Affinage

IGF1

Insulin-like growth factor 1 · UniProt P05019

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IGF1 is a secreted 70-amino acid mitogenic and anabolic peptide, synthesized as a precursor requiring signal peptide and C-terminal extension cleavage, that signals through the IGF-1R tyrosine kinase to activate PI3K/Akt/mTOR and MAPK cascades, driving cell survival, proliferation, protein synthesis, and differentiation across muscle, bone, neural, vascular, and reproductive tissues (PMID:632300, PMID:6358902, PMID:2003574, PMID:15193297). Hepatic IGF1 production is regulated by insulin and essential amino acid availability, and its bioavailability is modulated by IGF-binding proteins whose proteolytic cleavage (e.g., by PSA) releases free IGF-I (PMID:1936610, PMID:1901809, PMID:1383255). In bone, matrix-stored IGF1 released during remodeling drives osteoblastic differentiation of mesenchymal stem cells via mTOR and supports osteoclastogenesis through RANKL-dependent coupling, while in muscle, local IGF1 sustains hypertrophy, prevents age-related atrophy, and activates GATA-2 (PMID:22729283, PMID:16939393, PMID:11175789). IGF1/Akt signaling also confers neuroprotection by phosphorylating huntingtin to suppress polyglutamine toxicity, inactivating GSK3β to reduce caspase activation after hypoxia-ischemia, and modulating serotonergic tone in the hippocampus (PMID:12062094, PMID:15845077, PMID:18675266).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1978 High

    Determination of IGF-I's complete 70-amino acid sequence with three disulfide bridges and structural homology to proinsulin established its identity as a distinct insulin-family growth factor, framing all subsequent receptor and signaling studies.

    Evidence Protein sequencing and structural comparison with insulin

    PMID:632300

    Open questions at the time
    • Post-translational processing steps from precursor to mature peptide were not yet defined
    • Receptor identity unknown
  2. 1983 High

    cDNA cloning revealed that IGF-I is synthesized as a precursor with an N-terminal signal peptide and a 35-residue C-terminal extension, establishing that proteolytic processing at both termini is required for maturation — a prerequisite for understanding secretion and bioavailability.

    Evidence Human liver cDNA sequencing

    PMID:6358902

    Open questions at the time
    • Processing proteases not identified
    • Alternative splicing not yet characterized
  3. 1986 High

    Genomic characterization showed the IGF1 gene spans ≥45 kb with five exons generating at least two alternatively spliced precursor isoforms (153-aa and 195-aa), explaining tissue-specific transcript diversity.

    Evidence Genomic library cloning, Southern blotting, cDNA comparison

    PMID:2937782

    Open questions at the time
    • Functional significance of alternative E-peptides unknown
    • Promoter regulation not mapped
  4. 1991 High

    Demonstrating that IGF-I directly stimulates myofiber hypertrophy by increasing protein synthesis, decreasing protein degradation, and raising myosin heavy-chain content resolved the longstanding question of whether IGF-I acts as a direct anabolic effector in skeletal muscle.

    Evidence In vitro 3D skeletal myofiber culture with protein synthesis/degradation measurements

    PMID:2003574

    Open questions at the time
    • Intracellular signaling pathway not dissected
    • In vivo relevance not yet shown
  5. 1991 Medium

    Studies showing that both insulin and essential amino acids (tryptophan, lysine) independently regulate hepatic IGF-I mRNA and secretion established the molecular basis for nutritional control of circulating IGF-I, linking metabolic status to growth factor output.

    Evidence Primary rat hepatocyte cultures with defined amino acid deprivation, insulin dose-response, Northern blot and RIA

    PMID:1901809 PMID:1936610

    Open questions at the time
    • Transcription factor mediators of amino acid sensing on IGF1 promoter not identified
    • In vivo validation in human liver not performed
  6. 1992 High

    The discovery that PSA specifically cleaves IGFBP-3 to reduce its IGF-I binding affinity established proteolytic IGFBP processing as a mechanism for modulating IGF-I bioavailability, particularly in the reproductive tract.

    Evidence In vitro incubation of purified PSA with IGFBP-3, Western ligand blotting, competition binding

    PMID:1383255

    Open questions at the time
    • In vivo relevance of PSA-mediated IGFBP cleavage in seminal fluid not demonstrated
    • Whether other tissue-specific proteases act similarly was unknown
  7. 1999 High

    Reconstitution of IGF-IR in receptor-null (R⁻) cells demonstrated a PI3K-independent anti-apoptotic pathway distinct from insulin receptor signaling, while ligand-bound ERα was shown to physically associate with and activate IGF-1R, revealing receptor crosstalk that expanded the canonical signaling model.

    Evidence R⁻ cell reconstitution with IR/IGF-IR, PI3K inhibitor pharmacology, co-immunoprecipitation of ERα–IGF-1R in COS7/HEK293 cells

    PMID:10226786 PMID:10749889

    Open questions at the time
    • Identity of the PI3K-independent survival pathway not resolved
    • Structural basis of ERα–IGF-1R interaction unknown
    • In vivo relevance of ERα–IGF-1R crosstalk not tested
  8. 2001 High

    Muscle-specific IGF-I transgenic mice demonstrated that local autocrine/paracrine IGF-I is sufficient to sustain hypertrophy, prevent age-related atrophy, and preserve regenerative capacity without systemic side effects, validating the concept of tissue-restricted IGF-I action.

    Evidence Transgenic mice with muscle-restricted mIgf-1 expression, histological, functional, and regeneration assays

    PMID:11175789

    Open questions at the time
    • Downstream transcriptional program beyond GATA-2 not characterized
    • Whether satellite cell activation is direct or indirect was unresolved
  9. 2002 High

    IGF-I/Akt-mediated phosphorylation of huntingtin was shown to reduce polyglutamine-expanded huntingtin toxicity and intranuclear inclusion formation, identifying a direct neuroprotective substrate of the IGF-I/Akt axis and linking IGF-I signaling to Huntington's disease pathogenesis.

    Evidence Neuronal cultures with Akt kinase assay on huntingtin substrate, phosphorylation-deficient mutants, HD patient brain Western blot

    PMID:12062094

    Open questions at the time
    • Phosphorylation site on huntingtin not mapped to a specific residue in this study
    • Therapeutic potential of IGF-I in HD not tested in vivo
  10. 2002 Medium

    Dual-pathway epistasis experiments in motor neurons showed that IGF-I neuroprotection against excitotoxicity requires simultaneous activation of both MAPK and PI3K/Akt cascades via IRS-1 and Shc phosphorylation, establishing that neither pathway alone is sufficient.

    Evidence Enriched embryonic rat motor neurons, combined PD98059 and LY294002 inhibition, caspase-3 and DNA fragmentation assays

    PMID:15193297

    Open questions at the time
    • Downstream convergence point of MAPK and Akt pathways not identified
    • Whether this dual requirement applies in vivo is untested
  11. 2005 Medium

    In vivo neonatal hypoxia-ischemia studies showed IGF-I activates Akt and inactivates GSK3β while reducing caspase-3/9 activity, reducing brain damage by 40%, delineating the Akt→GSK3β axis as a key neuroprotective mechanism.

    Evidence Neonatal rat HI model, i.c.v. IGF-I, phospho-Akt/GSK3β immunohistochemistry, caspase assays

    PMID:15845077

    Open questions at the time
    • Relative contributions of caspase-dependent vs. caspase-independent death not resolved
    • Cell-type specificity of IGF-I action in brain not determined
  12. 2006 High

    IGF-I knockout mice revealed that IGF-I is required in both osteoblasts and osteoclast precursors for normal RANKL/RANK-mediated osteoclast differentiation and bone resorption, establishing a dual-cell-type role in skeletal remodeling.

    Evidence IGF-I KO mice, co-culture genotype combinations of osteoblasts and osteoclast precursors, qRT-PCR for RANKL/M-CSF

    PMID:16939393

    Open questions at the time
    • Whether IGF-I acts on osteoclast precursors directly through IGF-1R or indirectly via RANKL upregulation was not fully resolved
    • Contribution of locally vs. systemically derived IGF-I unclear
  13. 2009 High

    Discovery that miR-1 targets IGF-I and IGF-1R mRNA, with reciprocal regulation of miR-1 by IGF-1 signaling through Foxo3a, established a feedback loop governing cardiac hypertrophy and muscle differentiation.

    Evidence Luciferase reporter assays, cardiac hypertrophy/failure models, C2C12 differentiation, acromegaly patient biopsies

    PMID:19933931

    Open questions at the time
    • Whether miR-1-IGF-I loop is causally required for hypertrophy reversal not tested
    • Additional miRNAs targeting IGF-I not systematically surveyed
  14. 2012 High

    Matrix-embedded IGF-1 released during bone remodeling was shown to recruit mesenchymal stem cells and drive osteoblastic differentiation via mTOR, with conditional IGF-1R deletion reducing bone mass and co-delivery of IGF-1 with IGFBP3 stimulating new bone formation in aged animals — unifying the roles of IGF-I as a coupling factor in the bone remodeling cycle.

    Evidence Conditional IGF-1R KO in pre-osteoblasts, rapamycin inhibition, IGF-1/IGFBP3 injection in aged rats

    PMID:22729283

    Open questions at the time
    • Mechanism of IGF-1 release from bone matrix not fully characterized
    • Whether IGFBP3 co-delivery is necessary for clinical translation not determined
  15. 2013 High

    Demonstration that IGF-IR is essential for FSH-stimulated AKT activation and aromatase (Cyp19) expression in granulosa cells across three species established IGF-I signaling as a required co-activator of gonadotropin-driven steroidogenesis.

    Evidence Pharmacological/siRNA/dominant-negative IGF-IR inhibition plus constitutively active AKT rescue in human/mouse/rat granulosa cells, in vivo mouse model

    PMID:23340251

    Open questions at the time
    • Whether IGF-I or IGF-II is the physiological ligand in this context not resolved
    • Upstream regulation of local ovarian IGF-I production not addressed
  16. 2018 High

    Identification of IGF-1R as a kinase that directly phosphorylates PTH1R at Y494, driving actin polymerization during osteoblast-to-osteocyte transition, revealed a non-canonical substrate of IGF-1R signaling and a specific mechanism for osteocyte dendrite formation.

    Evidence In vitro kinase assay, Y494 mutagenesis, phospho-PTH1R/actin immunofluorescence, conditional PTH1R knockout mice

    PMID:29507819

    Open questions at the time
    • Whether IGF-1R phosphorylates other GPCRs not explored
    • Structural details of IGF-1R–PTH1R interaction unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis of IGF-1R's selectivity for non-canonical substrates (huntingtin, PTH1R), the precise proteases and mechanisms governing IGF-I precursor processing in different tissues, and the relative contributions of autocrine/paracrine versus endocrine IGF-I pools to specific tissue phenotypes in humans.
  • No crystal structure of IGF-1R bound to non-canonical substrates
  • Processing enzymes for IGF-I propeptide not definitively identified
  • Human tissue-specific conditional deletion data lacking

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 5
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1474165 Reproduction 2
Partners
CAV1ESR1IGF1RIGFBP3IGFBP7IRS1PTH1RSHC1

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1978 IGF-I was determined to be a single-chain 70-amino acid polypeptide with three disulfide bridges and structural homology to proinsulin, with positions 1–29 homologous to the insulin B chain and positions 42–62 to the insulin A chain, establishing its evolutionary relationship to insulin. Protein sequencing and structural analysis The Journal of biological chemistry High 632300
1983 IGF-I is synthesized as a precursor protein with an amino-terminal signal peptide (≥25 residues) and a 35-amino acid carboxy-terminal extension peptide, requiring proteolytic processing at both ends to generate mature IGF-I. cDNA sequencing of human liver IGF-I transcript Nature High 6358902
1986 The human IGF-I gene spans at least 45 kilobase pairs, contains five exons, and generates at least two distinct mRNA transcripts (encoding 153-aa and 195-aa precursor peptides) by alternative RNA processing of the primary transcript. Genomic library cloning, Southern blotting, cDNA sequencing The Journal of biological chemistry High 2937782
1990 IGF-I mRNA and protein are localized to the smooth muscle layer of the aorta, and insulin acutely and chronically increases aortic IGF-I mRNA abundance (~2-fold), suggesting IGF-I functions as an autocrine growth factor in the vessel wall regulated by insulin. Immunohistochemistry, in situ hybridization, Northern blot in normal and diabetic rats with insulin administration Diabetes Medium 2140801
1990 Human leukemic (HL-60) cells express an altered IGF-I receptor beta-subunit of ~105 kDa (instead of the normal 95 kDa) that is autophosphorylated at tyrosine and threonine residues in response to IGF-I, with a distinct tryptic phosphopeptide map compared to the insulin receptor beta-subunit, representing a fetal isoform of the IGF-I receptor. Receptor binding assays, chemical cross-linking, Western analysis, HPLC tryptic peptide mapping, deglycosylation The Journal of biological chemistry Medium 1693149
1991 Insulin and IGF-I (but not IGF-II) induce myofiber hypertrophy in vitro by stimulating a 42–62% increase in total protein synthesis and a 28–38% decrease in protein degradation, increasing myosin heavy-chain content by 183–258%, and increasing myofiber nuclei number, demonstrating a direct anabolic role. In vitro skeletal myofiber culture in 3D collagen gel, protein synthesis and degradation measurements, myosin heavy-chain quantification The American journal of physiology High 2003574
1991 Insulin regulates hepatic IGF-I release at the mRNA level in primary rat hepatocyte culture: increasing insulin from 10⁻¹⁰ to 10⁻⁶ M raised IGF-I release by ~183% with correlated increases in IGF-I mRNA, across a broad range of amino acid concentrations. Primary rat hepatocyte culture, RIA for IGF-I protein, Northern blot for IGF-I mRNA Diabetes Medium 1936610
1991 Amino acid availability (specifically essential amino acids tryptophan and lysine) directly regulates IGF-I mRNA levels and secretion in cultured hepatocytes independently of regulatory hormones, establishing a direct molecular link between protein nutrition and hepatic IGF-I production. Primary rat hepatocyte culture with defined amino acid deprivation, RIA for IGF-I, Northern blot Diabetes Medium 1901809
1992 IGF-I increases tropoelastin mRNA steady-state levels and soluble elastin secretion in aortic smooth muscle cells (but not lung fibroblasts) via increased transcription or transcript stability, as shown by transfection of elastin gene 5′-flanking region–CAT reporter constructs; both cell types express the IGF-I type I receptor, indicating cell-type-specific transcriptional regulation of elastin by IGF-I. Northern blot, soluble elastin assay, transient transfection with elastin promoter–CAT reporter, receptor binding analysis The American journal of physiology Medium 1325131
1992 Prostate-specific antigen (PSA), a serine protease in seminal plasma, cleaves IGFBP-3 at a pattern identical to that of seminal plasma, markedly reducing the binding affinity of IGFBP-3 fragments for IGF-I (but not IGF-II), thereby potentially modulating bioavailable IGF-I in the reproductive system. In vitro incubation of purified PSA with 125I-IGFBP-3, Western ligand blotting, competition binding assays The Journal of clinical endocrinology and metabolism High 1383255
1994 High extracellular calcium (3–5 mM) stimulates osteoblastic cell (MC3T3-E1) DNA synthesis through a mechanism requiring new protein synthesis and dependent on autocrine IGF-I: neutralizing IGF-I antiserum and anti-IGF-I receptor antibody both blocked high-Ca²⁺-induced DNA synthesis, and high Ca²⁺ increased IGF-I secretion and mRNA expression. DNA synthesis assay, neutralizing antibody blockade, IGF-I RIA, Northern blot, cycloheximide inhibition The American journal of physiology Medium 8203509
1995 LPS-induced reduction in circulating IGF-I is primarily due to decreased hepatic production (46% reduction in perfused liver IGF-I output) from both parenchymal and Kupffer cells, not from altered whole-body clearance, as demonstrated by pharmacokinetic analysis of 125I-IGF-I decay curves. In situ liver perfusion, Kupffer/parenchymal cell isolation, pharmacokinetic analysis of 125I-IGF-I clearance The American journal of physiology Medium 7543247
1996 Recombinant mac25 protein specifically binds IGF-I and IGF-II with lower affinity than IGFBP-3 (5–6-fold lower for IGF-I; 20–25-fold lower for IGF-II), qualifying it as a new member of the IGFBP family (IGFBP-7), based on baculovirus-expressed recombinant protein and affinity cross-linking. Baculovirus expression of recombinant mac25, Western ligand blotting, affinity cross-linking, competition binding The Journal of biological chemistry High 8939990
1999 IGF-I receptor signaling protects mouse embryo fibroblasts from apoptosis (anoikis and okadaic acid-induced) via a PI3-kinase-independent anti-apoptotic pathway, distinct from the insulin receptor which uses a PI3K-dependent pathway, as shown using R⁻ cells (IGF-IR-null) reconstituted with IR or IGF-IR. Stable transfection of R⁻ cells with IR constructs, apoptosis assays, PI3K inhibitor pharmacology, IRS-1 overexpression Hormone and metabolic research Medium 10226786
1999 Ligand-bound estrogen receptor alpha (but not ERβ) rapidly activates IGF-1 receptor phosphorylation and ERK1/2 by physically associating with the IGF-1R upon 17β-estradiol stimulation; this interaction requires IGF-1R expression and is blocked by dominant-negative MEK, identifying ERα as a direct activator of the IGF-1R signaling cascade. Selective transfection in COS7/HEK293 and R⁻ cells, co-immunoprecipitation, phosphorylation assays, dominant-negative MEK, ERE-luciferase reporter The Journal of biological chemistry High 10749889
1999 IGF-I promotes migration of human colonic tumour cells (HT29-D4) by inducing rapid tyrosine phosphorylation of E-cadherin and β-catenin, reducing membranous E-cadherin expression, and reorganizing integrin receptors to the leading edge; tyrosine kinase inhibitors reversed these effects. Monolayer wounding assay, immunofluorescence, Western blot for tyrosine phosphorylation, neutralizing antibodies, tyrosine kinase inhibitors International journal of cancer Medium 10508486
2000 IGF-I induces caveolin-1 phosphorylation at tyrosine 14 and its translocation and formation of membrane patches on the cell surface; IGF-IR colocalizes with caveolin-1 in lipid raft-enriched fractions; these effects are IGF-I-specific and not replicated by insulin in IR-overexpressing cells. Lipid raft fractionation, Western blotting for phospho-caveolin-1, immunofluorescence/membrane patch visualization in R-IGF-IR cells vs. R⁻ cells Biochemical and biophysical research communications Medium 12135605
2000 Nitric oxide (NO) inhibits IGF-I-stimulated chondrocyte proteoglycan synthesis by reducing IGF-I receptor beta-subunit tyrosine autophosphorylation, identified as a mechanism underlying arthritic cartilage insensitivity to IGF-I; restoring NO synthesis inhibition (L-NMA) rescued IGF-I responsiveness in osteoarthritic cartilage. NO donors (SNAP, DETA NONOate), adenoviral iNOS transduction, IL-1 stimulation, ³⁵SO₄ proteoglycan synthesis assay, Western analysis of IGF-IR phosphotyrosine American journal of physiology. Cell physiology High 11003576
2001 Localized muscle-specific IGF-I transgene expression (mIgf-1 isoform) sustains skeletal muscle hypertrophy, prevents age-related atrophy, and preserves regenerative capacity in aged mice, activating GATA-2 in hypertrophic myocytes; the local isoform achieves these effects without systemic abnormalities seen in other IGF-I transgenics. Transgenic mouse model with muscle-restricted IGF-I expression, histological and functional analysis, GATA-2 immunostaining, injury/regeneration assays Nature genetics High 11175789
2001 IGF-I promotes cell cycle entry (S-phase recruitment) of oligodendrocyte progenitors (O-2A cells) and synergizes with FGF-2 and PDGF to amplify DNA synthesis; IGF-I does not affect cell cycle progression rate but increases the proportion of progenitors entering S-phase. BrdU incorporation, cell cycle kinetic analysis, DNA synthesis assays in O-2A progenitor cultures Developmental biology Medium 11401402
2002 IGF-I activates Akt/PKB via the PI3K pathway in motor neurons, phosphorylating IRS-1 and Shc (but not IRS-2), and requires both MAPK and PI3K/Akt pathways simultaneously to prevent glutamate-induced caspase-3 cleavage and DNA fragmentation; neither pathway alone was sufficient for neuroprotection. Enriched embryonic rat motor neuron culture, pharmacological inhibitors (PD98059, LY294002), caspase-3 activity assay, DNA fragmentation, Western blotting for IRS-1/Shc/IRS-2 phosphorylation Neurobiology of disease Medium 15193297
2002 PSM/SH2-B acts as a positive mitogenic signaling adapter downstream of IGF-I receptor: PSM expression stimulates IGF-I-induced DNA synthesis in an ecdysone dose-responsive manner; microinjection of dominant-negative PSM SH2 domain or a PSM Pro-rich peptide mimetic blocked IGF-I-induced DNA synthesis, requiring both the SH2 domain and the Pro-rich region. Ecdysone-regulated expression system, microinjection of dominant-negative domain, cell-permeable peptide mimetics, DNA synthesis assay in NIH3T3 fibroblasts Oncogene Medium 10644978
2002 IGF-I via Akt/PKB phosphorylates huntingtin at a site that is crucial for neuroprotection against mutant huntingtin (polyglutamine-expanded) toxicity; IGF-I/Akt activation also reduces mutant huntingtin intranuclear inclusion formation; Akt activity is reduced in Huntington's disease patient brains. IGF-I treatment of neuronal cultures, Akt inhibitor studies, Akt kinase assay with huntingtin substrate, phosphorylation-deficient huntingtin mutants, patient brain Western blot Developmental cell High 12062094
2002 High extracellular inorganic phosphate increases osteoblastic cell (MC3T3-E1) DNA synthesis in part through an autocrine IGF-I mechanism: high phosphate increases IGF-I secretion and mRNA, and neutralizing IGF-I antibody or anti-IGF-IR antibody significantly blocked (though not fully abolished) the phosphate-stimulated DNA synthesis. DNA synthesis assay, neutralizing antibodies to IGF-I and IGF-IR, IGF-I RIA, Northern blot Journal of cellular physiology Medium 11857446
2005 IGF-I activates PKB/Akt via PI3K in Achilles tendon cells and prevents anoxia-induced apoptosis (characterized by phosphatidylserine exposure, caspase activation, and DNA fragmentation) in a dose-dependent manner; LY294002 (PI3K inhibitor) blocked IGF-I-mediated PKB activation. Anaerobic chamber, flow cytometry (Annexin-V/PI), fluorometric caspase assay, Hoechst staining, LY294002 pharmacology Journal of orthopaedic research Medium 16140203
2005 IGF-I neuroprotection after hypoxia-ischemia in neonatal rat brain involves activation of Akt (phospho-Akt increase in ipsilateral hemisphere) and inactivation of GSK3β (increased phospho-GSK3β in cytosol and nuclear fractions), concomitant with reduced caspase-3 and caspase-9 activity; IGF-I reduced brain damage by 40%. Neonatal rat HI model, i.c.v. IGF-I injection, immunohistochemistry for pAkt/pGSK3β, fluorometric caspase activity assays The European journal of neuroscience Medium 15845077
2005 IGF-I stimulates caveolin-1-dependent eNOS phosphorylation in human endothelial cells (HUVECs); caveolin-1 knockdown abolishes IGF-I-stimulated eNOS phosphorylation, demonstrating that caveolae are required for differential IGF-IR vs. IR-mediated eNOS activation. siRNA knockdown of caveolin-1, Western blotting for phospho-eNOS in HUVECs Biochemical and biophysical research communications Medium 16225848
2006 IGF-I deficiency impairs osteoclastogenesis by reducing osteoclast number and resorptive capacity, and by decreasing RANKL, RANK, M-CSF, and c-fms mRNA levels in bone; co-culture experiments showed that IGF-I is required in both osteoblasts and osteoclast precursors for normal osteoclast differentiation and RANKL-dependent osteoblast–osteoclast coupling. IGF-I knockout mice, histological analysis, RANKL/M-CSF-stimulated osteoclast cultures, co-culture experiments with genotype combinations, quantitative RT-PCR Journal of bone and mineral research High 16939393
2008 IGF-I alleviates diabetes-induced myocardial dysfunction by inhibiting RhoA activation and restoring Akt and eNOS coupling: IGF-I transgenic mice showed reduced active RhoA, restored Akt phosphorylation, normalized eNOS coupling (reduced uncoupling-derived O₂⁻), and increased Kv1.2 expression; effects were mimicked by Rho kinase inhibitor Y27632. Echocardiography, IGF-I transgenic FVB mice, RhoA activation assay, Akt/eNOS phosphorylation Western blot, ROS/NO measurement, DHFR/Kv1.2 expression, pharmacological inhibitors American journal of physiology. Regulatory, integrative and comparative physiology Medium 18199585
2008 IGF-I administration increases basal serotonin levels in the ventral hippocampus and produces long-lasting antidepressant-like behavioral effects that require serotonin: serotonin depletion (by PCPA) blocked IGF-I behavioral effects; IGF-IR antagonist (JB1) given before (but not after) IGF-I prevented the behavioral response, indicating IGF-I initiates a sustained serotonin-dependent neurochemical cascade. i.c.v. IGF-I in rats, forced swim test, microdialysis for serotonin, serotonin depletion with PCPA, IGF-IR antagonist JB1 European journal of pharmacology Medium 18675266
2009 miR-1 targets IGF-I and IGF-1R mRNA (demonstrated by biochemical assays); miR-1 and IGF-1 protein levels are inversely correlated in cardiac hypertrophy/failure models and during C2C12 differentiation; the IGF-1 signaling cascade reciprocally regulates miR-1 expression through the Foxo3a transcription factor, establishing a feedback loop. Bioinformatics, luciferase reporter assays, Western blotting, in vivo cardiac hypertrophy/failure models, C2C12 differentiation, acromegaly patient myocardial biopsies Circulation High 19933931
2012 Matrix-embedded IGF-1 (most abundant growth factor in bone matrix) released during bone remodeling stimulates osteoblastic differentiation of recruited mesenchymal stem cells via activation of mTOR; conditional IGF-1R knockout in pre-osteoblasts reduced bone mass and mineral deposition; local IGF-1 injection with IGFBP3 (but not IGF-1 alone) increased matrix IGF-1 and stimulated new bone formation in aged rats. Conditional IGF-1R knockout mice, Cre-adenovirus deletion in MSCs, in vitro MSC implantation assay, mTOR inhibitor rapamycin, IGF-1 injection in aged rats, bone microarchitecture and marrow IGF-1 measurement Nature medicine High 22729283
2012 IGF-I enhances cellular senescence through a reactive oxygen species–p53 pathway: IGF-I induces γH2AX, elevated p53 and p21 proteins, and SA-β-gal in confluent primary cells; ROS scavenger NAC suppressed senescence markers; p53-null MEFs were resistant to IGF-I-induced senescence. Primary mouse/rat/human cell cultures, γH2AX/p53/p21 Western blot, SA-β-gal staining, NAC treatment, p53-null MEF genetic control Biochemical and biophysical research communications Medium 22877754
2013 IGF-IR signaling is essential for FSH-stimulated AKT activation and steroidogenic gene (Cyp19/aromatase) expression in granulosa cells: IGF-IR inhibition (pharmacological, siRNA, or dominant-negative) abolished FSH/cAMP-induced Cyp19 expression and AKT phosphorylation; constitutively active AKT rescued Cyp19 expression in IGF-IR-deficient cells; in vivo IGF-IR inactivation reduced gonadotropin-stimulated steroidogenesis. Pharmacological IGF-IR inhibitors, siRNA knockdown, dominant-negative IGF-IR, constitutively active AKT rescue, in vivo mouse model, human/mouse/rat granulosa cells Molecular endocrinology High 23340251
2015 Follistatin-induced skeletal muscle hypertrophy requires insulin/IGF-I receptor pathway activation by either insulin or IGF-I: follistatin retained full hypertrophic effect with low IGF-I (hypophysectomized animals) but failed when both insulin and IGF-I were deficient (STZ-diabetic animals); full anabolic response was restored by insulin or IGF-I infusion in STZ animals. Hypophysectomized rat model, STZ-diabetic rat model, follistatin injection, insulin/IGF-I rescue infusion, muscle mass and Akt/mTOR signaling analysis American journal of physiology. Endocrinology and metabolism Medium 26219865
2016 Insulin modulates astrocyte glucose handling (GLUT1 translocation to cell membrane) by cooperating with IGF-I through a synergistic MAPK/protein kinase D pathway; combinatorial IGF-I and insulin action involves GAIP-interacting protein C terminus (GIPC) scaffolding and RAC1 GTPase; this cooperation is required for recovery of neuronal activity after hypoglycemia. Astrocyte cultures, GLUT1 translocation imaging, kinase inhibitors, GIPC/RAC1 protein-protein interaction analysis, in vivo hypoglycemia model Diabetes Medium 27999108
2018 IGF-1R directly phosphorylates PTH1R at tyrosine 494 on its cytoplasmic domain in vitro; phosphorylated PTH1R localizes to barbed ends of actin filaments and enhances actin polymerization during osteoblast-to-osteocyte morphological transition; disruption of Y494 reduces actin polymerization and dendrite length; conditional PTH1R knockout in osteoblasts reduced osteocyte number and dendrite length. In vitro kinase assay (IGF1R phosphorylation of PTH1R), site-directed mutagenesis of Y494, immunofluorescence of phospho-PTH1R/actin, conditional PTH1R knockout mice Bone research High 29507819

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature genetics 1776 20081858
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
1999 Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature genetics 1381 10391209
1978 The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. The Journal of biological chemistry 1265 632300
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1972 Somatomedin: proposed designation for sulphation factor. Nature 845 4550398
1996 Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. The New England journal of medicine 836 8857020
2001 Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nature genetics 831 11175789
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nature genetics 661 22581228
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
2008 Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proceedings of the National Academy of Sciences of the United States of America 535 18316725
2012 Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nature medicine 504 22729283
1992 Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. The Journal of clinical endocrinology and metabolism 463 1383255
2003 Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels. Arteriosclerosis, thrombosis, and vascular biology 460 14604834
1983 Sequence of cDNA encoding human insulin-like growth factor I precursor. Nature 412 6358902
2005 Insulin-like growth factor signaling in fish. International review of cytology 399 15797461
2002 The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Developmental cell 396 12062094
2000 Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway. The Journal of biological chemistry 391 10749889
1999 Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signalling pathway. Nature 372 10448861
2002 Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. Journal of the National Cancer Institute 351 12122101
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
2009 Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation 324 19933931
2008 Regulation of muscle mass by growth hormone and IGF-I. British journal of pharmacology 318 18500379
2004 The prospective association of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-1 levels with all cause and cardiovascular disease mortality in older adults: the Rancho Bernardo Study. The Journal of clinical endocrinology and metabolism 316 14715837
1986 Organization and sequence of the human insulin-like growth factor I gene. Alternative RNA processing produces two insulin-like growth factor I precursor peptides. The Journal of biological chemistry 311 2937782
2002 Expression of IGF-I splice variants in young and old human skeletal muscle after high resistance exercise. The Journal of physiology 304 12562960
2007 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort. Diabetes 294 18003755
2001 A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes 293 11246885
2008 IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair. Circulation research 292 18948617
1999 The IGF-I receptor in cancer research. Experimental cell research 251 10579905
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