{"gene":"IGF1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1978,"finding":"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.","method":"Protein sequencing and structural analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — complete amino acid sequence determination, foundational study with 1265 citations","pmids":["632300"],"is_preprint":false},{"year":1983,"finding":"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.","method":"cDNA sequencing of human liver IGF-I transcript","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — cDNA sequencing establishing precursor structure, replicated and foundational","pmids":["6358902"],"is_preprint":false},{"year":1986,"finding":"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.","method":"Genomic library cloning, Southern blotting, cDNA sequencing","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct gene sequencing and genomic organization, foundational study","pmids":["2937782"],"is_preprint":false},{"year":1990,"finding":"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.","method":"Immunohistochemistry, in situ hybridization, Northern blot in normal and diabetic rats with insulin administration","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (IHC, ISH, Northern) in vivo, single lab","pmids":["2140801"],"is_preprint":false},{"year":1990,"finding":"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.","method":"Receptor binding assays, chemical cross-linking, Western analysis, HPLC tryptic peptide mapping, deglycosylation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods characterizing receptor variant, single lab","pmids":["1693149"],"is_preprint":false},{"year":1991,"finding":"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.","method":"In vitro skeletal myofiber culture in 3D collagen gel, protein synthesis and degradation measurements, myosin heavy-chain quantification","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro system with multiple biochemical readouts","pmids":["2003574"],"is_preprint":false},{"year":1991,"finding":"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.","method":"Primary rat hepatocyte culture, RIA for IGF-I protein, Northern blot for IGF-I mRNA","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — correlated mRNA and protein measurements, dose-response, single lab","pmids":["1936610"],"is_preprint":false},{"year":1991,"finding":"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.","method":"Primary rat hepatocyte culture with defined amino acid deprivation, RIA for IGF-I, Northern blot","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — multiple amino acid conditions tested with matched mRNA and protein readouts","pmids":["1901809"],"is_preprint":false},{"year":1992,"finding":"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.","method":"Northern blot, soluble elastin assay, transient transfection with elastin promoter–CAT reporter, receptor binding analysis","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay plus biochemical endpoints, single lab","pmids":["1325131"],"is_preprint":false},{"year":1992,"finding":"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.","method":"In vitro incubation of purified PSA with 125I-IGFBP-3, Western ligand blotting, competition binding assays","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 1 — purified enzyme reconstitution assay with functional binding consequence","pmids":["1383255"],"is_preprint":false},{"year":1994,"finding":"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.","method":"DNA synthesis assay, neutralizing antibody blockade, IGF-I RIA, Northern blot, cycloheximide inhibition","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple blocking strategies plus mRNA/protein induction, single lab","pmids":["8203509"],"is_preprint":false},{"year":1995,"finding":"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.","method":"In situ liver perfusion, Kupffer/parenchymal cell isolation, pharmacokinetic analysis of 125I-IGF-I clearance","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple complementary methods, single lab","pmids":["7543247"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Baculovirus expression of recombinant mac25, Western ligand blotting, affinity cross-linking, competition binding","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted binding with purified recombinant protein and multiple assays","pmids":["8939990"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Stable transfection of R⁻ cells with IR constructs, apoptosis assays, PI3K inhibitor pharmacology, IRS-1 overexpression","journal":"Hormone and metabolic research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic reconstitution in null cells with pharmacological dissection, single lab","pmids":["10226786"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Selective transfection in COS7/HEK293 and R⁻ cells, co-immunoprecipitation, phosphorylation assays, dominant-negative MEK, ERE-luciferase reporter","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple cell lines including IGF-1R-null cells, functional reporter, multiple methods","pmids":["10749889"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Monolayer wounding assay, immunofluorescence, Western blot for tyrosine phosphorylation, neutralizing antibodies, tyrosine kinase inhibitors","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (phosphorylation, localization, inhibition) in a single cell model","pmids":["10508486"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Lipid raft fractionation, Western blotting for phospho-caveolin-1, immunofluorescence/membrane patch visualization in R-IGF-IR cells vs. R⁻ cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — fractionation plus phosphorylation plus localization, single lab","pmids":["12135605"],"is_preprint":false},{"year":2000,"finding":"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.","method":"NO donors (SNAP, DETA NONOate), adenoviral iNOS transduction, IL-1 stimulation, ³⁵SO₄ proteoglycan synthesis assay, Western analysis of IGF-IR phosphotyrosine","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 — multiple NO delivery methods converging on receptor phosphorylation mechanism, with OA tissue validation","pmids":["11003576"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Transgenic mouse model with muscle-restricted IGF-I expression, histological and functional analysis, GATA-2 immunostaining, injury/regeneration assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — in vivo transgenic model with multiple functional readouts, highly cited foundational study","pmids":["11175789"],"is_preprint":false},{"year":2001,"finding":"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.","method":"BrdU incorporation, cell cycle kinetic analysis, DNA synthesis assays in O-2A progenitor cultures","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — defined cell cycle stage analysis with synergy experiments, single lab","pmids":["11401402"],"is_preprint":false},{"year":2002,"finding":"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.","method":"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","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 — dual pathway epistasis with pharmacological inhibitors plus biochemical readouts","pmids":["15193297"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Ecdysone-regulated expression system, microinjection of dominant-negative domain, cell-permeable peptide mimetics, DNA synthesis assay in NIH3T3 fibroblasts","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — three independent experimental strategies converging on same conclusion, single lab","pmids":["10644978"],"is_preprint":false},{"year":2002,"finding":"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.","method":"IGF-I treatment of neuronal cultures, Akt inhibitor studies, Akt kinase assay with huntingtin substrate, phosphorylation-deficient huntingtin mutants, patient brain Western blot","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 — direct substrate phosphorylation shown with kinase assay, mutagenesis, and human tissue validation","pmids":["12062094"],"is_preprint":false},{"year":2002,"finding":"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.","method":"DNA synthesis assay, neutralizing antibodies to IGF-I and IGF-IR, IGF-I RIA, Northern blot","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple antibody blockade strategies with mRNA/protein measurements, single lab","pmids":["11857446"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Anaerobic chamber, flow cytometry (Annexin-V/PI), fluorometric caspase assay, Hoechst staining, LY294002 pharmacology","journal":"Journal of orthopaedic research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple apoptosis readouts with pharmacological pathway dissection","pmids":["16140203"],"is_preprint":false},{"year":2005,"finding":"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%.","method":"Neonatal rat HI model, i.c.v. IGF-I injection, immunohistochemistry for pAkt/pGSK3β, fluorometric caspase activity assays","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo with multiple signaling and functional readouts, single lab","pmids":["15845077"],"is_preprint":false},{"year":2005,"finding":"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.","method":"siRNA knockdown of caveolin-1, Western blotting for phospho-eNOS in HUVECs","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockdown with signaling readout, single lab","pmids":["16225848"],"is_preprint":false},{"year":2006,"finding":"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.","method":"IGF-I knockout mice, histological analysis, RANKL/M-CSF-stimulated osteoclast cultures, co-culture experiments with genotype combinations, quantitative RT-PCR","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple co-culture genotype combinations and quantitative mRNA, strong preponderance","pmids":["16939393"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Echocardiography, IGF-I transgenic FVB mice, RhoA activation assay, Akt/eNOS phosphorylation Western blot, ROS/NO measurement, DHFR/Kv1.2 expression, pharmacological inhibitors","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mechanistic readouts in transgenic model with pharmacological validation","pmids":["18199585"],"is_preprint":false},{"year":2008,"finding":"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.","method":"i.c.v. IGF-I in rats, forced swim test, microdialysis for serotonin, serotonin depletion with PCPA, IGF-IR antagonist JB1","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological dissection with in vivo microdialysis, single lab","pmids":["18675266"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Bioinformatics, luciferase reporter assays, Western blotting, in vivo cardiac hypertrophy/failure models, C2C12 differentiation, acromegaly patient myocardial biopsies","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (reporter + protein + in vivo + human tissue), strong preponderance","pmids":["19933931"],"is_preprint":false},{"year":2012,"finding":"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.","method":"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","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic KO plus pharmacological inhibition plus in vivo rescue with human tissue correlation, multiple methods","pmids":["22729283"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Primary mouse/rat/human cell cultures, γH2AX/p53/p21 Western blot, SA-β-gal staining, NAC treatment, p53-null MEF genetic control","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and genetic approaches, multiple species, single lab","pmids":["22877754"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Pharmacological IGF-IR inhibitors, siRNA knockdown, dominant-negative IGF-IR, constitutively active AKT rescue, in vivo mouse model, human/mouse/rat granulosa cells","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal loss-of-function methods + rescue + in vivo, replicated across three species","pmids":["23340251"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Hypophysectomized rat model, STZ-diabetic rat model, follistatin injection, insulin/IGF-I rescue infusion, muscle mass and Akt/mTOR signaling analysis","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — multiple genetic/pharmacological models with rescue, single lab","pmids":["26219865"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Astrocyte cultures, GLUT1 translocation imaging, kinase inhibitors, GIPC/RAC1 protein-protein interaction analysis, in vivo hypoglycemia model","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — multiple signaling assays with functional in vivo readout, single lab","pmids":["27999108"],"is_preprint":false},{"year":2018,"finding":"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.","method":"In vitro kinase assay (IGF1R phosphorylation of PTH1R), site-directed mutagenesis of Y494, immunofluorescence of phospho-PTH1R/actin, conditional PTH1R knockout mice","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro kinase assay with mutagenesis plus in vivo genetic model","pmids":["29507819"],"is_preprint":false}],"current_model":"IGF-I is a 70-amino acid secreted peptide (synthesized as a precursor requiring proteolytic processing) that binds the IGF-1R tyrosine kinase, triggering autophosphorylation and phosphorylation of IRS-1, Shc, and other substrates, activating PI3K/Akt/mTOR and MAPK cascades to drive cell survival, protein synthesis, hypertrophy, osteoblast/osteoclast differentiation, steroidogenesis, and neuroprotection; its bioavailability is modulated by IGFBPs (cleaved by proteases such as PSA), its hepatic production is regulated by insulin and amino acid availability, and it directly phosphorylates substrates including huntingtin and PTH1R while engaging caveolin-1, caveolae, and cooperative receptors (ERα, TSHR) to exert tissue-specific effects."},"narrative":{"teleology":[{"year":1978,"claim":"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","pmids":["632300"],"confidence":"High","gaps":["Post-translational processing steps from precursor to mature peptide were not yet defined","Receptor identity unknown"]},{"year":1983,"claim":"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","pmids":["6358902"],"confidence":"High","gaps":["Processing proteases not identified","Alternative splicing not yet characterized"]},{"year":1986,"claim":"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","pmids":["2937782"],"confidence":"High","gaps":["Functional significance of alternative E-peptides unknown","Promoter regulation not mapped"]},{"year":1991,"claim":"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","pmids":["2003574"],"confidence":"High","gaps":["Intracellular signaling pathway not dissected","In vivo relevance not yet shown"]},{"year":1991,"claim":"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","pmids":["1936610","1901809"],"confidence":"Medium","gaps":["Transcription factor mediators of amino acid sensing on IGF1 promoter not identified","In vivo validation in human liver not performed"]},{"year":1992,"claim":"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","pmids":["1383255"],"confidence":"High","gaps":["In vivo relevance of PSA-mediated IGFBP cleavage in seminal fluid not demonstrated","Whether other tissue-specific proteases act similarly was unknown"]},{"year":1999,"claim":"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","pmids":["10226786","10749889"],"confidence":"High","gaps":["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"]},{"year":2001,"claim":"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","pmids":["11175789"],"confidence":"High","gaps":["Downstream transcriptional program beyond GATA-2 not characterized","Whether satellite cell activation is direct or indirect was unresolved"]},{"year":2002,"claim":"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","pmids":["12062094"],"confidence":"High","gaps":["Phosphorylation site on huntingtin not mapped to a specific residue in this study","Therapeutic potential of IGF-I in HD not tested in vivo"]},{"year":2002,"claim":"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","pmids":["15193297"],"confidence":"Medium","gaps":["Downstream convergence point of MAPK and Akt pathways not identified","Whether this dual requirement applies in vivo is untested"]},{"year":2005,"claim":"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","pmids":["15845077"],"confidence":"Medium","gaps":["Relative contributions of caspase-dependent vs. caspase-independent death not resolved","Cell-type specificity of IGF-I action in brain not determined"]},{"year":2006,"claim":"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","pmids":["16939393"],"confidence":"High","gaps":["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"]},{"year":2009,"claim":"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","pmids":["19933931"],"confidence":"High","gaps":["Whether miR-1-IGF-I loop is causally required for hypertrophy reversal not tested","Additional miRNAs targeting IGF-I not systematically surveyed"]},{"year":2012,"claim":"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","pmids":["22729283"],"confidence":"High","gaps":["Mechanism of IGF-1 release from bone matrix not fully characterized","Whether IGFBP3 co-delivery is necessary for clinical translation not determined"]},{"year":2013,"claim":"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","pmids":["23340251"],"confidence":"High","gaps":["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"]},{"year":2018,"claim":"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","pmids":["29507819"],"confidence":"High","gaps":["Whether IGF-1R phosphorylates other GPCRs not explored","Structural details of IGF-1R–PTH1R interaction unknown"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,5,18,22,31]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,12,30]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,5,9,31]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[27,31,36]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,9,12]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,7,33]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13,20,24,25]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[9,33]}],"complexes":[],"partners":["IGF1R","IGFBP3","IGFBP7","CAV1","ESR1","IRS1","PTH1R","SHC1"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"P05019","full_name":"Insulin-like growth factor 1","aliases":["Insulin-like growth factor I","IGF-I","Mechano growth factor","MGF","Somatomedin-C"],"length_aa":195,"mass_kda":21.8,"function":"The insulin-like growth factors, isolated from plasma, are structurally and functionally related to insulin but have a much higher growth-promoting activity. May be a physiological regulator of [1-14C]-2-deoxy-D-glucose (2DG) transport and glycogen synthesis in osteoblasts. Stimulates glucose transport in bone-derived osteoblastic (PyMS) cells and is effective at much lower concentrations than insulin, not only regarding glycogen and DNA synthesis but also with regard to enhancing glucose uptake. May play a role in synapse maturation (PubMed:21076856, PubMed:24132240). Ca(2+)-dependent exocytosis of IGF1 is required for sensory perception of smell in the olfactory bulb (By similarity). Acts as a ligand for IGF1R. Binds to the alpha subunit of IGF1R, leading to the activation of the intrinsic tyrosine kinase activity which autophosphorylates tyrosine residues in the beta subunit thus initiating a cascade of down-stream signaling events leading to activation of the PI3K-AKT/PKB and the Ras-MAPK pathways. Binds to integrins ITGAV:ITGB3 and ITGA6:ITGB4. Its binding to integrins and subsequent ternary complex formation with integrins and IGFR1 are essential for IGF1 signaling. Induces the phosphorylation and activation of IGFR1, MAPK3/ERK1, MAPK1/ERK2 and AKT1 (PubMed:19578119, PubMed:22351760, PubMed:23243309, PubMed:23696648). As part of the MAPK/ERK signaling pathway, acts as a negative regulator of apoptosis in cardiomyocytes via promotion of STUB1/CHIP-mediated ubiquitination and degradation of ICER-type isoforms of CREM (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P05019/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IGF1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IGF1","total_profiled":1310},"omim":[{"mim_id":"621380","title":"TRANSMEMBRANE PROTEIN 68; TMEM68","url":"https://www.omim.org/entry/621380"},{"mim_id":"621355","title":"KRI1 HOMOLOG; KRI1","url":"https://www.omim.org/entry/621355"},{"mim_id":"620839","title":"CHROMOSOME 6 OPEN READING FRAME 132; C6ORF132","url":"https://www.omim.org/entry/620839"},{"mim_id":"620186","title":"BRANCHIAL ARCH ABNORMALITIES, CHOANAL ATRESIA, ATHELIA, HEARING LOSS, AND HYPOTHYROIDISM SYNDROME; BCAHH","url":"https://www.omim.org/entry/620186"},{"mim_id":"619993","title":"PROLINE-RICH TRANSMEMBRANE PROTEIN 3; PRRT3","url":"https://www.omim.org/entry/619993"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Alternative RNA processing produces two insulin-like growth factor I precursor peptides.","date":"1986","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2937782","citation_count":311,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12562960","id":"PMC_12562960","title":"Expression of IGF-I splice variants in young and old human skeletal muscle after high resistance exercise.","date":"2002","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12562960","citation_count":304,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18003755","id":"PMC_18003755","title":"25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort.","date":"2007","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/18003755","citation_count":294,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11246885","id":"PMC_11246885","title":"A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction.","date":"2001","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/11246885","citation_count":293,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18948617","id":"PMC_18948617","title":"IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair.","date":"2008","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/18948617","citation_count":292,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44493,"output_tokens":6012,"usd":0.111829},"stage2":{"model":"claude-opus-4-6","input_tokens":9628,"output_tokens":3626,"usd":0.208185},"total_usd":0.719785,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":57964,"output_tokens":8732,"usd":0.152436},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":12873,"output_tokens":4021,"usd":0.247335}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"IGF-I receptor (IGF-IR) signals through two major substrates, IRS-1 and Shc, which determine whether IGF-IR will transform cells or cause differentiation; impairment of IGF-IR function causes apoptosis of tumor cells, establishing IGF-IR as essential for anchorage-independent growth\",\n      \"method\": \"Cell-based functional assays, dominant-negative and loss-of-function experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple labs, foundational paper with >250 citations describing mechanistic substrate hierarchy\",\n      \"pmids\": [\"10579905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"IGF-IR protection from apoptosis is partially PI3-kinase-independent, unlike the insulin receptor, suggesting IGF-IR uses an alternative anti-apoptotic pathway; R-cells lacking IGF-IR were stably transfected with insulin receptor to dissect pathway-specific contributions\",\n      \"method\": \"Stable transfection of IGF-IR-null R-cells with insulin receptor constructs; PI3K inhibitor treatment; apoptosis assays (anoikis, okadaic acid)\",\n      \"journal\": \"Hormone and metabolic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO cell system with pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"10226786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Nitric oxide (NO) inhibits IGF-I-stimulated proteoglycan synthesis in chondrocytes by reducing IGF-I receptor beta-subunit (IGF-IRβ) tyrosine autophosphorylation, explaining arthritic cartilage insensitivity to IGF-I\",\n      \"method\": \"Western blot for IGF-IR phosphotyrosine; NO donors (SNAP, DETA NONOate); adenoviral iNOS transduction; IL-1 activation; 35SO4 incorporation assay; iNOS-KO mouse cartilage\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (pharmacological, genetic, biochemical) with defined molecular readout\",\n      \"pmids\": [\"11003576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IGF-I promotes migration of colonic epithelial cells by inducing tyrosine phosphorylation of E-cadherin and β-catenin, causing reduced membranous E-cadherin expression, and by reorganizing integrin receptors to the leading edge of migrating cells\",\n      \"method\": \"Monolayer wounding assay; immunofluorescence; Western blot for phospho-tyrosine; tyrosine kinase inhibitor treatment; integrin-blocking experiments\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (inhibitor, imaging, biochemistry), single lab\",\n      \"pmids\": [\"10508486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IGF-I induces tyrosine phosphorylation of caveolin-1 at Y14 and causes its translocation, forming membrane patches on the cell surface; IGF-IR co-localizes with caveolin-1 in lipid raft-enriched fractions, an effect specific to IGF-I and not insulin\",\n      \"method\": \"Subcellular fractionation (lipid rafts); Western blot for phospho-caveolin-1 Y14; immunofluorescence; comparison with insulin-stimulated cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with biochemical validation, single lab\",\n      \"pmids\": [\"12135605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In motor neurons, IGF-I activates MAPK and PI3K/Akt pathways via phosphorylation of IRS-1 and Shc (but not IRS-2), and protects against glutamate-induced caspase-3 cleavage and DNA fragmentation; both MAPK and PI3K pathways together mediate neuroprotection\",\n      \"method\": \"Enriched embryonic motor neuron cultures; pathway inhibitors (PD98059, LY294002); IRS-1/Shc/IRS-2 phosphorylation assay; caspase-3 cleavage assay; DNA fragmentation assay\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple pharmacological dissections with defined molecular and phenotypic readouts, orthogonal methods\",\n      \"pmids\": [\"15193297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IGF-I activates Akt (PKB) after hypoxia-ischemia in neonatal rat brain and causes nuclear accumulation of phospho-GSK3β, concomitant with reduced caspase-3 and caspase-9 activity, resulting in ~40% reduction in brain damage\",\n      \"method\": \"In vivo neonatal rat HI model; intracerebroventricular IGF-I injection; immunoreactivity for pAkt and pGSK3β by subcellular fractionation; caspase activity assays; MAP-2 loss quantification\",\n      \"journal\": \"European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model with subcellular fractionation and multiple biochemical readouts, single lab\",\n      \"pmids\": [\"15845077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IGF-I activates PKB/PI3K pathway in Achilles tendon cells and prevents anoxia-induced apoptosis (phosphatidylserine exposure, caspase activation, DNA fragmentation) in a dose-dependent manner; this protection is blocked by the PI3K inhibitor LY294002\",\n      \"method\": \"Anaerobic chamber culture; Annexin-V/PI flow cytometry; fluorometric caspase assay; Hoechst staining; LY294002 inhibition of PKB\",\n      \"journal\": \"Journal of orthopaedic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple apoptosis readouts with pharmacological pathway validation, single lab\",\n      \"pmids\": [\"16140203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IGF-I deficiency impairs osteoclastogenesis by reducing RANKL, RANK, M-CSF, and c-fms mRNA levels, and by disrupting the interaction between osteoblasts and osteoclast precursors; direct addition of IGF-I increases osteoclast size, number, and resorptive area in vitro\",\n      \"method\": \"IGF-I knockout mouse model; histological analysis; co-culture of osteoblasts and osteoclast precursors; RANKL/M-CSF-stimulated osteoclast formation assay; TRACP staining; pit formation assay; quantitative RT-PCR\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO combined with multiple in vitro co-culture and molecular readouts, rigorous genetic dissection\",\n      \"pmids\": [\"16939393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IGF-I rescues diabetic cardiomyopathy by inhibiting RhoA activity, restoring phospho-Akt and eNOS coupling, and recovering Kv1.2 and DHFR expression; these effects are mimicked by the Rho kinase inhibitor Y27632\",\n      \"method\": \"IGF-I transgenic mice on diabetic background; echocardiography; cardiomyocyte contractility assay; RhoA mRNA and activity assay; NO/O2- measurements; pharmacological tools (Y27632, L-NAME, folate, methotrexate); Western blot for pAkt/eNOS\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic model combined with pharmacological dissection and multiple biochemical readouts, single lab\",\n      \"pmids\": [\"18199585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IGF-I activates the PI3K-AKT pathway in otic neural progenitors, maintaining them in an undifferentiated, proliferative state with upregulation of FoxM1; as neurons mature, IGF-1R expression decreases while TrkC increases, rendering them IGF-I-independent\",\n      \"method\": \"Organotypic cultures of chicken otic vesicles; Western blotting; immunohistochemistry; in situ hybridization; PI3K inhibitor treatments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in organotypic model, single lab\",\n      \"pmids\": [\"22292041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IGF-I enhances cellular senescence through a ROS-p53 pathway: IGF-I induces γH2AX, elevated p53 and p21, and SA-β-gal activity in confluent primary cells; ROS scavenger N-acetylcysteine blocks these effects, and p53-null cells are resistant to IGF-I-induced senescence\",\n      \"method\": \"Primary mouse, rat, and human cells; SA-β-gal staining; γH2AX immunostaining; Western blot for p53/p21; ROS scavenger treatment; p53-null MEFs\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell types and genetic (p53-KO) plus pharmacological validation, single lab\",\n      \"pmids\": [\"22877754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IGF-I receptor signaling is required for FSH-stimulated AKT phosphorylation and steroidogenic gene (Cyp19) expression in granulosa cells; blocking IGF-IR by pharmacological, genetic, or biochemical means abolishes FSH-induced AKT activation and estradiol production; constitutively active AKT rescues Cyp19 expression in IGF-IR-deficient cells\",\n      \"method\": \"Human, mouse, and rat granulosa cells; IGF-IR inhibitors; siRNA knockdown; pharmacological IGF-IR inactivation; AKT phosphorylation assay; constitutively active AKT rescue; in vivo IGF-IR inactivation in mice\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal methods (pharmacological, genetic, biochemical), genetic rescue experiment, multi-species validation\",\n      \"pmids\": [\"23340251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IGF-I cooperates with insulin in astrocytes to regulate brain glucose metabolism; the combined action synergistically stimulates a MAPK/protein kinase D pathway leading to GLUT1 translocation to the cell membrane through protein-protein interactions involving GAIP-interacting protein C terminus (GIPC) and RAC1\",\n      \"method\": \"Astrocyte culture; glucose metabolism assays; MAPK/PKD pathway inhibitors; GLUT1 membrane translocation assay; co-immunoprecipitation for GIPC and RAC1; in vivo hypoglycemia rescue model\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissection with multiple interactors identified, single lab\",\n      \"pmids\": [\"27999108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IGF-IR directly phosphorylates tyrosine Y494 on the cytoplasmic domain of PTH1R, causing phospho-PTH1R to localize to barbed ends of actin filaments and increasing actin polymerization during osteoblast-to-osteocyte transition; disruption of Y494 reduces dendrite length and actin polymerization\",\n      \"method\": \"In vitro kinase assay (IGF1R phosphorylating PTH1R Y494); site-directed mutagenesis of Y494; actin polymerization assay; immunofluorescence co-localization; conditional PTH1R KO mouse model\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted kinase assay plus mutagenesis plus in vivo mouse model validation\",\n      \"pmids\": [\"29507819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IGF-I-induced caveolin-1 phosphorylation and IGF-IR localization to caveolae is required for eNOS phosphorylation in human endothelial cells; caveolin-1 downregulation abolishes both insulin- and IGF-I-stimulated eNOS phosphorylation\",\n      \"method\": \"siRNA knockdown of caveolin-1 in HUVECs; Western blot for phospho-eNOS; comparison of insulin vs IGF-I responses\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA KD with defined biochemical readout, single lab\",\n      \"pmids\": [\"16225848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"IGF-I (but not IGF-II) induces myofiber hypertrophy in vitro by stimulating a 42–62% increase in total protein synthesis and a 28–38% decrease in protein degradation, including specific stimulation of myosin heavy-chain synthesis and inhibition of its degradation, accompanied by increased myonuclear accretion\",\n      \"method\": \"Avian primary myofiber cultures in 3D collagen gel; protein synthesis/degradation measurements; myosin heavy-chain content assay; nuclear count per unit fiber length\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with quantitative protein turnover measurements, foundational paper >150 citations\",\n      \"pmids\": [\"2003574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Insulin regulates hepatic IGF-I production at the mRNA level; increasing insulin concentrations dose-dependently stimulate IGF-I release and IGF-I mRNA content in primary rat hepatocytes, with release strongly correlated to mRNA levels\",\n      \"method\": \"Primary rat hepatocyte cultures; radioimmunoassay for IGF-I; Northern/RNA quantification; dose-response with insulin; correlation analysis of IGF-I mRNA vs. protein release\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — primary cell culture with quantitative mRNA-protein correlation, single lab but replicated by related studies\",\n      \"pmids\": [\"1936610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PSM/SH2-B functions as a positive mitogenic signaling adapter downstream of IGF-IR; microinjection of the dominant-negative PSM SH2 domain inhibits IGF-I-induced DNA synthesis, and PSM expression amplifies IGF-I-stimulated mitogenesis through its SH2 domain and Pro-rich SH3-binding region\",\n      \"method\": \"Ecdysone-regulated cDNA expression; microinjection of dominant-negative SH2 domain; cell-permeable inhibitory peptides; DNA synthesis assay in NIH3T3 fibroblasts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — three independent experimental strategies converging on same conclusion, single lab\",\n      \"pmids\": [\"10644978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IGF-I synergizes with FGF-2 to promote recruitment of oligodendrocyte progenitors into S-phase of the cell cycle, acting as a cell cycle progression factor without affecting the rate of cell cycle progression\",\n      \"method\": \"O-2A progenitor cultures; DNA synthesis assay (BrdU/tritiated thymidine); cell cycle kinetics analysis; combination dose-response experiments\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotype (S-phase entry) with mechanistic dissection from rate of progression, single lab\",\n      \"pmids\": [\"11401402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"IGF-I increases tropoelastin mRNA steady-state levels and soluble elastin production in aortic smooth muscle cells but not pulmonary fibroblasts, acting at the level of transcription or transcript stability; both cell types express IGF-IR, indicating cell-type-specific downstream regulation of elastin gene expression\",\n      \"method\": \"Cell culture; elastin mRNA steady-state measurements; soluble elastin quantification; transient transfection with elastin promoter-CAT reporter; IGF-IR receptor binding assays\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — reporter gene assay combined with receptor binding and biochemical measurements, single lab\",\n      \"pmids\": [\"1325131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"IGF-I mediates high extracellular calcium-stimulated osteoblast proliferation: high [Ca2+]e increases IGF-I secretion and IGF-I mRNA expression in MC3T3-E1 cells, and neutralizing IGF-I antibody abolishes the calcium-induced DNA synthesis\",\n      \"method\": \"MC3T3-E1 osteoblastic cell cultures; neutralizing IGF-I antiserum and antibody; IGF-I receptor antibody blocking; DNA synthesis (3H-thymidine); IGF-I immunoassay; IGF-I mRNA measurement\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — neutralizing antibody plus receptor antibody converging on same phenotype, single lab\",\n      \"pmids\": [\"8203509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"High extracellular inorganic phosphate stimulates osteoblast DNA synthesis in part through autocrine IGF-I: high [Pi] increases IGF-I mRNA expression and secretion, and neutralizing IGF-I antibody or IGF-IR antibody partially blocks phosphate-induced proliferation\",\n      \"method\": \"MC3T3-E1 cells; neutralizing IGF-I antiserum and IGF-IR antibody; DNA synthesis assay; IGF-I immunoassay; IGF-I mRNA measurement; cycloheximide experiments\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody blockade at both ligand and receptor level, single lab\",\n      \"pmids\": [\"11857446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IGF-I produces antidepressant-like behavioral effects that require intact serotonin transmission; serotonin depletion (by PCPA) blocks IGF-I's antidepressant effect; IGF-I increases basal serotonin levels in the ventral hippocampus; IGF-I receptor blockade (JB1 antagonist) prevents behavioral effects when given before IGF-I\",\n      \"method\": \"Rat forced swim test; i.c.v. IGF-I administration; IGF-I receptor antagonist JB1; tryptophan hydroxylase inhibitor PCPA; in vivo microdialysis for serotonin; [3H]citalopram binding; RT-PCR for TPH and SERT\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological receptor blockade combined with neurochemical measurements, single lab\",\n      \"pmids\": [\"18675266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Follistatin-induced skeletal muscle hypertrophy requires activation of the insulin/IGF-I pathway (type 1 IGF-IR/Akt/mTOR); IGF-I alone is dispensable (hypophysectomized animals retain full hypertrophy), but when both insulin and IGF-I are deficient (streptozotocin model), follistatin fails to stimulate muscle growth, and either insulin or IGF-I infusion restores the response\",\n      \"method\": \"Hypophysectomized rats; streptozotocin-induced diabetes; follistatin treatment; IGF-I and insulin infusion rescue; muscle mass measurement; Akt phosphorylation assay; IGF-I mRNA measurement\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic/hormonal deprivation models with hormone replacement rescue, single lab\",\n      \"pmids\": [\"26219865\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGF-I signals primarily through the IGF-I receptor (IGF-IR), a transmembrane tyrosine kinase that, upon ligand binding, autophosphorylates and phosphorylates adapter substrates IRS-1 and Shc to activate PI3K/Akt and MAPK pathways, promoting cell survival, proliferation, and differentiation; IGF-IR also directly phosphorylates interacting proteins such as PTH1R, localizes with caveolin-1 in lipid rafts to regulate eNOS activity, can be inhibited at the receptor level by nitric oxide (reducing autophosphorylation), and drives context-specific downstream outcomes including muscle hypertrophy via increased protein synthesis/decreased proteolysis, osteoclastogenesis via RANKL/RANK regulation, neuronal survival via PI3K/Akt/GSK3β, and steroidogenesis via AKT in granulosa cells.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1978,\n      \"finding\": \"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.\",\n      \"method\": \"Protein sequencing and structural analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — complete amino acid sequence determination, foundational study with 1265 citations\",\n      \"pmids\": [\"632300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1983,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA sequencing of human liver IGF-I transcript\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cDNA sequencing establishing precursor structure, replicated and foundational\",\n      \"pmids\": [\"6358902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"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.\",\n      \"method\": \"Genomic library cloning, Southern blotting, cDNA sequencing\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct gene sequencing and genomic organization, foundational study\",\n      \"pmids\": [\"2937782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry, in situ hybridization, Northern blot in normal and diabetic rats with insulin administration\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (IHC, ISH, Northern) in vivo, single lab\",\n      \"pmids\": [\"2140801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"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.\",\n      \"method\": \"Receptor binding assays, chemical cross-linking, Western analysis, HPLC tryptic peptide mapping, deglycosylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods characterizing receptor variant, single lab\",\n      \"pmids\": [\"1693149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro skeletal myofiber culture in 3D collagen gel, protein synthesis and degradation measurements, myosin heavy-chain quantification\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro system with multiple biochemical readouts\",\n      \"pmids\": [\"2003574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"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.\",\n      \"method\": \"Primary rat hepatocyte culture, RIA for IGF-I protein, Northern blot for IGF-I mRNA\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — correlated mRNA and protein measurements, dose-response, single lab\",\n      \"pmids\": [\"1936610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"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.\",\n      \"method\": \"Primary rat hepatocyte culture with defined amino acid deprivation, RIA for IGF-I, Northern blot\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple amino acid conditions tested with matched mRNA and protein readouts\",\n      \"pmids\": [\"1901809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"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.\",\n      \"method\": \"Northern blot, soluble elastin assay, transient transfection with elastin promoter–CAT reporter, receptor binding analysis\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay plus biochemical endpoints, single lab\",\n      \"pmids\": [\"1325131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro incubation of purified PSA with 125I-IGFBP-3, Western ligand blotting, competition binding assays\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — purified enzyme reconstitution assay with functional binding consequence\",\n      \"pmids\": [\"1383255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"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.\",\n      \"method\": \"DNA synthesis assay, neutralizing antibody blockade, IGF-I RIA, Northern blot, cycloheximide inhibition\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple blocking strategies plus mRNA/protein induction, single lab\",\n      \"pmids\": [\"8203509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"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.\",\n      \"method\": \"In situ liver perfusion, Kupffer/parenchymal cell isolation, pharmacokinetic analysis of 125I-IGF-I clearance\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary methods, single lab\",\n      \"pmids\": [\"7543247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Baculovirus expression of recombinant mac25, Western ligand blotting, affinity cross-linking, competition binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted binding with purified recombinant protein and multiple assays\",\n      \"pmids\": [\"8939990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Stable transfection of R⁻ cells with IR constructs, apoptosis assays, PI3K inhibitor pharmacology, IRS-1 overexpression\",\n      \"journal\": \"Hormone and metabolic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic reconstitution in null cells with pharmacological dissection, single lab\",\n      \"pmids\": [\"10226786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Selective transfection in COS7/HEK293 and R⁻ cells, co-immunoprecipitation, phosphorylation assays, dominant-negative MEK, ERE-luciferase reporter\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple cell lines including IGF-1R-null cells, functional reporter, multiple methods\",\n      \"pmids\": [\"10749889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Monolayer wounding assay, immunofluorescence, Western blot for tyrosine phosphorylation, neutralizing antibodies, tyrosine kinase inhibitors\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (phosphorylation, localization, inhibition) in a single cell model\",\n      \"pmids\": [\"10508486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Lipid raft fractionation, Western blotting for phospho-caveolin-1, immunofluorescence/membrane patch visualization in R-IGF-IR cells vs. R⁻ cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — fractionation plus phosphorylation plus localization, single lab\",\n      \"pmids\": [\"12135605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"NO donors (SNAP, DETA NONOate), adenoviral iNOS transduction, IL-1 stimulation, ³⁵SO₄ proteoglycan synthesis assay, Western analysis of IGF-IR phosphotyrosine\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple NO delivery methods converging on receptor phosphorylation mechanism, with OA tissue validation\",\n      \"pmids\": [\"11003576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Transgenic mouse model with muscle-restricted IGF-I expression, histological and functional analysis, GATA-2 immunostaining, injury/regeneration assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic model with multiple functional readouts, highly cited foundational study\",\n      \"pmids\": [\"11175789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"BrdU incorporation, cell cycle kinetic analysis, DNA synthesis assays in O-2A progenitor cultures\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cell cycle stage analysis with synergy experiments, single lab\",\n      \"pmids\": [\"11401402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual pathway epistasis with pharmacological inhibitors plus biochemical readouts\",\n      \"pmids\": [\"15193297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Ecdysone-regulated expression system, microinjection of dominant-negative domain, cell-permeable peptide mimetics, DNA synthesis assay in NIH3T3 fibroblasts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — three independent experimental strategies converging on same conclusion, single lab\",\n      \"pmids\": [\"10644978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"IGF-I treatment of neuronal cultures, Akt inhibitor studies, Akt kinase assay with huntingtin substrate, phosphorylation-deficient huntingtin mutants, patient brain Western blot\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct substrate phosphorylation shown with kinase assay, mutagenesis, and human tissue validation\",\n      \"pmids\": [\"12062094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"DNA synthesis assay, neutralizing antibodies to IGF-I and IGF-IR, IGF-I RIA, Northern blot\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple antibody blockade strategies with mRNA/protein measurements, single lab\",\n      \"pmids\": [\"11857446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Anaerobic chamber, flow cytometry (Annexin-V/PI), fluorometric caspase assay, Hoechst staining, LY294002 pharmacology\",\n      \"journal\": \"Journal of orthopaedic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple apoptosis readouts with pharmacological pathway dissection\",\n      \"pmids\": [\"16140203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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%.\",\n      \"method\": \"Neonatal rat HI model, i.c.v. IGF-I injection, immunohistochemistry for pAkt/pGSK3β, fluorometric caspase activity assays\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo with multiple signaling and functional readouts, single lab\",\n      \"pmids\": [\"15845077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of caveolin-1, Western blotting for phospho-eNOS in HUVECs\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown with signaling readout, single lab\",\n      \"pmids\": [\"16225848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"IGF-I knockout mice, histological analysis, RANKL/M-CSF-stimulated osteoclast cultures, co-culture experiments with genotype combinations, quantitative RT-PCR\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple co-culture genotype combinations and quantitative mRNA, strong preponderance\",\n      \"pmids\": [\"16939393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Echocardiography, IGF-I transgenic FVB mice, RhoA activation assay, Akt/eNOS phosphorylation Western blot, ROS/NO measurement, DHFR/Kv1.2 expression, pharmacological inhibitors\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic readouts in transgenic model with pharmacological validation\",\n      \"pmids\": [\"18199585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"i.c.v. IGF-I in rats, forced swim test, microdialysis for serotonin, serotonin depletion with PCPA, IGF-IR antagonist JB1\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological dissection with in vivo microdialysis, single lab\",\n      \"pmids\": [\"18675266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Bioinformatics, luciferase reporter assays, Western blotting, in vivo cardiac hypertrophy/failure models, C2C12 differentiation, acromegaly patient myocardial biopsies\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter + protein + in vivo + human tissue), strong preponderance\",\n      \"pmids\": [\"19933931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus pharmacological inhibition plus in vivo rescue with human tissue correlation, multiple methods\",\n      \"pmids\": [\"22729283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Primary mouse/rat/human cell cultures, γH2AX/p53/p21 Western blot, SA-β-gal staining, NAC treatment, p53-null MEF genetic control\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic approaches, multiple species, single lab\",\n      \"pmids\": [\"22877754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological IGF-IR inhibitors, siRNA knockdown, dominant-negative IGF-IR, constitutively active AKT rescue, in vivo mouse model, human/mouse/rat granulosa cells\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal loss-of-function methods + rescue + in vivo, replicated across three species\",\n      \"pmids\": [\"23340251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Hypophysectomized rat model, STZ-diabetic rat model, follistatin injection, insulin/IGF-I rescue infusion, muscle mass and Akt/mTOR signaling analysis\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic/pharmacological models with rescue, single lab\",\n      \"pmids\": [\"26219865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Astrocyte cultures, GLUT1 translocation imaging, kinase inhibitors, GIPC/RAC1 protein-protein interaction analysis, in vivo hypoglycemia model\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling assays with functional in vivo readout, single lab\",\n      \"pmids\": [\"27999108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay (IGF1R phosphorylation of PTH1R), site-directed mutagenesis of Y494, immunofluorescence of phospho-PTH1R/actin, conditional PTH1R knockout mice\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro kinase assay with mutagenesis plus in vivo genetic model\",\n      \"pmids\": [\"29507819\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGF-I is a 70-amino acid secreted peptide (synthesized as a precursor requiring proteolytic processing) that binds the IGF-1R tyrosine kinase, triggering autophosphorylation and phosphorylation of IRS-1, Shc, and other substrates, activating PI3K/Akt/mTOR and MAPK cascades to drive cell survival, protein synthesis, hypertrophy, osteoblast/osteoclast differentiation, steroidogenesis, and neuroprotection; its bioavailability is modulated by IGFBPs (cleaved by proteases such as PSA), its hepatic production is regulated by insulin and amino acid availability, and it directly phosphorylates substrates including huntingtin and PTH1R while engaging caveolin-1, caveolae, and cooperative receptors (ERα, TSHR) to exert tissue-specific effects.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IGF1 is a secreted growth factor that acts as a central mediator of cell survival, proliferation, differentiation, and tissue-specific growth by signaling through the IGF-I receptor (IGF-IR), a transmembrane tyrosine kinase that autophosphorylates and recruits the adapter substrates IRS-1 and Shc to activate PI3K/Akt and MAPK cascades [PMID:10579905, PMID:15193297]. IGF1 drives skeletal muscle hypertrophy by simultaneously increasing protein synthesis (including myosin heavy chain) and decreasing protein degradation [PMID:2003574], promotes osteoclastogenesis through regulation of RANKL/RANK and M-CSF expression [PMID:16939393], and is required for FSH-stimulated AKT activation and steroidogenic gene expression in granulosa cells [PMID:23340251]. Neuroprotective signaling proceeds through PI3K/Akt-mediated phosphorylation of GSK3β and suppression of caspase-3/9 activity [PMID:15845077, PMID:15193297], while in endothelial cells IGF-IR localizes to caveolin-1-containing lipid rafts to couple to eNOS phosphorylation [PMID:12135605, PMID:16225848]. Hepatic IGF1 production is transcriptionally regulated by insulin [PMID:1936610], and nitric oxide inhibits IGF-IR signaling by reducing receptor autophosphorylation [PMID:11003576].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing IGF1 as an anabolic effector in muscle: it was unknown how IGF-I drives myofiber hypertrophy, and quantitative measurements showed it simultaneously stimulates protein synthesis and suppresses degradation, including myosin heavy chain turnover, while promoting myonuclear accretion.\",\n      \"evidence\": \"Primary avian myofiber cultures in 3D collagen gel with quantitative protein turnover measurements\",\n      \"pmids\": [\"2003574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathway mediating the dual protein synthesis/degradation effect was not identified\", \"Whether the mechanism operates identically in mammalian muscle was not tested\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Identifying a key upstream regulator of IGF1 production: insulin was shown to dose-dependently stimulate hepatic IGF-I mRNA and protein secretion, establishing the GH–insulin–IGF-I endocrine axis at the molecular level.\",\n      \"evidence\": \"Primary rat hepatocyte cultures with radioimmunoassay and RNA quantification\",\n      \"pmids\": [\"1936610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether insulin acts at the transcriptional or post-transcriptional level on IGF1 mRNA was not resolved\", \"GH-independent vs GH-dependent regulation not dissected\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defining the receptor-proximal signaling hierarchy: IRS-1 and Shc were identified as the two major IGF-IR substrates that bifurcate signaling toward transformation versus differentiation, and loss of IGF-IR function was shown to be sufficient for tumor cell apoptosis.\",\n      \"evidence\": \"Dominant-negative and loss-of-function experiments in cell-based transformation and apoptosis assays\",\n      \"pmids\": [\"10579905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How relative IRS-1/Shc activation ratios are regulated in different cell contexts remained unclear\", \"Whether additional substrates contribute was not excluded\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Revealing a PI3K-independent anti-apoptotic arm: unlike insulin receptor signaling, IGF-IR provided partial protection from apoptosis even when PI3K was inhibited, indicating an alternative survival pathway.\",\n      \"evidence\": \"IGF-IR-null R-cells reconstituted with insulin receptor; PI3K inhibitor treatment; anoikis and okadaic acid apoptosis assays\",\n      \"pmids\": [\"10226786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The identity of the PI3K-independent survival pathway was not determined\", \"Single cell line system limits generalizability\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Explaining arthritic cartilage IGF-I resistance: nitric oxide was found to directly inhibit IGF-IR β-subunit autophosphorylation, blocking downstream proteoglycan synthesis in chondrocytes.\",\n      \"evidence\": \"NO donors, adenoviral iNOS, and iNOS-KO mouse cartilage with phosphotyrosine Western blots and 35SO4 incorporation\",\n      \"pmids\": [\"11003576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of NO-mediated inhibition of IGF-IR autophosphorylation (S-nitrosylation vs other) was not defined\", \"In vivo therapeutic relevance not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linking IGF-IR to lipid raft signaling: IGF-I was shown to induce caveolin-1 Y14 phosphorylation and IGF-IR co-localization with caveolin-1 in lipid rafts, a specificity not shared by insulin, establishing a compartmentalized signaling platform.\",\n      \"evidence\": \"Lipid raft fractionation and phospho-caveolin-1 Western blots in fibroblasts\",\n      \"pmids\": [\"12135605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of raft localization for specific downstream pathways was not shown in this study\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Dissecting neuroprotective signaling: in motor neurons, IGF-I was shown to activate both MAPK and PI3K/Akt via IRS-1 and Shc (but not IRS-2), and both pathways were jointly required to protect against glutamate-induced caspase-3 activation.\",\n      \"evidence\": \"Enriched embryonic motor neuron cultures with pathway inhibitors PD98059 and LY294002; caspase-3 cleavage and DNA fragmentation assays\",\n      \"pmids\": [\"15193297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream convergence point of MAPK and PI3K pathways in neuroprotection not identified\", \"Whether IRS-2 exclusion is motor-neuron-specific was not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connecting caveolar IGF-IR signaling to endothelial NO production: caveolin-1 was shown to be required for IGF-I-stimulated eNOS phosphorylation, linking lipid raft compartmentalization to vascular function.\",\n      \"evidence\": \"siRNA knockdown of caveolin-1 in HUVECs with phospho-eNOS Western blots\",\n      \"pmids\": [\"16225848\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether caveolin-1 acts as scaffold vs. signaling intermediate was not resolved\", \"Only endothelial cells tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extending Akt-mediated neuroprotection in vivo: IGF-I was shown to activate Akt and cause nuclear accumulation of phospho-GSK3β in neonatal brain after hypoxia-ischemia, reducing caspase-3/9 activity and brain damage by ~40%.\",\n      \"evidence\": \"Neonatal rat HI model with intracerebroventricular IGF-I; subcellular fractionation for pAkt/pGSK3β; caspase assays\",\n      \"pmids\": [\"15845077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type specificity of neuroprotection (neurons vs glia) was not resolved\", \"Whether GSK3β is the critical downstream effector or a correlate was not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing IGF1 as a regulator of osteoclastogenesis: IGF-I knockout mice had impaired osteoclast formation due to reduced RANKL, RANK, M-CSF, and c-fms expression, and exogenous IGF-I rescued osteoclast size, number, and resorptive activity.\",\n      \"evidence\": \"IGF-I KO mice with histology; co-culture osteoblast/osteoclast precursor assays; qRT-PCR for RANKL axis genes\",\n      \"pmids\": [\"16939393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IGF-I acts directly on osteoclast precursors or only via osteoblast-mediated RANKL was not fully dissected\", \"Downstream signaling within osteoclasts not characterized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defining a RhoA-eNOS axis in cardiac protection: IGF-I was found to rescue diabetic cardiomyopathy by inhibiting RhoA, restoring Akt/eNOS coupling and Kv1.2 expression, effects recapitulated by the Rho kinase inhibitor Y27632.\",\n      \"evidence\": \"IGF-I transgenic mice crossed to diabetic background; echocardiography; RhoA activity assays; pharmacological tools\",\n      \"pmids\": [\"18199585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which IGF-I inhibits RhoA activity was not identified\", \"Whether cardiac effects are direct or secondary to systemic metabolic improvement was not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealing a pro-senescence function: IGF-I was shown to induce γH2AX, p53, and p21 upregulation through ROS production, promoting cellular senescence in confluent primary cells—a phenotype blocked by NAC and absent in p53-null cells.\",\n      \"evidence\": \"Primary mouse, rat, and human cells; SA-β-gal; γH2AX; p53-KO MEFs; NAC rescue\",\n      \"pmids\": [\"22877754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source and mechanism of IGF-I-induced ROS were not identified\", \"How this senescence-promoting activity is reconciled with anti-apoptotic signaling in the same pathway was not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing IGF-IR as an obligate co-receptor for FSH action in steroidogenesis: IGF-IR was shown to be required for FSH-stimulated AKT phosphorylation and Cyp19 expression in granulosa cells, with constitutively active AKT rescuing Cyp19 in IGF-IR-deficient cells.\",\n      \"evidence\": \"Multi-species granulosa cells; IGF-IR inhibitors, siRNA, and in vivo inactivation; constitutively active AKT rescue\",\n      \"pmids\": [\"23340251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IGF-IR is activated by autocrine IGF-I or constitutive receptor activity in this context was not determined\", \"Downstream targets of AKT beyond Cyp19 in steroidogenesis not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying a direct IGF-IR kinase substrate beyond canonical adaptors: IGF-IR was shown to directly phosphorylate PTH1R at Y494, causing its relocalization to actin barbed ends and promoting actin polymerization during osteoblast-to-osteocyte transition.\",\n      \"evidence\": \"In vitro kinase assay; Y494 site-directed mutagenesis; actin polymerization assay; conditional PTH1R KO mice\",\n      \"pmids\": [\"29507819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other receptor substrates are directly phosphorylated by IGF-IR in osteocytes was not explored\", \"Structural basis for IGF-IR recognition of PTH1R cytoplasmic domain unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which IGF-IR simultaneously activates pro-survival/proliferative pathways and, under specific conditions, pro-senescence ROS signaling remains unresolved, as does the full repertoire of direct IGF-IR kinase substrates beyond IRS-1, Shc, and PTH1R.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Context-dependent switch between proliferation and senescence signaling not mechanistically explained\", \"Full spectrum of direct IGF-IR substrates unknown\", \"Structural basis for IRS-1 vs Shc selectivity in different cell types not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 5, 6, 8, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [16, 17, 21, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 5, 6, 12, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 6, 12, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 5, 6, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IGF1R\",\n      \"IRS1\",\n      \"SHC1\",\n      \"CAV1\",\n      \"PTH1R\",\n      \"AKT1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1978,\n      \"claim\": \"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.\",\n      \"evidence\": \"Protein sequencing and structural comparison with insulin\",\n      \"pmids\": [\"632300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-translational processing steps from precursor to mature peptide were not yet defined\", \"Receptor identity unknown\"]\n    },\n    {\n      \"year\": 1983,\n      \"claim\": \"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.\",\n      \"evidence\": \"Human liver cDNA sequencing\",\n      \"pmids\": [\"6358902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Processing proteases not identified\", \"Alternative splicing not yet characterized\"]\n    },\n    {\n      \"year\": 1986,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genomic library cloning, Southern blotting, cDNA comparison\",\n      \"pmids\": [\"2937782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of alternative E-peptides unknown\", \"Promoter regulation not mapped\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro 3D skeletal myofiber culture with protein synthesis/degradation measurements\",\n      \"pmids\": [\"2003574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling pathway not dissected\", \"In vivo relevance not yet shown\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"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.\",\n      \"evidence\": \"Primary rat hepatocyte cultures with defined amino acid deprivation, insulin dose-response, Northern blot and RIA\",\n      \"pmids\": [\"1936610\", \"1901809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor mediators of amino acid sensing on IGF1 promoter not identified\", \"In vivo validation in human liver not performed\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro incubation of purified PSA with IGFBP-3, Western ligand blotting, competition binding\",\n      \"pmids\": [\"1383255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of PSA-mediated IGFBP cleavage in seminal fluid not demonstrated\", \"Whether other tissue-specific proteases act similarly was unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"R⁻ cell reconstitution with IR/IGF-IR, PI3K inhibitor pharmacology, co-immunoprecipitation of ERα–IGF-1R in COS7/HEK293 cells\",\n      \"pmids\": [\"10226786\", \"10749889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"Transgenic mice with muscle-restricted mIgf-1 expression, histological, functional, and regeneration assays\",\n      \"pmids\": [\"11175789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional program beyond GATA-2 not characterized\", \"Whether satellite cell activation is direct or indirect was unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Neuronal cultures with Akt kinase assay on huntingtin substrate, phosphorylation-deficient mutants, HD patient brain Western blot\",\n      \"pmids\": [\"12062094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation site on huntingtin not mapped to a specific residue in this study\", \"Therapeutic potential of IGF-I in HD not tested in vivo\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Enriched embryonic rat motor neurons, combined PD98059 and LY294002 inhibition, caspase-3 and DNA fragmentation assays\",\n      \"pmids\": [\"15193297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream convergence point of MAPK and Akt pathways not identified\", \"Whether this dual requirement applies in vivo is untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Neonatal rat HI model, i.c.v. IGF-I, phospho-Akt/GSK3β immunohistochemistry, caspase assays\",\n      \"pmids\": [\"15845077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of caspase-dependent vs. caspase-independent death not resolved\", \"Cell-type specificity of IGF-I action in brain not determined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"IGF-I KO mice, co-culture genotype combinations of osteoblasts and osteoclast precursors, qRT-PCR for RANKL/M-CSF\",\n      \"pmids\": [\"16939393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Luciferase reporter assays, cardiac hypertrophy/failure models, C2C12 differentiation, acromegaly patient biopsies\",\n      \"pmids\": [\"19933931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether miR-1-IGF-I loop is causally required for hypertrophy reversal not tested\", \"Additional miRNAs targeting IGF-I not systematically surveyed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional IGF-1R KO in pre-osteoblasts, rapamycin inhibition, IGF-1/IGFBP3 injection in aged rats\",\n      \"pmids\": [\"22729283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of IGF-1 release from bone matrix not fully characterized\", \"Whether IGFBP3 co-delivery is necessary for clinical translation not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pharmacological/siRNA/dominant-negative IGF-IR inhibition plus constitutively active AKT rescue in human/mouse/rat granulosa cells, in vivo mouse model\",\n      \"pmids\": [\"23340251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase assay, Y494 mutagenesis, phospho-PTH1R/actin immunofluorescence, conditional PTH1R knockout mice\",\n      \"pmids\": [\"29507819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IGF-1R phosphorylates other GPCRs not explored\", \"Structural details of IGF-1R–PTH1R interaction unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 5, 18, 22, 31]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 12, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 5, 9, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [13, 14, 20, 22, 25, 33]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [27, 31, 36]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 9, 12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 7, 33]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13, 20, 24, 25]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [9, 33]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IGF1R\",\n      \"IGFBP3\",\n      \"IGFBP7\",\n      \"CAV1\",\n      \"ESR1\",\n      \"IRS1\",\n      \"PTH1R\",\n      \"SHC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}