and CD20; IGF2R neutralizing antibody; calcineurin/NFAT pathway assays; SERCA activity; in vivo mdx mouse model EMBO molecular medicine Medium 31793167
1999 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. Deletion mapping and protein-binding assays (gel shift/footprint) of the 113-bp imprinting box; de novo methylation assays Nature Medium 9892358
2017 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. Immunoblotting; TUNEL assay; high-glucose treatment of H9c2 cells and STZ-diabetic rat hearts; expression analysis of calcineurin pathway components Biomedicine & pharmacotherapy Low 29136764

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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.) 409 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
1994 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. Development (Cambridge, England) 262 7720562
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
2017 Sequence-dependent cargo recognition by SNX-BARs mediates retromer-independent transport of CI-MPR. The Journal of cell biology 155 28935633
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
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 106 8595419
2001 Non-imprinted Igf2r expression decreases growth and rescues the Tme mutation in mice. Development (Cambridge, England) 101 11311167
2007 Structure and functional analysis of the IGF-II/IGF2R interaction. The EMBO journal 100 18046459
2000 M6P/IGF2R is mutated in squamous cell carcinoma of the lung. Oncogene 98 10734317
1998 The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R), a putative breast tumor suppressor gene. Breast cancer research and treatment 95 9516081
2007 N-Acetyltransferase Mpr1 confers ethanol tolerance on Saccharomyces cerevisiae by reducing reactive oxygen species. Applied microbiology and biotechnology 87 17387467
2003 Conservation of IGF2-H19 and IGF2R imprinting in sheep: effects of somatic cell nuclear transfer. Mechanisms of development 86 14654216
2009 Keeping IGF-II under control: lessons from the IGF-II-IGF2R crystal structure. Trends in biochemical sciences 82 19796953
2013 Imprinted Igf2r silencing depends on continuous Airn lncRNA expression and is not restricted to a developmental window. Development (Cambridge, England) 78 23444351
2006 A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking. The EMBO journal 78 16977309
2004 Role of the yeast acetyltransferase Mpr1 in oxidative stress: regulation of oxygen reactive species caused by a toxic proline catabolism intermediate. Proceedings of the National Academy of Sciences of the United States of America 78 15308773
2003 Imprinted silencing of Slc22a2 and Slc22a3 does not need transcriptional overlap between Igf2r and Air. The EMBO journal 73 12853484
2003 Erasure of methylation imprinting of Igf2r during mouse primordial germ-cell development. Molecular reproduction and development 71 12658632
1998 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. Molecular biology of the cell 68 9763452
2020 IGF2R-initiated proton rechanneling dictates an anti-inflammatory property in macrophages. Science advances 60 33239287
2004 Promoter-restricted histone code, not the differentially methylated DNA regions or antisense transcripts, marks the imprinting status of IGF2R in human and mouse. Human molecular genetics 59 15294879
2001 Imprint status of M6P/IGF2R and IGF2 in chickens. Development genes and evolution 59 11455432
1996 Maternal-specific methylation of the human IGF2R gene is not accompanied by allele-specific transcription. Genomics 59 8824797
2009 Interactions of IGF-II with the IGF2R/cation-independent mannose-6-phosphate receptor mechanism and biological outcomes. Vitamins and hormones 58 19251056
2009 Mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) in carcinogenesis. Cancer letters 56 19646808
2005 Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air. Human molecular genetics 56 16037066
2008 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. Brain research 55 18786520
2002 M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan. Hepatology (Baltimore, Md.) 55 11981765
2009 An in vitro ES cell imprinting model shows that imprinted expression of the Igf2r gene arises from an allele-specific expression bias. Development (Cambridge, England) 54 19141673
2003 The histone code regulating expression of the imprinted mouse Igf2r gene. Endocrinology 54 12975326
2019 Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins. Cell death & disease 53 31748500
1997 Paternal repression of the imprinted mouse Igf2r locus occurs during implantation and is stable in all tissues of the post-implantation mouse embryo. Mechanisms of development 53 9076684
2003 Tissue-specific inactivation of murine M6P/IGF2R. The American journal of pathology 49 12507915
2010 An antioxidative mechanism mediated by the yeast N-acetyltransferase Mpr1: oxidative stress-induced arginine synthesis and its physiological role. FEMS yeast research 47 20550582
2007 Cell surface-expressed cation-independent mannose 6-phosphate receptor (CD222) binds enzymatically active heparanase independently of mannose 6-phosphate to promote extracellular matrix degradation. The Journal of biological chemistry 46 18073203
2008 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. Biochemical and biophysical research communications 45 18602895
2006 High throughput detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer. Nucleic acids research 43 16432260
2005 N-acetyltransferase Mpr1 confers freeze tolerance on Saccharomyces cerevisiae by reducing reactive oxygen species. Journal of biochemistry 41 16272133
2001 Allelic IGF2R repression does not correlate with expression of antisense RNA in human extraembryonic tissues. Genomics 41 11350125
2020 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. Environment international 40 32645488
1997 Deletion of the M6P/IGF2r gene in primary hepatocellular carcinoma. Cancer letters 40 9570384
2007 Structural insights into the interaction of insulin-like growth factor 2 with IGF2R domain 11. Structure (London, England : 1993) 39 17850746
2002 Unregulated expression of the imprinted genes H19 and Igf2r in mouse uniparental fetuses. The Journal of biological chemistry 39 11805093
2012 An exon splice enhancer primes IGF2:IGF2R binding site structure and function evolution. Science (New York, N.Y.) 38 23197533
2021 Autophagy-associated circular RNA hsa_circ_0007813 modulates human bladder cancer progression via hsa-miR-361-3p/IGF2R regulation. Cell death & disease 37 34365465
2017 The Metalloprotease, Mpr1, Engages AnnexinA2 to Promote the Transcytosis of Fungal Cells across the Blood-Brain Barrier. Frontiers in cellular and infection microbiology 36 28713781
2021 The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C. Science translational medicine 35 34851695
2010 Protein intake during gestation affects postnatal bovine skeletal muscle growth and relative expression of IGF1, IGF1R, IGF2 and IGF2R. Molecular and cellular endocrinology 34 21056085
1998 Imprinting of the mouse Igf2r gene depends on an intronic CpG island. Molecular and cellular endocrinology 34 9722161
2006 Cross-species clues of an epigenetic imprinting regulatory code for the IGF2R gene. Cytogenetic and genome research 33 16575181
2016 Spatiotemporal Resolution of Rab9 and CI-MPR Dynamics in the Endocytic Pathway. Traffic (Copenhagen, Denmark) 32 26663757
2006 Delayed onset of Igf2-induced mammary tumors in Igf2r transgenic mice. Cancer research 32 16452186
2001 Sequence polymorphisms, allelic expression status and chromosome locations of the chicken IGF2 and MPR1 genes. Cytogenetics and cell genetics 32 11474191
1997 Characterization of the C3 YAC contig from proximal mouse chromosome 17 and analysis of allelic expression of genes flanking the imprinted Igf2r gene. Genomics 32 9268631
2021 Trop2 binding IGF2R induces gefitinib resistance in NSCLC by remodeling the tumor microenvironment. Journal of Cancer 31 34335947
2011 Soluble M6P/IGF2R released by TACE controls angiogenesis via blocking plasminogen activation. Circulation research 31 21273553
1999 Failure to detect genetic alteration of the mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) gene in hepatocellular carcinomas in Japan. Hepatology (Baltimore, Md.) 31 10347113
2019 Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy. EMBO molecular medicine 30 31793167
2012 Quantitative allele-specific expression and DNA methylation analysis of H19, IGF2 and IGF2R in the human placenta across gestation reveals H19 imprinting plasticity. PloS one 29 23227253
2006 Igf-2r expression regulated by epigenetic modification and the locus of gene imprinting disrupted in cloned cattle. Gene 29 17150312
2006 Imprinting of opossum Igf2r in the absence of differential methylation and air. Epigenetics 29 17998818
2021 CircRNF111 Protects Against Insulin Resistance and Lipid Deposition via Regulating miR-143-3p/IGF2R Axis in Metabolic Syndrome. Frontiers in cell and developmental biology 27 34485272
2006 Zygote donor nitrogen metabolism and in vitro embryo culture perturbs in utero development and IGF2R expression in ovine fetal tissues. Theriogenology 27 16777210
2001 Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor (M6P/IGF2R) locus predisposes patients to radiation-induced lung injury. International journal of radiation oncology, biology, physics 27 11163495
2019 Detection and targeting insulin growth factor receptor type 2 (IGF2R) in osteosarcoma PDX in mouse models and in canine osteosarcoma tumors. Scientific reports 26 31391495
2012 M6P/IGF2R modulates the invasiveness of liver cells via its capacity to bind mannose 6-phosphate residues. Journal of hepatology 26 22521359
2005 Long-range DNase I hypersensitivity mapping reveals the imprinted Igf2r and Air promoters share cis-regulatory elements. Genome research 26 16204191
2014 Structure and function of MPN (Mpr1/Pad1 N-terminal) domain-containing proteins. Current protein & peptide science 25 24555901
2001 Mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) variants in American and Japanese populations. Human mutation 25 11438990
2016 Targeted therapy of osteosarcoma with radiolabeled monoclonal antibody to an insulin-like growth factor-2 receptor (IGF2R). Nuclear medicine and biology 24 27744117
2002 Mitochondrial effects of the pleiotropic proteasomal mutation mpr1/rpn11: uncoupling from cell cycle defects in extragenic revertants. Gene 24 11943459
2002 Polymorphism of the MPR1 gene required for toxic proline analogue resistance in the Saccharomyces cerevisiae complex species. Yeast (Chichester, England) 24 12478591
2017 Cardiac apoptosis induced under high glucose condition involves activation of IGF2R signaling in H9c2 cardiomyoblasts and streptozotocin-induced diabetic rat hearts. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 29136764
2015 The association of soluble IGF2R and IGF2R gene polymorphism with type 2 diabetes. Journal of diabetes research 23 25922844
2014 The late endosomal transporter CD222 directs the spatial distribution and activity of Lck. Journal of immunology (Baltimore, Md. : 1950) 23 25127865
2011 The molecular basis of IGF-II/IGF2R recognition: a combined molecular dynamics simulation, free-energy calculation and computational alanine scanning study. Journal of molecular modeling 23 21761181
2021 IGF2R circular RNA hsa_circ_0131235 expression in the middle temporal cortex is associated with AD pathology. Brain and behavior 22 33704916
2020 Environmental Factor-Mediated Transgenerational Inheritance of Igf2r Hypomethylation and Pulmonary Allergic Response via Targeting Dendritic Cells. Frontiers in immunology 22 33424850
2009 Structure and function of the human Gly1619Arg polymorphism of M6P/IGF2R domain 11 implicated in IGF2 dependent growth. Journal of molecular endocrinology 22 19208780
2016 Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist. Proceedings of the National Academy of Sciences of the United States of America 21 27140600
2014 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. Gene 21 24613755
2014 Knockdown of IGF2R suppresses proliferation and induces apoptosis in hemangioma cells in vitro and in vivo. International journal of oncology 21 24968760
2013 Structural and functional analysis of the yeast N-acetyltransferase Mpr1 involved in oxidative stress tolerance via proline metabolism. Proceedings of the National Academy of Sciences of the United States of America 21 23818613
2013 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. PloS one 21 24204972
2010 Antioxidant N-acetyltransferase Mpr1/2 of industrial baker's yeast enhances fermentation ability after air-drying stress in bread dough. International journal of food microbiology 20 20096471
2007 Imprinted expression of the canine IGF2R, in the absence of an anti-sense transcript or promoter methylation. Evolution & development 20 17976054
2018 The structure-function analysis of the Mpr1 metalloprotease determinants of activity during migration of fungal cells across the blood-brain barrier. PloS one 19 30161190
2015 Tissue-specific regulation of Igf2r/Airn imprinting during gastrulation. Epigenetics & chromatin 19 25918552
2013 Epistasis between IGF2R and ADAMTS19 polymorphisms associates with premature ovarian failure. Human reproduction (Oxford, England) 19 24014609
2006 Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer. Prostate cancer and prostatic diseases 19 16304558
2020 Involvement of CASP9 (caspase 9) in IGF2R/CI-MPR endosomal transport. Autophagy 18 32397873
2013 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. Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie 18 24398995

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