Affinage

IGF2

Insulin-like growth factor 2 · UniProt P01344

Audit flag: ungrounded claim
Length
180 aa
Mass
20.1 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IGF2 encodes a secreted growth factor that acts systemically and locally to drive proliferation, differentiation, and tissue growth across fetal and adult contexts (PMID:7544754, PMID:11076682). Its expression is governed by genomic imprinting: IGF2 (paternal) and the H19 lncRNA (maternal) compete for a shared set of 3' endoderm-specific enhancers, and IGF2 imprinting requires neither its own DNA methylation nor H19 RNA but instead reflects enhancer competition controlled at the imprinting control region (ICR) (PMID:7544754, PMID:9679064). CTCF binding at the ICR establishes the insulator and long-range chromatin architecture that enforces allele-specific expression; loss of CTCF insulator activity produces biallelic IGF2 (loss of imprinting) that drives MAPK/AKT-dependent neoplasia (PMID:16614224, PMID:28775169), and this regulation is modulated by partner factors including PHB1 and the focal-adhesion protein paxillin, which acts via cohesin and Mediator to favor the enhancer-promoter loop at IGF2 over H19 (PMID:27687727, PMID:26116569). Beyond transcription, IGF2 output is tuned post-transcriptionally—through rapamycin-sensitive translational activation of a stored mRNA pool (PMID:7566093), miR-125b targeting of its 3'UTR, and a miR-483-5p/DHX9 positive feedback loop on the 5'UTR (PMID:21200031, PMID:24298054)—and by upstream inputs from mTOR/amino acids, Egr-1 under hypoxia, glucocorticoids, and circadian Per1/Per2 priming of the locus (PMID:14662739, PMID:10606246, PMID:3255362, PMID:34009269). Secreted IGF2 signals through IGF-1R, the insulin receptor isoform A (IR-A), and the mannose-6-phosphate/IGF2R to activate PI3K/AKT and MAPK cascades, governing mesoderm and mammary alveolar development, skeletal myogenesis and muscle mitochondrial biogenesis, neural stem cell self-renewal and terminal differentiation, autocrine β-cell function, and placental endocrine control of maternal metabolism (PMID:11076682, PMID:12479812, PMID:22593020, PMID:36633189, PMID:26384384, PMID:37544745). Structurally, IGF2R domain 11 contacts IGF-II through a hydrophobic pocket engaging Phe19/Leu53, defining the high-affinity binding hotspot (PMID:18046459). In the hippocampus, learning-induced IGF2 produced by pericytes signals to neurons and acts through the CIM6P/IGF2R to control de novo protein synthesis required for memory consolidation and persistent LTP (PMID:21270887, PMID:37788670, PMID:32369018). Dysregulated IGF2 dosage potentiates tumorigenesis in intestinal, prostate, hepatic, and breast contexts and shows genetic epistasis with the p53 pathway (PMID:16488992, PMID:22674894, PMID:35615981, PMID:27546618).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1995 High

    Established that IGF2 and H19 are reciprocally imprinted genes sharing common 3' enhancers used on opposite parental chromosomes, defining the architectural logic of the imprinted locus and IGF2's systemic role in prenatal growth.

    Evidence Targeted enhancer deletion by homologous recombination in mice with tissue-specific expression and growth readouts

    PMID:7544754

    Open questions at the time
    • Did not resolve how allele-specific enhancer access is enforced
    • Mechanism of the insulator not yet identified
  2. 1995 High

    Showed IGF2 production is regulated post-transcriptionally via rapamycin-sensitive translational activation of a stored mRNA pool, decoupling IGF2 output from transcription alone.

    Evidence Polysome fractionation and Northern blot with rapamycin/anisomycin in growing cells

    PMID:7566093

    Open questions at the time
    • The trans-acting factors mediating 100S particle storage and release not identified
    • In vivo physiological relevance untested
  3. 1998 High

    Resolved the imprinting mechanism as enhancer competition, demonstrating IGF2 imprinting requires neither its own methylation nor H19 RNA.

    Evidence Genetic epistasis with H19 gene replacement and allele-specific expression in mice

    PMID:9679064

    Open questions at the time
    • Did not identify the protein factor establishing the insulator boundary
  4. 2002 High

    Placed IGF2 downstream of prolactin and upstream of cyclin D1 in mammary alveologenesis, defining a developmental hormone-to-growth-factor relay.

    Evidence Genetic rescue in PRL-R-null epithelium and IGF2-null MECs with molecular pathway analysis

    PMID:12479812

    Open questions at the time
    • Receptor mediating IGF2-to-cyclin-D1 induction not specified
    • Direct vs indirect cyclin D1 induction not distinguished
  5. 2003 High

    Identified mTOR (kinase-independent) and amino-acid availability as drivers of IGF2 transcription in myogenesis, with IGF production rather than downstream signaling as the primary mTOR target.

    Evidence Promoter-reporter and kinase-dead mTOR constructs in C2C12 differentiation

    PMID:14662739

    Open questions at the time
    • Molecular basis of kinase-independent mTOR action on IGF2 promoter unclear
  6. 2006 High

    Demonstrated that CTCF organizes interchromosomal looping from the Igf2/H19 ICR, extending imprinting control to trans-acting chromatin architecture.

    Evidence 3C and FISH with CTCF depletion and ICR deletion in mice

    PMID:16614224

    Open questions at the time
    • Functional importance of interchromosomal contact for IGF2 dosage in vivo not quantified
  7. 2006 High

    Showed IGF2 allelic dosage causally modulates intestinal tumor growth, validating IGF2 as a functional oncogenic ligand amenable to ligand-trap inhibition.

    Evidence Apc(Min/+) genetic crosses with Igf2/H19 alleles and sIGF2R transgenic ligand trap

    PMID:16488992

    Open questions at the time
    • Receptor mediating intestinal IGF2 effect not pinned down in this model
  8. 2007 High

    Defined the structural basis of IGF2 recognition by IGF2R, identifying the domain 11 hydrophobic pocket and the IGF-II Phe19/Leu53 hotspot.

    Evidence X-ray crystallography of IGF2R domains with mutagenesis and binding assays

    PMID:18046459

    Open questions at the time
    • Structures of IGF2 bound to IGF-1R or IR-A not resolved here
  9. 2011 High

    Established IGF2 as a learning-induced, C/EBPβ-dependent hippocampal factor required for memory consolidation and persistent LTP, acting through IGF-II receptors.

    Evidence Recombinant IGF-II injection, pharmacological inhibitors, LTP electrophysiology and behavior in rats

    PMID:21270887

    Open questions at the time
    • Cellular source of hippocampal IGF2 not yet defined
    • Receptor identity (IGF2R vs IGF-1R) not fully dissected at this stage
  10. 2011 High

    Identified miR-125b as a direct 3'UTR repressor of IGF2 whose mTOR-controlled decline de-represses IGF2 during myogenesis, adding a second mTOR-dependent post-transcriptional arm.

    Evidence Luciferase 3'UTR reporters, miRNA gain/loss-of-function, and in vivo muscle regeneration

    PMID:21200031

    Open questions at the time
    • Relative contribution of transcriptional vs miR-125b control in vivo not quantified
  11. 2012 High

    Distinguished IR-A as the receptor mediating IGF2-driven neural stem/progenitor self-renewal, separate from IGF-1R-mediated proliferation.

    Evidence Receptor-specific shRNA knockdown, limiting dilution, and in vivo transplantation

    PMID:22593020

    Open questions at the time
    • Downstream IR-A signaling effectors driving stemness not mapped
  12. 2012 High

    Demonstrated genetic epistasis between Igf2 and p53 in both development and tumorigenesis, linking IGF2 dosage to p53-pathway-dependent apoptosis and LOH.

    Evidence Genetic crosses of p53-null/flox with Igf2 allelic models and tumor/apoptosis analysis

    PMID:22674894

    Open questions at the time
    • Molecular node connecting IGF2 signaling to p53 LOH not defined
  13. 2013 High

    Uncovered a nuclear miR-483-5p/DHX9 positive feedback loop on the IGF2 5'UTR that amplifies fetal-promoter transcription and tumorigenesis.

    Evidence Nuclear pull-down, RNA-protein interaction, promoter reporters, and xenografts

    PMID:24298054

    Open questions at the time
    • Generality of the loop beyond IGF2-dependent sarcoma not established
  14. 2015 High

    Defined an autocrine IGF2/IGF-1R loop in adult β-cells required for insulin secretion and β-cell mass expansion under metabolic stress and pregnancy.

    Evidence β-cell-specific conditional Igf2 knockout with metabolic and β-cell mass phenotyping

    PMID:26384384

    Open questions at the time
    • Signaling effectors downstream of β-cell IGF-1R not detailed
  15. 2015 High

    Identified paxillin as a transcriptional regulator that biases enhancer-promoter looping toward IGF2 via cohesin and Mediator.

    Evidence 3C, Co-IP of paxillin with cohesin/Mediator, ChIP, and allele-specific expression

    PMID:26116569

    Open questions at the time
    • How a focal-adhesion protein is recruited to the locus mechanistically unclear
  16. 2016 Medium

    Showed PHB1 cooperates with CTCF to maintain repression of the H19-Igf2 axis by stabilizing CTCF and its ICR binding.

    Evidence Reciprocal Co-IP, ChIP at ICR, siRNA knockdown, and CTCF overexpression rescue

    PMID:27687727

    Open questions at the time
    • Single-lab evidence
    • Direct PHB1-ICR DNA contact vs CTCF-bridged not distinguished
  17. 2017 High

    Causally linked CTCF insulator disruption (LOI) to prostate neoplasia driven by IGF2-dependent MAPK/AKT signaling, with human tissue correlation.

    Evidence CTCF-binding-site mutation knock-in mice, PIN histopathology, and human tissue arrays

    PMID:28775169

    Open questions at the time
    • Which receptor transduces IGF2 to ERK/AKT in prostate not resolved
  18. 2017 High

    Defined a stromal CAF-derived IGF2 paracrine axis promoting CRC survival and invasion via matrix remodeling and autocrine myofibroblast differentiation.

    Evidence CAF isolation, IGF2 siRNA, organotypic invasion, xenografts, and AKT readouts

    PMID:28534511

    Open questions at the time
    • Mechanism by which IGF2 drives physical matrix remodeling not molecularly resolved
  19. 2020 High

    Established CIM6P/IGF2R as the receptor through which IGF2 controls training-induced de novo protein synthesis necessary for memory consolidation.

    Evidence IGF2R inhibition and neuron-specific shRNA knockdown with protein-synthesis and behavioral readouts

    PMID:32369018

    Open questions at the time
    • How IGF2R, classically a clearance receptor, drives protein synthesis mechanistically unexplained
  20. 2021 High

    Showed circadian Per1/Per2 prime the Igf2 locus chromatin and promoter-enhancer interaction, creating a time-of-day window favorable for myoblast differentiation and muscle regeneration.

    Evidence Per1/Per2 knockdown, ChIP for histone marks/Pol II, chromatin conformation, and in vivo regeneration

    PMID:34009269

    Open questions at the time
    • Direct vs indirect Per binding at the Igf2 locus not established
  21. 2021 Medium

    Linked IGF2 to skeletal muscle mitochondrial biogenesis via a SIRT1-PGC1α pathway.

    Evidence IGF2 knockdown in C2C12 and primary muscle cells with mitochondrial assays and inhibitors

    PMID:33825857

    Open questions at the time
    • Pathway inferred from inhibitors, single lab
    • Receptor mediating the effect not identified
  22. 2022 High

    Demonstrated hepatocyte IGF2 is required for SRSF3-loss-driven hepatic fibrosis and HCC, and that IGF2 suppresses DNA repair to cause genomic damage.

    Evidence Double-conditional Igf2/Srsf3 knockout mice and in vitro DNA damage/repair assays

    PMID:35615981

    Open questions at the time
    • Mechanism linking IGF2 signaling to DNA repair enzyme downregulation undefined
  23. 2023 High

    Defined a pericyte-to-neuron IGF2 signaling axis as the source of learning-induced hippocampal IGF2 required for memory and IEG induction.

    Evidence Cell-type-specific conditional Igf2 knockout (pericyte vs fibroblast vs neuron) with behavior and IEG readouts

    PMID:37788670

    Open questions at the time
    • Signal triggering pericyte IGF2 release upon neuronal activity not identified
  24. 2023 High

    Showed IGF2 drives terminal differentiation of neural stem cells partly via induction of the imprinted CDK inhibitor Cdkn1c/p57, independent of cell-cycle exit.

    Evidence Conditional Cdkn1c-knockout NSCs with intraventricular recombinant IGF2 rescue

    PMID:36633189

    Open questions at the time
    • Receptor and signaling route from IGF2 to Cdkn1c induction not mapped
  25. 2023 High

    Established placental endocrine IGF2 as a fetal effector reprogramming maternal metabolism and nutrient partitioning, with lifelong offspring metabolic effects.

    Evidence Conditional Igf2 knockout in placental endocrine cells with endocrine and metabolic phenotyping

    PMID:37544745

    Open questions at the time
    • Receptor/signaling controlling endocrine cell protein synthesis and energy homeostasis not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the same IGF2 ligand is routed to distinct receptors (IGF-1R, IR-A, IGF2R) to produce context-specific outcomes, and how IGF2R—a clearance receptor—mechanistically controls protein synthesis.
  • Receptor-choice determinants per cell type unknown
  • IGF2R-to-protein-synthesis mechanism undefined
  • Integration of transcriptional, translational, and miRNA control quantitatively unmodeled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CTCFDHX9IGF1RIGF2RINSRPHB1PXN

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 IGF2 and H19 share the same endoderm-specific enhancers located 3' of H19, but utilize them on different parental chromosomes (IGF2 paternally, H19 maternally). Deletion of these enhancers via homologous recombination abolished H19 expression on maternal inheritance and IGF2 expression on paternal inheritance, establishing that IGFII acts systemically to affect prenatal growth. Targeted enhancer deletion by homologous recombination in mouse ES cells; analysis of tissue-specific gene expression and growth phenotypes in mice Genes & development High 7544754
1998 Igf2 imprinting does not require its own DNA methylation or H19 RNA. Silencing of Igf2 due to loss of DNA methylation could be overridden by a mutation at H19, and replacement of the H19 gene with a protein-coding gene did not affect Igf2 expression. These epistasis experiments support a transcriptional model in which Igf2 and H19 compete for access to a common set of enhancers. Genetic epistasis using targeted mutations and H19 gene replacement in mice; allele-specific expression analysis Genes & development High 9679064
1995 Translation of the major 6.0-kb IGF2 mRNA (normally stored in a 100S ribonucleoprotein particle) is selectively activated in exponentially growing cells via a rapamycin-sensitive pathway (p70S6k/85S6k kinase signaling), providing post-transcriptional regulation of IGF-II production independent of the constitutively translated 4.8-kb mRNA. Rapamycin and anisomycin treatment of cultured cells; polysome fractionation; Northern blot analysis of mRNA distribution Nature High 7566093
2006 CTCF mediates an interchromosomal colocalization between the Igf2/H19 imprinting control region (ICR) on chromosome 7 and the Wsb1/Nf1 locus on chromosome 11. Omission of CTCF or deletion of the maternal ICR abrogated this association and altered Wsb1/Nf1 gene expression, demonstrating that CTCF-dependent chromosome looping regulates allele-specific long-range gene expression. Modified chromosome conformation capture (3C) and fluorescence in situ hybridization (FISH); CTCF depletion and ICR deletion experiments Science High 16614224
2007 Crystal structures of IGF2R domains 11–12, 11–12–13–14, and the domain 11–12–13/IGF-II complex revealed that domain 11 directly contacts IGF-II while domain 13 modulates binding site flexibility. Phe19 and Leu53 of IGF-II lock into a hydrophobic pocket unique to domain 11 of mammalian IGF2R; mutagenesis confirmed this as the IGF-II binding hotspot, and showed convergent evolution with IGF-binding proteins on the same high-affinity site. X-ray crystallography; site-directed mutagenesis; binding affinity assays The EMBO journal High 18046459
2011 Hippocampal IGF-II (IGF2) is upregulated after inhibitory avoidance learning in a C/EBPβ-dependent manner, and is required for memory consolidation. Post-training hippocampal injection of recombinant IGF-II enhances memory retention; this requires IGF-II receptors, new protein synthesis, ARC function, and GSK3 activity, and correlates with activation of synaptic GSK3β and increased GluR1 AMPA receptor subunit expression. IGF-II also promotes persistent LTP after weak stimulation in hippocampal slices in an IGF-II receptor-dependent manner. Recombinant protein injection into rat hippocampus; pharmacological inhibitors; Western blot; electrophysiology (LTP in hippocampal slices); behavioral assays Nature High 21270887
2003 IGF-II transcription in skeletal myogenesis is regulated by mTOR (independently of its kinase activity) and by amino acid availability, acting through IGF-II promoter 3 and a downstream enhancer during C2C12 myoblast differentiation. IGF production—not downstream IGF signaling—is the primary mTOR target in initiating differentiation, and mTOR's myogenic signaling is mediated by the PI3K-Akt pathway. Promoter-reporter assays; pharmacological inhibitors (rapamycin, wortmannin); kinase-dead mTOR constructs; C2C12 myoblast differentiation assays The Journal of cell biology High 14662739
2011 miR-125b directly targets IGF2 mRNA in myocytes, as demonstrated by luciferase reporter assays with the IGF2 3′UTR. Declining miR-125b during myogenesis de-represses IGF2, promoting myoblast differentiation; mTOR (via kinase-independent signaling) negatively controls miR-125b biogenesis, establishing a dual mechanism for mTOR regulation of IGF2 production. Luciferase 3′UTR reporter assays; miRNA overexpression/knockdown; in vivo muscle regeneration assays; RT-qPCR The Journal of cell biology High 21200031
2002 IGF-2 is a downstream mediator of prolactin-induced mammary alveologenesis acting upstream of cyclin D1 transcription. Prolactin induces IGF-2 mRNA; IGF-2 induces cyclin D1 protein in primary MECs; ectopic IGF-2 restores alveologenesis in prolactin receptor-null epithelium; and alveologenesis is retarded in IGF-2-deficient MECs. Genetic rescue (ectopic IGF-2 expression in PRL-R−/− epithelium); IGF-2 knockout MECs; primary MEC stimulation assays; Northern and Western blot Developmental cell High 12479812
1999 Hypoxia activates IGF-II transcription from the P3 promoter in HepG2 cells via increased Egr-1 DNA binding activity. Deletion of Egr-1 binding sites in the P3 promoter abolished hypoxic induction; cotransfection with Egr-1 expression vector synergistically activated P3-driven reporter expression; WT1 (a repressor of IGF-II) was decreased by hypoxia. Transient promoter-luciferase reporter assays; EMSA with supershift; cotransfection; mRNA stability assays; Western blot; deletion mutagenesis of P3 promoter Cancer research High 10606246
2000 IGF-II promotes mesoderm formation by binding to the IGF1R on mesoderm precursor cells. Androgenetic Igf2-null ES cells (which lack IGF-II) showed severely impaired mesoderm development in teratoma and in vitro differentiation assays, while exogenous IGF-II addition specifically increased expression of mesoderm markers. Teratoma formation assays using ES cell lines with different Igf2 dosages; in vitro ES cell differentiation with exogenous IGF-II; expression analysis of mesoderm markers Developmental biology High 11076682
2015 Autocrine IGF2 produced and secreted by adult β-cells activates the β-cell IGF-1 receptor signaling pathway. β-cell-specific Igf2 knockout (βIGF2KO) mice showed reduced glucose-stimulated insulin secretion in aging and on high-fat diet, impaired β-cell mass expansion during pregnancy and in response to acute insulin resistance, demonstrating a physiological autocrine role for IGF2 in β-cell function. Conditional β-cell-specific Igf2 knockout mice; glucose tolerance tests; insulin secretion assays; β-cell mass quantification; metabolic stress experiments Diabetes High 26384384
2013 miR-483-5p, encoded within the IGF2 gene, forms a positive feedback loop by binding directly to the 5′UTR of fetal IGF2 mRNA in the nucleus, enhancing recruitment of the RNA helicase DHX9 to the IGF2 transcript and promoting IGF2 transcription from fetal promoters. Ectopic miR-483-5p expression in IGF2-dependent sarcoma cells increased tumorigenesis in vivo. miRNA screen in primary Wilms' tumors; nuclear pull-down; RNA-protein interaction assays (DHX9); in vivo xenograft tumorigenesis; promoter-reporter assays Genes & development High 24298054
2006 IGF2 allelic dosage directly modulates intestinal adenoma development in Apc(Min/+) mice: biallelic Igf2 expression (LOI) elongated intestinal crypts, increased adenoma growth, and elevated nuclear β-catenin. A soluble form of the IGF2/mannose-6-phosphate receptor (sIGF2R) expressed as a transgenic ligand trap rescued the Igf2-dependent intestinal and adenoma phenotypes, demonstrating functional potency of IGF2 ligand in intestinal cancer. Genetic crosses of Apc(Min/+) with Igf2 paternal-null or H19 maternal-null mice; sIGF2R ligand-trap transgene rescue; histomorphometry; β-catenin immunostaining Cancer research High 16488992
2023 The highest hippocampal IGF2 is produced by pericytes. Learning-induced increases in hippocampal Igf2 expression originate specifically from pericytes and require neuronal activity. Conditional Igf2 knockout in pericytes (but not fibroblasts or neurons) impaired long-term memory and blunted learning-dependent neuronal immediate early gene (IEG) induction, establishing a pericyte-to-neuron IGF2 signaling axis for memory consolidation. Cell-type-specific conditional Igf2 knockout in rats and mice; in situ hybridization and immunofluorescence for cell-type identification; behavioral memory assays; immediate early gene protein quantification Neuron High 37788670
2023 IGF2 promotes terminal differentiation of neural stem cells (NSCs) into neurons, astrocytes, and oligodendrocytes by inducing expression of the imprinted gene Cdkn1c (encoding p57). Intraventricular infusion of recombinant IGF2 into mice with Cdkn1c-deficient NSCs confirmed that p57 partially mediates IGF2's differentiation effects independently of cell-cycle progression. Conditional Cdkn1c-knockout NSCs; intraventricular recombinant IGF2 infusion; in vitro NSC differentiation assays; gene expression analysis Development High 36633189
2012 IGF2 promotes stemness of neural stem/progenitor cells (NSPs) via the insulin receptor isoform A (IR-A), distinct from IGF-1R-mediated proliferation. IR-A was predominantly expressed in NSPs, and IR knockdown (but not IGF-1R knockdown) impaired self-renewal. IGF-II increased Oct4, Sox1, and FABP7 mRNA levels in NSPs, and NSPs expanded in IGF-II preferentially colonized periventricular niches in vivo. shRNA knockdown of IR vs IGF-1R; limiting dilution assays; in vivo NSP transplantation; RT-qPCR for stemness markers Stem cells High 22593020
2008 IGF2 activates PI3K and TGFβ signaling pathways in chondrocytes. IGF2 treatment activated phosphorylation of Akt and GSK3β; selective PI3K inhibition (LY294002) blocked Akt phosphorylation and abolished IGF2-driven elevation of proteoglycan (Aggrecan and Versican) mRNA. The TGFβ pathway activation by IGF2 was not suppressed by LY294002, indicating two independent downstream pathways. Western blot for pathway phosphorylation; pharmacological PI3K inhibition; genome-wide mRNA microarray; RT-PCR Cell biology international Medium 18675921
2021 Circadian regulators Per1 and Per2 are required for Igf2 transcriptional activation during myoblast differentiation. Per1 and Per2 drive dynamic histone modifications at the Igf2 promoter and enhancer, and promote promoter-enhancer interaction, creating a preferred circadian time window for myoblast differentiation. Muscle regeneration was faster when initiated at night, when Per1, Per2, and Igf2 were highly expressed. Per1/Per2 knockdown; ChIP for histone modifications and RNA Pol II at Igf2 locus; chromatin conformation assays (promoter-enhancer interaction); muscle regeneration assays in vivo The Journal of cell biology High 34009269
2017 Stromal IGF2, derived mainly from cancer-associated fibroblasts (CAFs), activates pro-survival AKT signaling in CRC cells via the paracrine IGF1R/insulin receptor axis. In CAFs, autocrine IGF2/IGF1R signaling induces myofibroblast differentiation (αSMA expression, gel contractility), and IGF2-mediated physical matrix remodeling by CAFs (not soluble factors) facilitates tumor cell invasion in organotypic cultures. IGF2-expressing CAFs co-injected with colon cancer cells increased invasiveness and local recurrence in xenograft models. CAF isolation; IGF2 siRNA knockdown; organotypic co-culture invasion assays; xenograft mouse models; AKT phosphorylation Western blot; floating collagen gel assays Oncogene High 28534511
2011 Endostatin inhibits IGF-II-induced migration and invasion of trophoblasts by suppressing downstream signaling kinases ERK1/2, Akt/mTOR/p70S6K, and focal adhesion kinase. The inhibitory effect on IGF-II-induced Akt phosphorylation is critically dependent on Akt1 expression, as shown by virus-mediated stable Akt1 silencing. Transwell migration/invasion assays with primary trophoblasts and SGHPL-5 cells; villous explant cultures; Western blot for signaling kinases; stable viral Akt1 knockdown Endocrinology Medium 21933871
2015 Paxillin, a focal adhesion protein, acts as a transcriptional regulator of IGF2 by stimulating the chromosomal interaction between the distal shared enhancer and the IGF2 promoter (while restraining the H19 promoter-enhancer interaction). Paxillin interacts with cohesin and the mediator complex, and co-occupies the IGF2/H19 locus, facilitating long-range chromatin looping to activate IGF2 transcription. Chromosome conformation capture; Co-IP of paxillin with cohesin and mediator; ChIP; allele-specific expression analysis; paxillin overexpression/knockdown Journal of cell science High 26116569
2023 Fetal manipulation of maternal metabolism is a critical function of placental endocrine Igf2. Igf2 deletion specifically in placental endocrine cells impairs placental hormone production (including prolactins), prevents establishment of pregnancy-related insulin resistance, and restricts nutrient partitioning to the fetus. Mechanistically, Igf2 controls protein synthesis and cellular energy homeostasis in an endocrine cell-type-dependent manner, and has long-lasting effects on offspring metabolism in adulthood. Conditional Igf2 knockout in placental endocrine cells; placental hormone profiling; metabolic phenotyping of mothers and offspring; molecular analysis of protein synthesis and energy homeostasis pathways Cell metabolism High 37544745
2011 IGF2 precursor isoforms ('big' and pro-IGF-II) are present in normal human plasma (16% and 13%, respectively, of total IGF-II). Mature and 'big' IGF-II exhibit similar activation of IR-A and IR-B signaling, while pro-IGF-II shows significantly less activation. Downstream Akt activation by mature and 'big' IGF-II was greater in IR-A cells than IR-B cells, consistent with higher IR-A affinity for IGF-II. Human plasma isoform quantification by immunoassay; cell-based receptor activation assays in IGF-1R-deficient cells expressing IR-A or IR-B; Akt phosphorylation by Western blot Endocrinology Medium 21285309
2016 PHB1 (Prohibitin 1) and CTCF cooperate to negatively regulate the H19-Igf2 axis. PHB1 knockdown reduces CTCF protein levels (~30%) and its binding to the ICR, leading to induction of H19 and Igf2 (~2-fold). PHB1 and CTCF co-immunoprecipitate and co-localize on the ICR element; CTCF overexpression suppresses Phb1-knockdown-mediated H19/Igf2 induction. Co-IP of PHB1 and CTCF; ChIP at ICR; siRNA knockdown; CTCF overexpression rescue; quantitative RT-PCR The Journal of biological chemistry Medium 27687727
2012 Loss of p53 creates an Igf2-dependent phenotype: developmental lethality occurred in p53-null mice lacking the paternal Igf2 allele, and conditional Igf2 deletion attenuated rapid tumor onset in p53-null mice. Accelerated tumor formation in p53+/- mice with biallelic Igf2 was associated with reductions in p53 loss of heterozygosity and apoptosis, establishing genetic epistasis between Igf2 and p53 pathways in development and tumorigenesis. Genetic crosses of p53-null and conditional p53-flox with Igf2-null and biallelic Igf2 mice; tumor incidence and phenotype analysis; apoptosis assays; LOH analysis EMBO molecular medicine High 22674894
2022 Hepatocyte-specific Igf2 deletion in SRSF3-knockout mice completely prevents hepatic fibrosis, inflammation, and tumor formation. In vitro, IGF2 treatment of HepG2 cells decreases DNA repair enzyme expression and causes DNA damage, linking IGF2 overexpression to homologous recombination and mismatch repair defects in HCC. Double-conditional knockout mice (Igf2 and Srsf3); tumor incidence assays; in vitro IGF2 treatment of HepG2 cells; DNA damage assays; DNA repair enzyme expression analysis; mutational signature analysis Advanced science High 35615981
1988 Glucocorticoids (cortisone acetate) rapidly extinguish IGF-II mRNA expression in neonatal rat liver (the major endocrine IGF-II production site), while having minimal effect at autocrine/paracrine sites such as skeletal muscle and choroid plexus, demonstrating tissue-specific transcriptional control of the IGF2 gene by glucocorticoids. Northern blot and in situ hybridization after cortisone acetate administration to neonatal rats; tissue-specific comparison Journal of molecular endocrinology Medium 3255362
2020 Hippocampal CIM6P/IGF2R is necessary for memory consolidation (but not learning, retrieval, or reconsolidation). CIM6P/IGF2R controls training-induced de novo protein synthesis (including Arc, Egr1, and c-Fos protein but not their mRNAs). Mannose-6-phosphate, like IGF2, enhances memory retention in a CIM6P/IGF2R-dependent manner, establishing that IGF2 acts through this receptor to regulate protein metabolism during memory consolidation. CIM6P/IGF2R pharmacological inhibition in rats; neuron-specific shRNA knockdown in mice; behavioral memory tests; Western blot for protein synthesis markers; intrahippocampal injections eLife High 32369018
2003 A methylated oligonucleotide (MON1) complementary to IGF2 promoter P4 induces de novo DNA methylation at that locus, specifically reducing IGF2 mRNA accumulation in HCC cells in vitro. Treatment of nude mice bearing Hep 3B liver tumors with MON1 markedly prolonged survival, demonstrating that epigenetic silencing of IGF2 via targeted DNA methylation inhibits hepatocellular tumor growth in vivo. Methylated oligonucleotide treatment; bisulfite sequencing for de novo methylation; RT-PCR for IGF2 mRNA; in vivo HCC xenograft mouse model with survival analysis The Journal of clinical investigation Medium 12531883
1993 IGF-II mRNAs in human, rat, and mouse are subjected to specific endonucleolytic cleavage, indicating post-transcriptional regulation of IGF-II expression by mRNA stability mechanisms. Promoter activity alone does not account for species-specific expression, as maximal promoter activity requires homologous cellular environments, suggesting adaptation to tissue-specific transcription factor levels. Promoter-luciferase reporter assays in heterologous and homologous cell lines; Northern blot mRNA stability analysis; comparative cross-species promoter analysis Regulatory peptides Medium 8265819
2008 IGF2 is imprinted and expressed in the marsupial (tammar wallaby) yolk sac placenta. Both IGF1R and IGF2R were present in the placenta, and IGF2 increased vascular endothelial growth factor (VEGF) expression in placental explant cultures, suggesting that IGF2 promotes vascularization of the yolk sac placenta. RT-PCR and in situ hybridization for IGF2 mRNA; immunohistochemistry for protein localization; placental explant culture with IGF2 treatment; VEGF expression by RT-PCR BMC developmental biology Medium 18284703
2017 CTCF-binding site mutations at the Igf2-H19 imprint control region that abolish CTCF insulator activity result in biallelic Igf2 expression (LOI) in prostate, increasing the prevalence and severity of prostatic intraepithelial neoplasia. Prostates with LOI displayed increased MAPK signaling and epithelial proliferation; human prostate tissues showed positive correlation between IGF2 levels and phospho-ERK/phospho-AKT. CTCF-binding site mutation knock-in mice; PIN histopathology; MAPK/AKT signaling by immunohistochemistry and Western blot; correlation analysis in human prostate tissue arrays Cancer research High 28775169
2012 NF-κB, activated by HER2/HER3 signaling, identifies IGF2 as a key target to drive breast cancer stem cell (CSC) tumor sphere formation. IGF2-PI3K signaling induces expression of the stemness transcription factor ID1 and IGF2 itself, forming an IGF2-ID1-IGF2 positive feedback loop. Anti-IGF1/2 antibodies blocked tumorigenesis from the IGF1R-high CSC-enriched population in a patient-derived xenograft model. Sphere formation assays; shRNA knockdown of ID1 and IGF2; PI3K pathway inhibition; patient-derived xenograft model with anti-IGF1/2 antibodies; gene expression analysis Oncogene Medium 27546618
2021 IGF2 deficiency in skeletal muscle cells (C2C12 myotubes and primary skeletal muscle cells) causes impaired mitochondrial function, reduced mitochondria-related protein content, and decreased mitochondrial biogenesis. The mechanism involves the IGF2-SIRT1-PGC1α signaling pathway. IGF2 knockdown in C2C12 myotubes and primary skeletal muscle cells; mitochondrial function assays; Western blot for mitochondrial proteins; pathway inhibitor analysis Clinical science Medium 33825857
2013 INS-IGF2, a read-through fusion protein consisting of the preproinsulin signal peptide, insulin B-chain, eight C-peptide amino acids, and 138 IGF2-derived amino acids, is expressed primarily in pancreatic beta cells. Autoantibodies against INS-IGF2 are elevated in newly diagnosed type 1 diabetes patients, and INS-IGF2 shares autoantibody-binding sites with insulin. Immunohistochemistry for INS-IGF2 in human pancreatic islets; autoantibody measurement by radiobinding assay; displacement studies with cold insulin and INS-IGF2 The Journal of biological chemistry Medium 23935095

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1. Science (New York, N.Y.) 378 16614224
1995 An enhancer deletion affects both H19 and Igf2 expression. Genes & development 348 7544754
2011 A critical role for IGF-II in memory consolidation and enhancement. Nature 333 21270887
2008 IGF2: epigenetic regulation and role in development and disease. Cytokine & growth factor reviews 260 18308616
2013 IGF2 and cancer. Endocrine-related cancer 252 24080445
1998 Insulin-like growth factor II (IGF-II). The international journal of biochemistry & cell biology 232 9722981
2011 IGF-II is regulated by microRNA-125b in skeletal myogenesis. The Journal of cell biology 201 21200031
2013 Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive. Endocrine reviews 173 23671155
2015 Paternally Inherited IGF2 Mutation and Growth Restriction. The New England journal of medicine 159 26154720
1999 IGF-I and IGF-II in relation to colorectal cancer. International journal of cancer 159 10449601
1995 Growth-dependent translation of IGF-II mRNA by a rapamycin-sensitive pathway. Nature 157 7566093
2002 IGF-2 is a mediator of prolactin-induced morphogenesis in the breast. Developmental cell 146 12479812
2014 Epigenetic regulation of the Igf2/H19 gene cluster. Cell proliferation 142 24738971
2013 The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis. Genes & development 133 24298054
2003 IGF-II transcription in skeletal myogenesis is controlled by mTOR and nutrients. The Journal of cell biology 123 14662739
2006 Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer. Molecular cancer research : MCR 118 16603642
2007 Structure and functional analysis of the IGF-II/IGF2R interaction. The EMBO journal 100 18046459
2000 Mechanisms of Igf2/H19 imprinting: DNA methylation, chromatin and long-distance gene regulation. Journal of biochemistry 100 10788777
2005 Role of IGFBP2, IGF-I and IGF-II in regulating long bone growth. Bone 94 16183342
2003 H19 and Igf2--enhancing the confusion? Trends in genetics : TIG 92 12493244
2003 A methylated oligonucleotide inhibits IGF2 expression and enhances survival in a model of hepatocellular carcinoma. The Journal of clinical investigation 87 12531883
1998 Igf2 imprinting does not require its own DNA methylation or H19 RNA. Genes & development 87 9679064
1999 Egr-1 mediates transcriptional activation of IGF-II gene in response to hypoxia. Cancer research 85 10606246
1992 Expression of IGF-I and IGF-II mRNA in breast tissue. Breast cancer research and treatment 83 1421422
2009 Keeping IGF-II under control: lessons from the IGF-II-IGF2R crystal structure. Trends in biochemical sciences 82 19796953
2022 IGF2: Development, Genetic and Epigenetic Abnormalities. Cells 79 35741015
2012 IGF-II promotes stemness of neural restricted precursors. Stem cells (Dayton, Ohio) 75 22593020
2011 Biology and significance of signalling pathways activated by IGF-II. Growth factors (Chur, Switzerland) 72 22136428
2000 Symmetric and asymmetric DNA methylation in the human IGF2-H19 imprinted region. Genomics 72 10729220
2017 Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms. Oncogene 69 28534511
2000 Igf2 imprinting in development and disease. The International journal of developmental biology 69 10761859
2007 Loss of imprinting of IGF2 as an epigenetic marker for the risk of human cancer. Disease markers 67 17325430
2017 Curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway. Journal of drug targeting 66 28286973
2023 IGF2 in memory, neurodevelopmental disorders, and neurodegenerative diseases. Trends in neurosciences 64 37031050
1997 Biallelic expression of the H19 and IGF2 genes in hepatocellular carcinoma. Cancer letters 63 9570364
2020 Understanding IGF-II Action through Insights into Receptor Binding and Activation. Cells 62 33053840
2019 Insulin-Like Growth Factor 2 (IGF2) Signaling in Colorectal Cancer-From Basic Research to Potential Clinical Applications. International journal of molecular sciences 62 31623387
2019 The Neglected Insulin: IGF-II, a Metabolic Regulator with Implications for Diabetes, Obesity, and Cancer. Cells 59 31590432
2012 IGF2 mRNA binding protein p62/IMP2-2 in hepatocellular carcinoma: antiapoptotic action is independent of IGF2/PI3K signaling. American journal of physiology. Gastrointestinal and liver physiology 59 23257922
2000 IGF-II promotes mesoderm formation. Developmental biology 58 11076682
2023 Fetal manipulation of maternal metabolism is a critical function of the imprinted Igf2 gene. Cell metabolism 56 37437545
2016 Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells. Oncogene 55 27546618
2006 Soluble IGF2 receptor rescues Apc(Min/+) intestinal adenoma progression induced by Igf2 loss of imprinting. Cancer research 53 16488992
1999 Association of IGF-I and IGF-II with myofiber regeneration in vivo. Muscle & nerve 52 10086895
1995 IGF2 expression is a marker for paraganglionic/SIF cell differentiation in neuroblastoma. The American journal of pathology 51 7717451
2015 Autocrine Action of IGF2 Regulates Adult β-Cell Mass and Function. Diabetes 50 26384384
2023 IGF2: A Role in Metastasis and Tumor Evasion from Immune Surveillance? Biomedicines 48 36672737
2015 DNA methylation in imprinted genes IGF2 and GNASXL is associated with prenatal maternal stress. Genes, brain, and behavior 46 26333472
2013 HIF2A and IGF2 expression correlates in human neuroblastoma cells and normal immature sympathetic neuroblasts. Neoplasia (New York, N.Y.) 43 23479510
2007 IGF-II gene region polymorphisms related to exertional muscle damage. Journal of applied physiology (Bethesda, Md. : 1985) 43 17289909
2013 PEG1/MEST and IGF2 DNA methylation in CIN and in cervical cancer. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 42 23775149
2016 Current ideas on the biology of IGFBP-6: More than an IGF-II inhibitor? Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 39 27681092
2011 Hepatoprotection and neuroprotection induced by low doses of IGF-II in aging rats. Journal of translational medicine 39 21733157
2022 Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2. Theranostics 38 35154476
2016 HMGA1P7-pseudogene regulates H19 and Igf2 expression by a competitive endogenous RNA mechanism. Scientific reports 38 27874091
2008 IGF2-driven PI3 kinase and TGFbeta signaling pathways in chondrogenesis. Cell biology international 38 18675921
2018 IGF2 induces CD133 expression in esophageal cancer cells to promote cancer stemness. Cancer letters 36 29604392
1990 Expression of IGF-I and IGF-II genes in the adult rat eye. Current eye research 36 1692782
2021 Per1/Per2-Igf2 axis-mediated circadian regulation of myogenic differentiation. The Journal of cell biology 35 34009269
1988 Control of IGF-II mRNA levels by glucocorticoids in the neonatal rat. Journal of molecular endocrinology 35 3255362
2019 IGF2 role in adrenocortical carcinoma biology. Endocrine 34 31378849
2022 Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 33 35615981
2020 IGF2 Mutations. The Journal of clinical endocrinology and metabolism 32 31544945
2020 A role for CIM6P/IGF2 receptor in memory consolidation and enhancement. eLife 32 32369018
2012 Akt1 and insulin-like growth factor 2 (Igf2) regulate placentation and fetal/postnatal development. The International journal of developmental biology 31 22562201
2012 IGF2BP2 and IGF2 genetic effects in diabetes and diabetic nephropathy. Journal of diabetes and its complications 31 22770937
2020 lncRNA IGF2 AS Regulates Bovine Myogenesis through Different Pathways. Molecular therapy. Nucleic acids 29 32805490
2013 Autoimmunity against INS-IGF2 protein expressed in human pancreatic islets. The Journal of biological chemistry 28 23935095
2012 Igf2 pathway dependency of the Trp53 developmental and tumour phenotypes. EMBO molecular medicine 28 22674894
2013 The prevalence of loss of imprinting of H19 and IGF2 at birth. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 23620526
2011 Endostatin suppresses IGF-II-mediated signaling and invasion of human extravillous trophoblasts. Endocrinology 27 21933871
1996 Variable imprinting of H19 and IGF2 in fetal cerebellum and medulloblastoma. Journal of neuropathology and experimental neurology 27 8957451
1993 Differential expression of the human, mouse and rat IGF-II genes. Regulatory peptides 27 8265819
2020 The IGF-II-Insulin Receptor Isoform-A Autocrine Signal in Cancer: Actionable Perspectives. Cancers 26 32033443
2018 Is ZFP57 binding to H19/IGF2:IG-DMR affected in Silver-Russell syndrome? Clinical epigenetics 26 29484033
2021 IGF2 deficiency causes mitochondrial defects in skeletal muscle. Clinical science (London, England : 1979) 25 33825857
2016 IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis. Endocrine-related cancer 25 27185872
2009 Expression of the imprinted IGF2 and H19 genes in the endometrium of cases with unexplained infertility. European journal of obstetrics, gynecology, and reproductive biology 25 20042264
2020 Critical role of SOX2-IGF2 signaling in aggressiveness of bladder cancer. Scientific reports 24 32427884
2020 IGF2 improves the developmental competency and meiotic structure of oocytes from aged mice. Aging 24 33318299
2019 Effects of Sprifermin, IGF1, IGF2, BMP7, or CNP on Bovine Chondrocytes in Monolayer and 3D Culture. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 24 31608492
2017 Associations between maternal prenatal stress, methylation changes in IGF1 and IGF2, and birth weight. Journal of developmental origins of health and disease 24 29017633
2000 Genomic imprinting of IGF2 and H19 in human meningiomas. European journal of cancer (Oxford, England : 1990) 24 10738131
2023 Neuronal activity drives IGF2 expression from pericytes to form long-term memory. Neuron 23 37788670
2020 Igf2 deletion alters mouse placenta endocrine capacity in a sexually dimorphic manner. The Journal of endocrinology 23 32380473
2012 Cell type and context-specific function of PLAG1 for IGF2 P3 promoter activity. International journal of oncology 23 23023303
2000 IGF-II ameliorates the dystrophic phenotype and coordinately down-regulates programmed cell death. Cell death and differentiation 23 11139285
2019 IGF-II-Conjugated Nanocarrier for Brain-Targeted Delivery of p11 Gene for Depression. AAPS PharmSciTech 22 30617637
2015 Paxillin-dependent regulation of IGF2 and H19 gene cluster expression. Journal of cell science 22 26116569
2011 Plasma distribution and signaling activities of IGF-II precursors. Endocrinology 22 21285309
2017 Associations of IGF2 and DRD2 polymorphisms with laying traits in Muscovy duck. PeerJ 21 29181280
2011 The distribution of IGF2 and IMP3 in osteosarcoma and its relationship with angiogenesis. Journal of molecular histology 21 22042095
2020 Long non-coding RNA IGF2-AS represses breast cancer tumorigenesis by epigenetically regulating IGF2. Experimental biology and medicine (Maywood, N.J.) 20 33175607
2017 Loss of Igf2 Gene Imprinting in Murine Prostate Promotes Widespread Neoplastic Growth. Cancer research 20 28775169
2016 Prohibitin 1 Regulates the H19-Igf2 Axis and Proliferation in Hepatocytes. The Journal of biological chemistry 20 27687727
2014 Upregulation of IGF2 expression during vascular calcification. Journal of molecular endocrinology 19 24482492
1998 Promoter-specific methylation and expression alterations of igf2 and h19 are involved in human hepatoblastoma. International journal of cancer 19 9462704
2024 Targeting IGF2 to reprogram the tumor microenvironment for enhanced viro-immunotherapy. Neuro-oncology 18 38853689
2023 IGF2 interacts with the imprinted gene Cdkn1c to promote terminal differentiation of neural stem cells. Development (Cambridge, England) 18 36633189
2008 Expression and protein localisation of IGF2 in the marsupial placenta. BMC developmental biology 18 18284703

Missed literature

Know a paper Affinage missed for IGF2? Flag it for the maintainers and the community.

No submissions yet.