Affinage

IGF2

Insulin-like growth factor 2 · UniProt P01344

Round 2 corrected
Length
180 aa
Mass
20.1 kDa
Annotated
2026-04-28
130 papers in source corpus 38 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IGF2 encodes a paternally imprinted, secreted 67-amino-acid mitogenic peptide (processed from a 180-aa preproprotein) that signals through IGF-1R and insulin receptor isoform A (IR-A) to activate PI3K/Akt/GSK3β and MAPK pathways, functioning as an autocrine/paracrine growth factor in fetal development, placental endocrine signaling, β-cell mass regulation, muscle regeneration, and long-term memory consolidation (PMID:658418, PMID:6382021, PMID:26384384, PMID:37788670, PMID:37437545). Monoallelic paternal expression is enforced by allele-specific DNA methylation of the H19 imprinting control region, which governs CTCF/cohesin-dependent chromatin insulation and enhancer access; loss of imprinting leading to biallelic expression drives overexpression in Wilms' tumor, intestinal adenoma, and other cancers (PMID:10839546, PMID:19956766, PMID:8385745, PMID:16488992). IGF2 translation is post-transcriptionally regulated by the mTOR/p70S6K pathway, and its transcription is controlled by circadian regulators Per1/Per2, hypoxia-responsive Egr-1, and the oncogenic factor PLAG1 (PMID:7566093, PMID:34009269, PMID:10606246, PMID:14695992). In the hippocampus, pericyte-derived IGF2 acts through CIM6P/IGF2R to promote de novo protein synthesis required for long-term memory consolidation (PMID:37788670, PMID:32369018, PMID:21270887).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1978 High

    Establishing the primary identity of IGF-II as a distinct insulin-family peptide resolved the molecular basis of non-suppressible insulin-like activity in serum and enabled all subsequent functional studies.

    Evidence Protein purification and amino acid sequencing from human serum

    PMID:658418

    Open questions at the time
    • Post-translational processing pathway not yet elucidated
    • Receptor identity unknown
    • Genomic organization unknown
  2. 1984 High

    cDNA cloning revealed IGF2 is synthesized as a 180-aa preproprotein with an 89-aa E-peptide, defining the precursor-to-mature processing step and linking IGF2 to the insulin gene family.

    Evidence cDNA cloning and sequencing from human adult liver mRNA

    PMID:6382021 PMID:6382022

    Open questions at the time
    • Proprotein convertase(s) responsible for E-peptide cleavage not identified
    • Biological activity of E-peptide unknown
  3. 1993 High

    Demonstrating monoallelic paternal expression of IGF2 in normal tissues and biallelic expression (loss of imprinting) in Wilms' tumors established epigenetic deregulation as a cancer mechanism, opening the imprinting field to oncology.

    Evidence Allele-specific RT-PCR using exonic polymorphisms in human tumor and normal tissue cohorts

    PMID:8385745

    Open questions at the time
    • Molecular mechanism enforcing monoallelic silencing not yet identified
    • Causality of LOI in tumorigenesis versus bystander effect unresolved
  4. 1995 High

    Enhancer deletion and transgenic studies together established that IGF2 acts as both a local mitogen increasing cell number and a systemic growth factor controlling prenatal body size through shared enhancers 3′ of H19.

    Evidence Targeted enhancer deletion by homologous recombination in mice; keratin-driven Igf2 transgenic mice with tissue DNA content and growth measurements

    PMID:7524092 PMID:7544754

    Open questions at the time
    • Identity of tissue-specific enhancers beyond endoderm not mapped
    • Relative contributions of IGF-1R versus other receptors in fetal growth unknown
  5. 1995 High

    Discovery that IGF2 mRNA is stored in untranslated 100S ribonucleoprotein particles and mobilized via the mTOR/p70S6K pathway revealed a post-transcriptional control layer linking nutrient sensing to IGF2 protein output.

    Evidence Sucrose gradient sedimentation, rapamycin/anisomycin pharmacological inhibition, polysome profiling

    PMID:7566093

    Open questions at the time
    • RNA-binding proteins composing the 100S particle not identified
    • Cis-regulatory elements in IGF2 mRNA mediating translational repression unknown
  6. 2000 High

    Identification of the CTCF-dependent enhancer-blocking insulator at the H19 ICR, silenced on the paternal allele by CpG methylation, provided the mechanistic basis for allele-specific IGF2 expression and linked DNA methylation directly to chromatin insulator function.

    Evidence In vitro CTCF binding assays with methylated/unmethylated DNA; in vivo deletion of CTCF sites; episomal methylation propagation and insulator assays

    PMID:10839546 PMID:11509237

    Open questions at the time
    • How methylation is established and maintained at the paternal ICR during development not fully resolved
    • Contribution of individual CTCF sites versus cluster not dissected
  7. 2006 High

    Biallelic IGF2 expression in Apc(Min/+) mice accelerated intestinal adenoma growth and was rescued by a soluble IGF2R ligand trap, directly establishing IGF2 epigenetic dosage as a functional driver in intestinal tumorigenesis.

    Evidence Allelic dosage genetic crosses with Apc(Min/+); sIGF2R transgene rescue; intestinal crypt and adenoma measurements

    PMID:16488992

    Open questions at the time
    • Whether IGF2 acts on tumor cells, stroma, or both in this context not resolved
    • Therapeutic window for IGF2R-based ligand trapping not defined
  8. 2007 High

    Crystal structures of IGF2R domains 11-13 in complex with IGF-II revealed the hydrophobic binding pocket (Phe19, Leu53) for clearance/signaling via the mannose-6-phosphate receptor, showing convergent evolution with IGFBPs on the same IGF-II surface.

    Evidence X-ray crystallography of IGF2R domain complexes with site-directed mutagenesis validation

    PMID:18046459

    Open questions at the time
    • Full-length IGF2R structure and mechanism of IGF-II internalization/degradation not resolved
    • How domain 13 flexibility modulates affinity in vivo unknown
  9. 2009 High

    Cohesin was shown to be required for CTCF-mediated chromatin looping at the IGF2-H19 locus independently of its cohesion function, establishing the architectural co-dependence of CTCF and cohesin in imprinting control.

    Evidence 3C and RNAi-mediated cohesin depletion with allele-specific expression readout, cell-cycle phase analysis

    PMID:19956766

    Open questions at the time
    • Whether cohesin loading at the ICR requires CTCF directly or other factors not determined
    • Impact of cohesin mutations on IGF2 imprinting in human disease not tested
  10. 2011 High

    Intrahippocampal IGF-II injection enhanced memory consolidation and promoted persistent LTP through IGF2R (not IGF-1R), GSK3β, and de novo protein synthesis, establishing a cognitive function for IGF2 beyond its classical growth role.

    Evidence Recombinant IGF-II hippocampal injection, inhibitory avoidance learning, receptor antagonists, protein synthesis inhibitors, hippocampal slice electrophysiology

    PMID:21270887

    Open questions at the time
    • Cellular source of endogenous hippocampal IGF2 not identified at this point
    • Downstream translational targets mediating memory enhancement not catalogued
  11. 2013 High

    Discovery of a positive feedback loop in which the intronic miR-483-5p binds the 5′UTR of IGF2 mRNA in the nucleus and recruits RNA helicase DHX9 to enhance IGF2 transcription revealed an embedded cis-regulatory amplification circuit overexpressed in Wilms' tumor.

    Evidence Nuclear miRNA pulldown, DHX9 co-association assay, promoter-specific transcription assays, in vivo tumorigenesis in sarcoma model

    PMID:24298054

    Open questions at the time
    • Whether miR-483-5p feedback operates in non-tumor tissues unknown
    • Structural basis of 5′UTR recognition by miR-483-5p not resolved
  12. 2015 High

    β-cell-specific Igf2 knockout demonstrated that autocrine IGF2/IGF-1R signaling is required for adaptive β-cell mass expansion during pregnancy and insulin resistance, extending IGF2's role to metabolic adaptation in adults.

    Evidence Conditional β-cell Igf2 knockout mice with GSIS assays, glucose tolerance tests, β-cell morphometry under pregnancy and high-fat diet challenges

    PMID:26384384

    Open questions at the time
    • Whether human β-cells maintain IGF2 expression to the same extent as mouse not established
    • Downstream transcriptional program in β-cells not characterized
  13. 2021 High

    Per1/Per2 were found to recruit RNA Pol II and enable promoter-enhancer looping at the Igf2 locus, linking circadian regulation to muscle regeneration timing and explaining why regeneration is faster at circadian peaks of Igf2 expression.

    Evidence Per1/Per2 knockdown in myoblasts, in vivo muscle regeneration, ChIP for Pol II and histone marks, 3C, circadian timing experiments

    PMID:34009269

    Open questions at the time
    • Whether other clock genes participate in Igf2 regulation not tested
    • Mechanism by which Per proteins recruit Pol II to Igf2 promoters not elucidated
  14. 2023 High

    Cell-type-specific knockouts identified pericytes as the critical hippocampal source of learning-induced IGF2 that signals to neurons to promote IEG-dependent protein synthesis for long-term memory, completing a neurovascular signaling circuit (neuronal activity → pericyte IGF2 → neuron).

    Evidence Pericyte-, fibroblast-, and neuron-specific Igf2 knockout; scRNA-seq; behavioral memory tests; neuronal IEG protein measurement

    PMID:37788670

    Open questions at the time
    • Receptor (IGF2R vs. IGF-1R) mediating pericyte-to-neuron signaling not definitively resolved in this context
    • Mechanism of neuronal activity sensing by pericytes unknown
  15. 2023 High

    Placental endocrine cell-specific Igf2 deletion revealed that IGF2 controls protein synthesis and energy homeostasis within the placenta and orchestrates maternal metabolic adaptation (insulin resistance, prolactin), establishing IGF2 as a master regulator of the feto-maternal metabolic dialogue.

    Evidence Placental endocrine cell-specific Igf2 knockout mice with placental hormone, maternal insulin resistance, fetal glucose, and protein synthesis measurements

    PMID:37437545

    Open questions at the time
    • Whether IGF2 acts via IGF-1R or IR-A in placental endocrine cells not resolved
    • How placental IGF2 programs offspring adult metabolism remains mechanistically open

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of differential IGF2 signaling through IGF-1R versus IR-A, the identity of the translational repression complex sequestering IGF2 mRNA, how neuronal activity is communicated to pericytes to induce IGF2, and whether IGF2 LOI is sufficient to initiate (rather than accelerate) tumorigenesis independently of cooperating mutations.
  • No IGF2/IGF-1R co-crystal structure available
  • RNA-binding proteins in the 100S storage particle unidentified
  • Pericyte activity-sensing mechanism unknown
  • Causality of LOI alone in tumor initiation not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 6
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 6 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-4839726 Chromatin organization 5 R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1640170 Cell Cycle 2
Partners
CTCFDHX9IGF1RIGF2RINSRPER1PER2PLAG1

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1978 IGF-II (IGF2) was identified as a 67-amino acid single-chain polypeptide (sharing sequence homology with insulin and IGF-I) that accounts for the majority of insulin-like activity remaining in serum after insulin depletion, establishing its primary structure. Protein purification and primary structure determination FEBS letters High 658418
1984 IGF2 is encoded as a 180-amino acid preproprotein (preproIGF-II) containing a C-terminal E-peptide propeptide of 89 amino acids; the gene organization is related to the insulin gene family. cDNA cloning and sequencing of human IGF2 from adult liver mRNA Nature High 6382021 6382022
1987 Human IGF2 is transcribed from at least two promoters with developmentally regulated usage; fetal tissues predominantly use a distinct promoter compared to adult liver, and steady-state IGF2 transcript levels are dramatically reduced in adult compared to fetal organs, indicating a second level of transcriptional control independent of promoter usage. Northern blot analysis and transcript characterization in fetal and adult human tissues Development Medium 3503697
1993 IGF2 is monoallelically expressed (from the paternal allele) in normal human tissues; 69% of Wilms' tumors show biallelic (loss of imprinting) expression of IGF2, establishing loss of imprinting as an epigenetic mutational mechanism in cancer. Allele-specific RT-PCR using exonic polymorphisms in human tumor and normal tissues Nature High 8385745
1994 Excess IGF-II acts locally to increase cell number (DNA content) at sites of transgene expression (skin, alimentary canal, uterus) and has systemic effects on adult body weight, demonstrating distinct local and systemic growth-promoting actions of IGF-II in vivo. Keratin promoter-driven Igf2 transgenic mice; tissue DNA content and organ weight measurements Proceedings of the National Academy of Sciences of the United States of America High 7524092
1995 IGF2 and H19 share common endoderm-specific enhancers located 3' of H19; paternal inheritance of an enhancer deletion abolishes Igf2 expression in endodermal tissues, and mice inheriting the deletion paternally are ~80% of normal size, demonstrating that IGF-II acts systemically to affect prenatal growth. Targeted deletion of enhancers by homologous recombination; allele-specific expression analysis; growth measurement Genes & development High 7544754
1995 The major 6.0-kb IGF2 mRNA is stored untranslated in a 100S ribonucleoprotein particle in quiescent cells and is selectively mobilized and translated in exponentially growing cells; translational activation is blocked by rapamycin and mimicked by anisomycin, implicating the p70S6K/85S6K kinase signaling pathway in post-transcriptional regulation of IGF2. Sucrose gradient sedimentation, rapamycin/anisomycin pharmacological inhibition, polysome profiling in dispersed cells Nature High 7566093
1995 IGF-II reduces programmed cell death (apoptosis) in skeletal muscle myoblasts both in vivo and in vitro, demonstrating a survival/anti-apoptotic function for IGF-II in muscle. Primary mdx and C57Bl muscle cell cultures; in vivo mouse models; apoptosis assays Cell death and differentiation Medium 17180029
1999 Hypoxia induces IGF2 transcription from the P3 promoter in HepG2 cells through enhanced DNA-binding activity and increased expression of the transcription factor Egr-1; deletion of Egr-1 binding sites in the IGF2 P3 promoter abolishes hypoxic induction, and WT1 (a repressor) is simultaneously downregulated. Luciferase reporter assays, EMSA/supershift, RT-PCR, Western blot, Egr-1 cotransfection and promoter deletion analysis Cancer research High 10606246
2000 A CTCF-binding element upstream of H19 acts as an enhancer-blocking insulator controlling imprinted Igf2 expression; methylation of CpGs within CTCF-binding sites abolishes CTCF binding in vitro, and deletion of these sites eliminates enhancer-blocking activity in vivo, allowing biallelic Igf2 expression. Insulator activity is restricted to the maternal allele by paternal allele DNA methylation. In vitro CTCF binding assays with methylated/unmethylated substrates; deletion mutant transfection enhancer-blocking assays; allele-specific expression Nature High 10839546
2001 CpG methylation of the H19 imprinting control region (ICR) attenuates its CTCF-dependent insulator function; methylated ICR propagates stably in episomes, lacks nuclease hypersensitive sites, and fails to block enhancer-promoter communication, providing experimental support that methylation controls insulator activity. Episomal methylation propagation, nuclease sensitivity assay, insulator function assay in transfected Hep3B cells Current biology High 11509237
2002 Most known enhancers for Igf2 are located 3' of H19; a radiation-induced inversion (minute mutation) whose breakpoint disrupts a mesodermal enhancer downstream of H19 causes drastic downregulation of Igf2 in all mesodermal tissues and placenta upon paternal transmission, establishing the positions of mesodermal and extra-embryonic enhancers for Igf2. Genetic characterization of radiation-induced inversion; allele-specific expression analysis; maternal transmission effects on H19 DMR methylation Development High 11923202
2003 mTOR and amino acid sufficiency regulate IGF-II transcription through IGF2 promoter 3 and a downstream enhancer during C2C12 myoblast differentiation; mTOR's function in initiating differentiation targets IGF production (not IGF signaling), and this is independent of mTOR kinase activity but mediated by the PI3K-Akt pathway. Promoter-reporter assays, mTOR inhibition (rapamycin), PI3K-Akt pathway dissection, C2C12 myoblast differentiation assays The Journal of cell biology High 14662739
2004 The oncogenic transcription factor PLAG1 is amplified and overexpressed in hepatoblastoma and transactivates IGF2 from the embryonic P3 promoter, providing a mechanism for IGF2 upregulation in this tumor type. Luciferase reporter assay (PLAG1 transactivation of IGF2 P3), real-time RT-PCR, comparative genomic hybridization Genes, chromosomes & cancer Medium 14695992
2006 CTCF mediates interchromosomal colocalization between the Igf2/H19 imprinting control region on chromosome 7 and Wsb1/Nf1 on chromosome 11; omission of CTCF or deletion of the maternal ICR abrogates this association and alters Wsb1/Nf1 gene expression, demonstrating CTCF-mediated long-range interchromosomal gene regulation. Modified chromosome conformation capture (3C) and fluorescence in situ hybridization (FISH) Science High 16614224
2006 Increased Igf2 allelic dosage (biallelic expression via H19 maternal allele disruption) in Apc(Min/+) mice elongates intestinal crypts and increases adenoma growth independently of systemic growth; a soluble form of IGF-II/mannose-6-phosphate receptor (sIGF2R) acting as an IGF-II ligand trap rescues this phenotype, demonstrating functional potency of IGF2 epigenetic dosage in intestinal cancer. Mouse genetic crosses (Igf2 null, biallelic, monoallelic), sIGF2R transgene expression, intestinal crypt and adenoma measurements, nuclear beta-catenin staining Cancer research High 16488992
2007 Crystal structures of IGF2R domains 11-12-13/IGF-II complex reveal that IGF-II Phe19 and Leu53 lock into a hydrophobic pocket unique to domain 11 of mammalian IGF2R; domain 13 modulates binding site flexibility. Mutagenesis confirms this 'binding hotspot' and shows that IGFBP and IGF2R have converged on the same high-affinity IGF-II binding site. X-ray crystallography (crystal structures of IGF2R domains 11-12, 11-12-13-14, and 11-12-13/IGF-II complex), site-directed mutagenesis The EMBO journal High 18046459
2008 IGF2 activates PI3K/Akt and TGFβ signaling pathways in chondrocytes; PI3K-selective inhibitor LY294002 blocks Akt/GSK3β phosphorylation and abolishes IGF2-driven transcriptional upregulation of proteoglycans (Aggrecan and Versican), but does not suppress IGF2-induced TGFβ upregulation, indicating two independent signaling arms. Microarray gene expression analysis, Western blot (Akt, GSK3β phosphorylation), PI3K inhibitor (LY294002) experiments in C28/I2 chondrocyte cells Cell biology international Medium 18675921
2009 Cohesin is required for CTCF-mediated higher-order chromatin conformation at the IGF2-H19 locus; RNAi-mediated cohesin depletion disrupts allele-specific chromatin looping and coincides with changes in IGF2 expression; this conformation exists in both G1 and G2 phases, independent of cohesin's sister chromatid cohesion function. Chromosome conformation capture (3C), RNAi cohesin depletion, cell-cycle phase analysis, allele-specific expression PLoS genetics High 19956766
2011 In rats, IGF-II enhances memory retention and prevents forgetting when injected into the hippocampus; learning-induced hippocampal IGF-II expression requires the transcription factor C/EBPβ and is essential for memory consolidation. IGF-II-dependent memory enhancement requires IGF-II receptors, new protein synthesis, ARC function, and GSK3; it correlates with GSK3β activation and increased GluR1/GRIA1 AMPA receptor subunit expression. In hippocampal slices, IGF-II promotes IGF-II receptor-dependent persistent LTP after weak stimulation. Intrahippocampal recombinant IGF-II injection, inhibitory avoidance learning, receptor antagonists, protein synthesis inhibitors, hippocampal slice LTP, Western blot Nature High 21270887
2011 Endostatin inhibits IGF-II-induced migration and invasion of extravillous trophoblasts but not proliferation; endostatin interferes with IGF-II-activated downstream signaling kinases ERK1/2, Akt/mTOR/p70S6K, and focal adhesion kinase. Akt1-specific silencing demonstrates that endostatin-mediated inhibition of IGF-II-induced Akt phosphorylation is critically dependent on Akt1 isoform expression. Transwell migration/invasion assays, villous explant cultures, kinase Western blots, Akt1 shRNA silencing in SGHPL-5 trophoblast cells Endocrinology Medium 21933871
2012 Autocrine IGF2/IGF1R signaling in cancer-associated fibroblasts (CAFs) induces myofibroblast differentiation (α-SMA expression and gel contractility); paracrine IGF2 from CAFs activates pro-survival AKT signaling in colorectal cancer cells via IGF1R/insulin receptor axis; IGF2-mediated physical matrix remodeling by CAFs (not secreted factors) facilitates tumor cell invasion in organotypic co-cultures. CAF co-culture, IGF2 knockdown, AKT signaling Western blot, floating collagen gel contractility, organotypic invasion assay, xenograft models Oncogene High 28534511
2012 Akt1 and Igf2 null mutations independently decrease placental weight, fetal weight, and viability in mice; disruption of Igf2 does not affect AKT expression or activation, suggesting IGF2 acts upstream through additional effectors; Igf2 loss has more severe impact on prenatal survival and postnatal growth than Akt1 loss, with IGF2 contributing more to post-weaning growth. Genetic null mouse models (Akt1-/- and Igf2-/-) on CD1 background; placental, fetal, and postnatal growth phenotyping; AKT Western blot The International journal of developmental biology Medium 22562201
2012 Loss of p53 function creates Igf2 pathway dependency in vivo: developmental lethality occurs in p53 null mice lacking the paternal Igf2 allele; conditional Igf2 deletion attenuates rapid tumor onset in p53 null mice; biallelic Igf2 expression accelerates carcinoma/sarcoma formation in p53+/- females with reductions in p53 LOH and apoptosis. Conditional and germline Igf2/p53 double mutant mouse models; tumor incidence; gene expression profiling; apoptosis assays EMBO molecular medicine High 22674894
2013 An intronic miRNA, miR-483-5p, embedded within IGF2 acts in a positive feedback loop by binding the 5'UTR of fetal IGF2 mRNA in the nucleus, enhancing the association of RNA helicase DHX9 with the IGF2 transcript, and promoting IGF2 transcription from fetal promoters; miR-483-5p is specifically overexpressed in Wilms' tumors and its ectopic expression increases tumorigenesis in IGF2-dependent sarcoma cells in vivo. miRNA screen in Wilms' tumors, nuclear miRNA pulldown, DHX9 co-association assay, promoter-specific transcription assays, in vivo tumorigenesis Genes & development High 24298054
2013 5-Aza-2'deoxycytidine-induced demethylation of the H19 ICR in choriocarcinoma cells increases CTCF and cohesin recruitment, alters histone modifications, and reshapes chromatin looping such that a CTCF site downstream of H19 enhancers switches its association from the CTCF site upstream of IGF2 promoters to the ICR; a stable chromatin looping domain containing IGF2, marked by H3K27me3, forms independently of DNA methylation. 5-AzaCdR treatment, CTCF/cohesin ChIP, histone modification ChIP, chromosome conformation capture (3C), allele-specific expression Nucleic acids research High 23585276
2015 β-cell-specific inactivation of Igf2 in mice (βIGF2KO) reveals that autocrine IGF2 regulates adult β-cell mass and function: βIGF2KO mice show reduced glucose-stimulated insulin secretion in aged females, impaired β-cell mass expansion during pregnancy and acute insulin resistance, and blunted β-cell proliferation, demonstrating that IGF2 produced and secreted by β-cells autocrinally activates IGF-1 receptor signaling. β-cell conditional Igf2 knockout mice; GSIS assays; glucose tolerance tests; β-cell mass morphometry; pregnancy and high-fat diet challenges Diabetes High 26384384
2015 IGF2 protein functions are mediated through IGF-1R and the insulin receptor isoform A (IR-A); IGF-2 activates Akt phosphorylation and GSK3β phosphorylation, induces β-catenin levels, and protects ALS patient-derived motor neurons from degeneration; AAV9-delivered IGF-2 to muscles of SOD1(G93A) ALS mice extended lifespan by 10% while preserving motor neurons and inducing motor axon regeneration. IGF-2 addition to patient motor neuron cultures, Akt/GSK3β Western blot, AAV9 muscle delivery in SOD1(G93A) mice, motor neuron counting, neuromuscular junction analysis Scientific reports Medium 27180807
2016 NF-κB activated by HER2/HER3 signaling targets IGF2 as a key downstream effector to promote tumor sphere formation in breast cancer; IGF2-PI3K signaling induces expression of the stemness transcription factor ID1, which in turn drives further IGF2 expression, forming a positive feedback loop (IGF2-ID1-IGF2 circuit) maintaining breast cancer stem-like cells; anti-IGF1/2 antibodies block tumorigenesis from IGF1Rhigh CSC populations in patient-derived xenografts. ID1 knockdown, IGF2 knockdown, NF-κB inhibition, anti-IGF1/2 antibody treatment, tumor sphere formation assay, patient-derived xenograft model Oncogene High 27546618
2016 Paternal Igf2 is specifically expressed in adult hematopoietic stem cells (HSCs); Igf2 deficiency prevents age-related attrition of the HSC pool and is necessary for tissue homeostasis and regeneration, indicating that Igf2 expression level is critical to maintain the balance between HSC self-renewal and differentiation. Igf2 null adult mouse analysis; HSC pool quantification by flow cytometry; transplantation assays; in situ expression analysis EBioMedicine Medium 28007480
2019 Hypomethylation of an enhancer within the IGF2 gene in prefrontal cortex neurons of schizophrenia and bipolar disorder patients is associated with increased tyrosine hydroxylase (TH) protein levels; chromatin conformation analysis shows this IGF2 enhancer contacts the TH gene promoter; mouse Igf2 enhancer deletion disrupts TH protein levels, striatal dopamine, and neuronal transcriptomic/proteomic organization. Neuron-specific DNA methylation profiling, chromatin conformation capture, proteomics, mouse Igf2 enhancer deletion, TH Western blot, dopamine measurements Nature communications High 31053723
2020 Hippocampal CIM6P/IGF2R (cation-independent mannose-6-phosphate/IGF2 receptor) is necessary for memory consolidation but not learning, retrieval, or reconsolidation; CIM6P/IGF2R controls training-induced upregulation of de novo protein synthesis (Arc, Egr1, c-Fos) without affecting their mRNA induction; hippocampal or systemic mannose-6-phosphate administration enhances memory in a CIM6P/IGF2R-dependent manner. CIM6P/IGF2R pharmacological inhibition in rats, neuron-specific Cre knockdown in mice, protein synthesis measurement, Western blot for IEG proteins vs. mRNA, behavioral memory assays eLife High 32369018
2020 IGF-II acts through both IGF-1R and insulin receptor isoform A (IR-A); mature and 'big' IGF-II exhibit similar activation of IR-A and IR-B signaling, while pro-IGF-II exhibits significantly less activation; downstream Akt activation by mature and 'big' IGF-II is greater in IR-A than IR-B cells, consistent with greater IR-A affinity for IGF-II. IGF-II isoform fractionation from human plasma, signaling assays in IGF-IR-deficient cells expressing IR-A or IR-B, Akt Western blot Endocrinology Medium 21285309
2021 Circadian master regulators Per1 and Per2 are required for proper myoblast differentiation and muscle regeneration; Per1 and Per2 activate Igf2 transcription by recruiting RNA polymerase II, enabling dynamic histone modifications, and establishing promoter-enhancer interactions at the Igf2 locus; muscle regeneration is faster when initiated at night when Per1, Per2, and Igf2 are maximally expressed. Per1/Per2 knockdown in myoblasts, in vivo muscle regeneration, ChIP for RNA Pol II and histone marks, chromatin conformation capture, circadian timing experiments The Journal of cell biology High 34009269
2022 Hepatocyte-specific Igf2 deletion in SRSF3 knockout mice completely prevents hepatic fibrosis, inflammation, and tumor formation; in vitro, IGF2 treatment of HepG2 hepatoma cells decreases DNA repair enzyme expression and causes DNA damage, indicating that IGF2 overexpression promotes genomic instability and drives liver cancer. Double conditional knockout mice (Igf2/Srsf3); tumor incidence; DNA damage markers (γH2AX); DNA repair enzyme expression; IGF2 treatment of hepatoma cells in vitro Advanced science High 35615981
2023 Hippocampal IGF2 is most highly expressed in pericytes; learning significantly increases pericytic Igf2 expression in the hippocampus in a neuronal activity-dependent manner; pericyte-specific (but not fibroblast- or neuron-specific) Igf2 knockout impairs long-term memory and blunts learning-dependent neuronal immediate early gene (IEG) induction, establishing a neuronal activity → pericyte IGF2 → neuron signaling axis required for long-term memory. Cell-type specific Igf2 knockout (pericyte, fibroblast, neuron), single-cell RNA-seq, activity-dependent expression measurement, behavioral memory tests, neuronal IEG Western blot Neuron High 37788670
2023 Igf2 deletion in placental endocrine cells impairs placental endocrine signaling (including prolactin production) to the mother, reduces pregnancy-related insulin resistance, and restricts fetal growth and causes fetal hypoglycemia; Igf2 controls protein synthesis and cellular energy homeostasis in placental endocrine cells in a cell-type-dependent manner, and has long-lasting effects on offspring metabolism in adulthood. Placental endocrine cell-specific Igf2 knockout mice; placental hormone (prolactin) measurement; maternal insulin resistance testing; fetal growth and glucose measurement; protein synthesis and energy metabolism assays Cell metabolism High 37437545

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proceedings of the National Academy of Sciences of the United States of America 1901 18955703
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2000 Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 1371 10839546
2007 Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature genetics 1174 17554260
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1993 Relaxation of imprinted genes in human cancer. Nature 742 8385745
1978 Primary structure of human insulin-like growth factor II. FEBS letters 712 658418
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2004 The human plasma proteome: a nonredundant list developed by combination of four separate sources. Molecular & cellular proteomics : MCP 658 14718574
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1996 Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nature genetics 612 8589713
2003 Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science (New York, N.Y.) 565 12637750
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2007 A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 422 17632545
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2005 Insulin-like growth factor signaling in fish. International review of cytology 399 15797461
2002 Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. The Journal of biological chemistry 393 12138094
2006 CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1. Science (New York, N.Y.) 377 16614224
2009 Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nature genetics 348 19767753
1995 An enhancer deletion affects both H19 and Igf2 expression. Genes & development 348 7544754
1996 Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I and -II. The Journal of biological chemistry 340 8939990
1984 Sequence of a cDNA clone encoding human preproinsulin-like growth factor II. Nature 337 6382021
2011 A critical role for IGF-II in memory consolidation and enhancement. Nature 333 21270887
2009 Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child. PloS one 329 19924280
2016 Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nature genetics 316 27869826
2007 Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. The Journal of molecular diagnostics : JMD 290 17591929
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
1984 Insulin-like growth factor II precursor gene organization in relation to insulin gene family. Nature 270 6382022
2009 Cohesin is required for higher-order chromatin conformation at the imprinted IGF2-H19 locus. PLoS genetics 269 19956766
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