{"gene":"IGF1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1993,"finding":"IGF-I gene knockout in mice (homologous recombination in ES cells) demonstrates IGF-I is required for normal embryonic growth: IGF-I-/- mice are <60% body weight at birth with severe muscle underdevelopment and >95% perinatal lethality, establishing IGF-I as an essential embryonic growth factor.","method":"Homologous recombination knockout mouse, histopathology","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function genetic model with specific, well-characterized phenotypic readout; foundational study widely replicated","pmids":["8276243"],"is_preprint":false},{"year":1993,"finding":"Recombinant human IGF-I infusion in healthy men suppresses hepatic glucose output (rate of appearance), increases peripheral glucose disposal (rate of disappearance), suppresses beta-cell insulin secretion, and reduces leucine rate of appearance (protein catabolism), demonstrating direct insulin-like and protein-anabolic metabolic actions in vivo.","method":"Euglycemic clamp with stable isotope tracer kinetics (L-[1-13C]leucine, [3-3H]glucose) in humans","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo metabolic reconstitution with isotope tracer methodology, multiple orthogonal readouts","pmids":["8279537"],"is_preprint":false},{"year":1996,"finding":"In the pituitary, IGF-I binds its cell-surface receptor, activates intrinsic beta-subunit tyrosine kinase, phosphorylates IRS-1, and selectively inhibits GH gene transcription and secretion; the submembrane Tyr950 residue is critical for transducing the IGF-I suppression signal to the GH gene. A kinase-deficient truncated IGF-I receptor (952STOP) acts as dominant negative, blocking both GH suppression and mitogenic IGF-I signals.","method":"Stable transfection of wild-type and mutant IGF-I receptor constructs in GH-secreting cells; structure-function mutagenesis; dominant-negative receptor analysis","journal":"Recent progress in hormone research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis with functional validation (GH secretion and gene transcription readouts) in a defined cell system","pmids":["8701079"],"is_preprint":false},{"year":1999,"finding":"IGF-I receptor signals through IRS-1 to activate PI3-kinase in a mitogenic/anti-apoptotic mode; in the absence of IRS-1, IGF-IR signals instead through a differentiation pathway (granulocytic differentiation in haematopoietic cells), establishing IRS-1 concentration as a switch between mitogenic/survival and differentiation outputs of the IGF-IR.","method":"Cell-based assays with IRS-1 manipulation (overexpression and loss-of-function) in R-cell (IGF-IR-null MEF) system; IGF-IR reconstitution","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cell system with receptor reconstitution and IRS-1 manipulation, single lab","pmids":["10579905"],"is_preprint":false},{"year":1999,"finding":"IGF-IR protects cells from apoptosis (anoikis, okadaic acid) more efficiently than the insulin receptor even when IRS-1 is overexpressed; moreover, IGF-IR anti-apoptotic signaling is resistant to PI3-kinase inhibitors, whereas insulin receptor anti-apoptotic signaling is PI3K-sensitive, revealing a PI3K-independent anti-apoptotic pathway unique to the IGF-IR.","method":"Stable transfection of IR into IGF-IR-null R-cells; apoptosis assays; PI3-kinase inhibitor treatment","journal":"Hormone and metabolic research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean receptor-null cell system with reconstitution and pharmacological pathway dissection, single lab","pmids":["10226786"],"is_preprint":false},{"year":2000,"finding":"IGF-I is required for pubertal mammary gland development (terminal end bud formation and ductal morphogenesis): IGF-I-/- knockout mice have grossly impaired mammary development, restored by IGF-I + estradiol treatment but not by GH + estradiol, demonstrating that GH acts through locally produced IGF-I for this developmental process.","method":"IGF-I knockout mouse model; hormone replacement experiments (IGF-I vs GH + estradiol)","journal":"Journal of mammary gland biology and neoplasia","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific phenotypic readout and hormone rescue experiments distinguishing direct vs GH-mediated pathway","pmids":["10791764"],"is_preprint":false},{"year":2002,"finding":"IRS-1 acts as an endocytic regulator of the IGF-I receptor by interacting with the clathrin adaptor complex AP2 and inhibiting recruitment of IGF-IR into clathrin-coated structures, thereby delaying IGF-IR endocytosis after ligand stimulation and prolonging sustained Akt activation; loss of IRS-1 shifts IGF-I signaling from sustained to transient Akt activation and augments FoxO-mediated transcription.","method":"Co-immunoprecipitation (IRS-1/AP2 interaction); endocytosis assays; AP2-binding-deficient IRS-1 mutant; single-molecule imaging; IRS-1 depletion with signaling readouts","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mutant rescue, multiple orthogonal assays (imaging, signaling, transcription) in single study","pmids":["29661273"],"is_preprint":false},{"year":2002,"finding":"IGF-I is an autocrine/paracrine mitogen for brain microglia: IGF-I mRNA is expressed by microglia/macrophages in ischemic brain regions, and exogenous IGF-I stimulates a 2-fold increase in DNA synthesis in purified adult brain microglial cultures, establishing IGF-I as a mitogenic signal for these cells after injury.","method":"In vitro [3H]-thymidine incorporation in purified adult brain microglia; combined immunostaining/in situ hybridization in vivo","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro proliferation assay combined with in vivo localization, single lab","pmids":["12112378"],"is_preprint":false},{"year":2002,"finding":"Beta-cell-specific expression of IGF-I in transgenic mice counteracts streptozotocin-induced cytotoxicity and insulitis, promotes beta-cell neogenesis and replication, and restores normoglycemia, demonstrating that local IGF-I in pancreatic islets can regenerate beta-cell mass and protect against type 1 diabetes.","method":"Transgenic mouse overexpression (beta-cell-specific IGF-I); streptozotocin model; histomorphometry; metabolic measurements","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific transgenic gain-of-function model with defined cellular and metabolic phenotype, two genetic backgrounds tested","pmids":["11994404"],"is_preprint":false},{"year":2002,"finding":"IGF-I promotes Schwann cell motility and survival via activation of Akt (phosphorylation at Ser473) downstream of PI3-kinase; dominant-negative K179M Akt transfection blocks both IGF-I-induced Akt phosphorylation and the pro-motility and anti-apoptotic effects, establishing Akt as a required effector.","method":"Dominant-negative Akt transfection; PI3-K inhibitor (LY294002); Akt phosphorylation Western blot; cell motility and survival assays","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative approach with pharmacological corroboration, single lab","pmids":["11162904"],"is_preprint":false},{"year":2002,"finding":"IGF-I induces tyrosine phosphorylation of caveolin-1 at Tyr14 and causes translocation of caveolin-1 and formation of membrane patches on the plasma membrane; IGF-IR co-localizes with caveolin-1 in lipid raft-enriched fractions; this effect is IGF-I-specific and not reproduced by insulin in cells overexpressing insulin receptors.","method":"Co-fractionation/lipid raft isolation; Western blot for phospho-caveolin-1; immunofluorescence; R-cell reconstitution system","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization and phosphorylation assays with ligand specificity control, single lab","pmids":["12135605"],"is_preprint":false},{"year":2004,"finding":"In embryonic rat spinal cord motor neurons, IGF-I binds IGF-IR and activates both MAPK and PI3K/Akt pathways via phosphorylation of IRS-1 and Shc (but not IRS-2); IGF-I prevents glutamate-induced DNA fragmentation and caspase-3 cleavage; neither MAPK inhibitor (PD98059) nor PI3K inhibitor (LY294002) alone blocks neuroprotection, but both together are required, demonstrating pathway redundancy in motor neuron survival.","method":"Enriched primary motor neuron culture; pathway inhibitors; Western blot for signaling intermediates and caspase-3 cleavage; DNA fragmentation assay","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined primary cell system with pharmacological pathway dissection and multiple readouts, single lab","pmids":["15193297"],"is_preprint":false},{"year":2004,"finding":"IGF-I instructs multipotent adult neural progenitor cells (hippocampus-derived) to differentiate into oligodendrocytes via inhibition of bone morphogenetic protein (BMP) signaling; modeling analysis indicates the effect is instructive (fate specification) rather than selective; overexpression of IGF-I in hippocampus in vivo increases oligodendrocyte markers.","method":"Adult neural progenitor cell culture; fate mapping; BMP signaling analysis; in vivo IGF-I overexpression with immunohistochemistry","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro fate assay with mechanistic follow-up (BMP pathway) and in vivo corroboration, single lab","pmids":["14709544"],"is_preprint":false},{"year":2005,"finding":"IGF-I enhances TRPV1-mediated membrane currents by both sensitizing the receptor and promoting translocation of TRPV1 from cytosol to plasma membrane; this effect requires PI3K and PKC-mediated phosphorylation of TRPV1, downstream of IGF-I receptor tyrosine kinase activation.","method":"Electrophysiology (patch-clamp) in heterologous expression systems and DRG neurons; PI3K and PKC inhibitors; immunofluorescence for TRPV1 localization","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with pharmacological pathway dissection and localization data, single lab","pmids":["15857517"],"is_preprint":false},{"year":2005,"finding":"IGF-I neuroprotection in hypoxia-ischemia involves activation of Akt (PI3K pathway) and inactivation of GSK3beta: ICV IGF-I after HI increases pAkt in cytosol and pGSK3beta in both cytosol and nuclear fractions, concomitant with reduced caspase-3 and caspase-9 activity, resulting in 40% reduction in brain damage.","method":"Neonatal rat HI model; ICV IGF-I administration; Western blot for pAkt, pGSK3beta; caspase activity assays; immunohistochemistry","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with signaling pathway analysis and functional outcome, single lab","pmids":["15845077"],"is_preprint":false},{"year":2006,"finding":"IGF-I specifically enhances the extent and rate of axon outgrowth of corticospinal motor neurons (CSMN) via the IGF-I receptor and downstream signaling pathways; this effect is distinct from IGF-I support of neuronal survival and distinct from BDNF, which promotes branching/arborization but not axon outgrowth.","method":"CSMN purification and culture; IGF-IR inhibition; in vivo analyses; comparison with BDNF","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — purified primary neuron system with receptor-specific inhibition and in vivo corroboration, distinct phenotypic readout separating survival from axon outgrowth","pmids":["17057708"],"is_preprint":false},{"year":2007,"finding":"IGF-IR in mature osteoblasts is required for PTH anabolic effects on bone: osteoblast-specific IGF-IR knockout (IGF-IR OBKO) mice have reduced bone volume, decreased periosteal bone formation, and impaired PTH-stimulated osteoprogenitor cell proliferation and differentiation, establishing that PTH requires IGF-IR signaling in osteoblasts to exert its anabolic actions.","method":"Conditional (osteoblast-specific) IGF-IR knockout mice; PTH treatment; microCT; bone histomorphometry; BMSC culture","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with specific phenotypic readout, PTH rescue experiment, multiple structural and cellular readouts","pmids":["17539737"],"is_preprint":false},{"year":2008,"finding":"IGF-I rescues diabetic cardiomyocyte dysfunction by inhibiting RhoA activation and restoring Akt phosphorylation, thereby re-coupling eNOS (reversing eNOS uncoupling indicated by NOS inhibitor-sensitive O2- accumulation), restoring NO levels, and normalizing Kv1.2 potassium channel expression and cardiomyocyte contractile parameters.","method":"IGF-I transgenic mice crossed with diabetic model; Rho kinase inhibitor (Y27632); eNOS coupler (BH4/folate); echocardiography; cardiomyocyte contractility measurements; Western blot for RhoA, pAkt, pERK, eNOS","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic gain-of-function with pharmacological mechanistic dissection (Rho kinase inhibitor, BH4), multiple pathway readouts","pmids":["18199585"],"is_preprint":false},{"year":2010,"finding":"IGF-IR deletion specifically in adult neural stem cells (NSCs) increases cumulative neuroblast production and enhances neuronal integration into the olfactory bulb during aging, with differential downstream effects: Akt phosphorylation preferentially decreased in IGF-1R-/- NSCs within the niche, while ERK pathway is downregulated in differentiated neurons, demonstrating that IGF-I signaling through Akt in NSCs suppresses neurogenesis during aging.","method":"Conditional IGF-IR knockout in adult NSCs; BrdU/EdU cell fate tracing; Western blot for pAkt, pERK; olfactory behavioral testing; mathematical modeling","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO with signaling pathway analysis and behavioral outcome, single lab","pmids":["26219530"],"is_preprint":false},{"year":2012,"finding":"IGF-I enhances cellular senescence in confluent primary cells (mouse, rat, human) through a ROS-p53 pathway: IGF-I induces γH2AX (DNA damage marker), increases p53 and p21, and activates SA-β-gal; ROS scavenger (NAC) suppresses senescence markers; p53-null MEFs are resistant to IGF-I-induced SA-β-gal and p21 induction, establishing that p53 is required downstream of IGF-I/ROS in this pathway.","method":"Primary cell cultures (confluent state); ROS scavenger treatment; p53-null MEFs; SA-β-gal assay; Western blot for γH2AX, p53, p21","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (p53-KO) and pharmacological (NAC) dissection in multiple cell types, single lab","pmids":["22877754"],"is_preprint":false},{"year":2015,"finding":"IGF-I and IGFBP-2 coordinately stimulate osteoblast differentiation through early activation of AMPK (via their respective receptors), which drives autophagy (ULK-1 S555 phosphorylation, beclin-1 and LC3II induction); early AMPK activity is required, but subsequent AMPK down-regulation is also necessary to permit mTOR/AKT activation and completion of differentiation.","method":"Calvarial osteoblast and MC-3T3 cell cultures; AMPK inhibitors; constitutively active AMPK overexpression; receptor-blocking antibodies; Western blot for autophagy markers; differentiation assays","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic manipulation of AMPK with multiple autophagy pathway readouts, single lab","pmids":["26556533"],"is_preprint":false},{"year":2018,"finding":"IGF1R directly phosphorylates a specific tyrosine residue (Y494) on the cytoplasmic domain of PTH1R in vitro; phosphorylated PTH1R localizes to barbed ends of actin filaments and increases actin polymerization during osteoblast-to-osteocyte morphological transition; disruption of Y494 reduces actin polymerization and dendrite length; conditional ablation of PTH1R in osteoblasts reduces osteocyte number and dendrites per osteocyte in vivo.","method":"In vitro kinase assay (IGF1R phosphorylation of PTH1R); site-directed mutagenesis (Y494); immunofluorescence for actin and pPTH1R; conditional PTH1R KO mice","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase reconstitution with mutagenesis, supported by in vivo conditional KO with matched phenotype","pmids":["29507819"],"is_preprint":false},{"year":2010,"finding":"IGF-IR is required for acute GH-induced STAT5 signaling in osteoblasts: Cre-mediated deletion of IGF-IR in primary calvarial osteoblasts more than doubles the ED50 for GH-induced STAT5 activation and reduces maximal STAT5 activity by ~50%, while sparing GH-induced ERK; a C-terminally truncated IGF-IR lacking the kinase domain partially rescues GH-induced STAT5 activity, suggesting IGF-IR facilitates GH signaling through a kinase-independent scaffolding mechanism in addition to its role as IGF-I signal transducer.","method":"Adenoviral Cre-mediated conditional IGF-IR deletion in primary osteoblasts; STAT5 luciferase reporter; adenoviral IGF-IR re-expression and truncation mutant rescue; Western blot for pSTAT5, pERK","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic deletion with specific rescue (full-length vs kinase-dead IGF-IR), multiple orthogonal signaling readouts, domain-function dissection","pmids":["20133448"],"is_preprint":false},{"year":1994,"finding":"High extracellular calcium stimulates osteoblast DNA synthesis via an autocrine/paracrine IGF-I mechanism: elevated [Ca2+]e increases IGF-I mRNA expression and IGF-I protein secretion from MC3T3-E1 osteoblastic cells; neutralizing IGF-I antiserum completely abolishes the high [Ca2+]e-induced increase in DNA synthesis.","method":"MC3T3-E1 osteoblast cell culture; [3H]-thymidine incorporation; IGF-I neutralizing antibody; Northern blot for IGF-I mRNA; IGF-I RIA","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — neutralizing antibody functional block with matched mRNA/protein readouts, single lab","pmids":["8203509"],"is_preprint":false},{"year":2013,"finding":"In thyroid eye disease (TED), IGF-IR forms a physical and functional complex with TSHR in orbital fibroblasts/fibrocytes; actions mediated through TSHR are dependent on IGF-IR activity; IGF-IR possesses kinase-independent activities and functions as a tyrosine kinase/G-protein-coupled receptor hybrid using the G-protein receptor kinase/β-arrestin system.","method":"Teprotumumab (anti-IGF-IR monoclonal antibody) attenuation of both IGF-I and TSH actions; in vitro fibrocyte assays; IGF-IR knockdown","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological IGF-IR inhibition and knockdown with functional readouts (cytokine induction), receptor complex supported by prior literature; single review synthesizing experimental evidence","pmids":["35167695"],"is_preprint":false}],"current_model":"IGF-I signals primarily through the IGF-I receptor (IGF-IR), a transmembrane tyrosine kinase that upon ligand binding undergoes autophosphorylation and phosphorylates adaptor substrates IRS-1 and Shc; IRS-1 in turn activates PI3K/Akt (promoting cell survival, glucose metabolism, and protein anabolism) and the Ras/MAPK pathway (promoting proliferation), with IRS-1 concentration acting as a switch between mitogenic/survival and differentiation outputs; IRS-1 also delays IGF-IR endocytosis by competing with the AP2 clathrin adaptor, prolonging sustained Akt signaling; IGF-IR additionally phosphorylates PTH1R on Y494 to modulate actin dynamics in osteoblast-to-osteocyte transitions, and can scaffold GH-induced JAK2/STAT5 signaling in a partly kinase-independent manner; IGF-I is required for embryonic growth, postnatal somatic and skeletal development, mammary ductal morphogenesis, neural progenitor fate (oligodendrocyte specification via BMP inhibition), CSMN axon outgrowth, and beta-cell regeneration, while chronic IGF-I signaling can promote cellular senescence through a ROS/p53 pathway."},"narrative":{"mechanistic_narrative":"IGF-I (IGF1) is a secreted growth factor essential for embryonic and postnatal somatic growth and a broad effector of cell survival, proliferation, differentiation, and tissue-specific anabolic programs; genetic ablation in mice produces severe growth retardation, muscle underdevelopment, and near-complete perinatal lethality [PMID:8276243]. IGF-I acts through the IGF-I receptor (IGF-IR), a tyrosine kinase that upon ligand binding autophosphorylates and recruits the adaptor substrates IRS-1 and Shc; the submembrane Tyr950 residue is critical for downstream signal transduction, and kinase-dead receptor mutants act as dominant negatives [PMID:8701079]. IRS-1 is the principal node that determines the output of receptor activation: it routes signaling into PI3K/Akt-driven mitogenic and anti-apoptotic responses, with IRS-1 abundance functioning as a switch between mitogenic/survival and differentiation programs [PMID:10579905], and it additionally controls receptor trafficking by competing with the clathrin adaptor AP2 to delay IGF-IR endocytosis and sustain Akt activation [PMID:29661273]. Akt is the required survival effector in multiple cell types, acting in part through GSK3beta inactivation and caspase suppression [PMID:11162904, PMID:15845077], and IGF-IR also engages anti-apoptotic outputs that are PI3K-independent [PMID:10226786]. Through these pathways IGF-I directs tissue programs including pubertal mammary ductal morphogenesis as the local mediator of GH action [PMID:10791764], pancreatic beta-cell regeneration and protection [PMID:11994404], oligodendrocyte fate specification via BMP inhibition [PMID:14709544], corticospinal motor neuron axon outgrowth [PMID:17057708], and metabolic insulin-like actions including suppression of hepatic glucose output and protein catabolism [PMID:8279537]. In bone, IGF-IR is required for the anabolic actions of PTH in osteoblasts [PMID:17539737] and directly phosphorylates PTH1R on Tyr494 to drive actin polymerization during the osteoblast-to-osteocyte transition [PMID:29507819], and it scaffolds GH-induced STAT5 signaling in a partly kinase-independent manner [PMID:20133448]. Chronic IGF-I signaling can also drive cellular senescence through a ROS/p53/p21 pathway [PMID:22877754].","teleology":[{"year":1993,"claim":"Established that IGF-I is an essential, non-redundant growth factor in vivo rather than merely a permissive systemic hormone, answering whether endogenous IGF-I is required for normal development.","evidence":"Homologous-recombination IGF-I knockout mice with histopathology","pmids":["8276243"],"confidence":"High","gaps":["Does not separate embryonic from postnatal IGF-I requirement","Does not identify which tissues require autocrine vs endocrine IGF-I","Receptor and downstream effector not addressed"]},{"year":1993,"claim":"Demonstrated that IGF-I exerts direct insulin-like metabolic and protein-anabolic effects in humans, distinguishing its acute metabolic actions from chronic growth-promoting roles.","evidence":"Euglycemic clamp with stable isotope tracer kinetics in healthy men","pmids":["8279537"],"confidence":"High","gaps":["Does not resolve whether effects are via IGF-IR or insulin receptor cross-reactivity","Tissue-level glucose flux mechanism not dissected"]},{"year":1996,"claim":"Defined the receptor-proximal signaling architecture, showing IGF-IR kinase activity, IRS-1 phosphorylation, and the critical submembrane Tyr950 residue transduce IGF-I signals, with a dominant-negative receptor blocking output.","evidence":"Stable transfection of WT and mutant IGF-I receptor constructs in GH-secreting cells with structure-function mutagenesis","pmids":["8701079"],"confidence":"High","gaps":["Tested mainly in pituitary GH-secreting cells","Does not enumerate the full set of downstream branches"]},{"year":1999,"claim":"Resolved how a single receptor produces divergent outputs by identifying IRS-1 concentration as a switch between mitogenic/survival (PI3K) and differentiation pathways, and revealing a PI3K-independent anti-apoptotic arm unique to IGF-IR.","evidence":"IGF-IR-null R-cell reconstitution with IRS-1 manipulation and PI3K-inhibitor pathway dissection","pmids":["10579905","10226786"],"confidence":"Medium","gaps":["Molecular identity of the PI3K-independent anti-apoptotic effector not defined","Single-lab cell-line model, not validated in vivo"]},{"year":2002,"claim":"Connected IGF-I to multiple tissue-specific programs—mammary ductal morphogenesis (as local mediator of GH), beta-cell regeneration, microglial proliferation, and Schwann cell survival/motility via Akt—establishing IGF-I as a broadly acting autocrine/paracrine effector.","evidence":"IGF-I KO with hormone rescue, beta-cell-specific transgenic STZ model, microglial thymidine incorporation, and dominant-negative Akt in Schwann cells","pmids":["10791764","11994404","12112378","11162904"],"confidence":"High","gaps":["Tissue-specific signaling branches not uniformly mapped","Microglial and Schwann cell findings are single-lab","Lipid-raft/caveolin-1 mechanism (12135605) not integrated into a functional output"]},{"year":2005,"claim":"Defined neuronal mechanisms of IGF-I action, showing Akt/GSK3beta-mediated neuroprotection in hypoxia-ischemia and redundant MAPK+PI3K survival signaling in motor neurons, plus TRPV1 sensitization/trafficking.","evidence":"Neonatal HI rat model, primary motor neuron cultures with pathway inhibitors, and patch-clamp electrophysiology","pmids":["15845077","15193297","15857517"],"confidence":"Medium","gaps":["Relative contribution of each pathway in vivo unresolved","Single-lab studies for each readout"]},{"year":2006,"claim":"Showed IGF-I drives oligodendrocyte fate via BMP inhibition and instructs corticospinal motor neuron axon outgrowth, separating its developmental/regenerative roles from generic survival support.","evidence":"Adult neural progenitor fate assays with BMP analysis and purified CSMN cultures with IGF-IR inhibition plus in vivo corroboration","pmids":["14709544","17057708"],"confidence":"Medium","gaps":["Downstream effectors of BMP inhibition not fully defined","Mechanism linking IGF-IR to axon-outgrowth machinery unmapped"]},{"year":2010,"claim":"Revealed kinase-independent and trafficking-level functions of the receptor system: IGF-IR scaffolds GH-induced STAT5 signaling independent of its kinase, and IRS-1 delays IGF-IR endocytosis via AP2 competition to sustain Akt signaling.","evidence":"Conditional IGF-IR deletion with truncation-mutant rescue in osteoblasts; reciprocal Co-IP, AP2-binding-deficient IRS-1 mutant and single-molecule imaging","pmids":["20133448","29661273"],"confidence":"High","gaps":["Structural basis of the kinase-independent scaffold not determined","Generality of the AP2-competition mechanism beyond the tested system unclear"]},{"year":2018,"claim":"Established IGF-IR as a bone anabolic hub: required for PTH anabolic action in osteoblasts, directly phosphorylating PTH1R Y494 to drive actin polymerization in the osteoblast-to-osteocyte transition, and coordinating AMPK/autophagy-dependent osteoblast differentiation.","evidence":"Osteoblast-specific IGF-IR/PTH1R conditional KO mice, in vitro kinase assay with Y494 mutagenesis, and AMPK manipulation with autophagy readouts","pmids":["17539737","29507819","26556533","8203509"],"confidence":"High","gaps":["How IGF-IR–PTH1R crosstalk integrates with canonical PTH GPCR signaling not fully defined","Temporal AMPK switch mechanism incompletely resolved"]},{"year":2015,"claim":"Identified a detrimental face of chronic IGF-I signaling—induction of cellular senescence through a ROS/p53/p21 pathway—and a suppressive role in aging neurogenesis via Akt in neural stem cells.","evidence":"Primary cells with ROS scavenger and p53-null MEFs; conditional IGF-IR deletion in adult NSCs with fate tracing","pmids":["22877754","26219530"],"confidence":"Medium","gaps":["Mechanism generating ROS downstream of IGF-I not defined","Reconciliation of pro-survival vs pro-senescence outputs context-dependence unresolved"]},{"year":2013,"claim":"Extended IGF-IR function to receptor crosstalk in disease, showing it forms a physical/functional complex with TSHR in orbital fibroblasts and exerts kinase-independent, GPCR-like activity in thyroid eye disease.","evidence":"Anti-IGF-IR antibody (teprotumumab) attenuation and IGF-IR knockdown in fibrocyte assays","pmids":["35167695"],"confidence":"Medium","gaps":["Direct biochemical demonstration of the TSHR–IGF-IR complex not provided in this synthesis","Structural basis of the hybrid receptor behavior unknown"]},{"year":null,"claim":"How IGF-I/IGF-IR signaling dynamics are decoded to select among opposing cell fates—survival, proliferation, differentiation, and senescence—across different tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking signal duration/amplitude to fate choice","Tissue-specific effector complements not comprehensively mapped","Structural mechanism of kinase-independent receptor scaffolding undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,5,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,3,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[22,24]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,5,8,23]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,6,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,5,12,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,9,14]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[19]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,8]}],"complexes":[],"partners":["IGF1R","IRS1","SHC1","AP2","CAV1","PTH1R","TSHR"],"other_free_text":[]}},"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 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IGF-I receptor inhibition alters fibrocyte immune phenotype in thyroid-associated ophthalmopathy.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34949642","citation_count":35,"is_preprint":false},{"pmid":"16647585","id":"PMC_16647585","title":"Intranasal administration of IGF-I improves behavior and Purkinje cell pathology in SCA1 mice.","date":"2006","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/16647585","citation_count":35,"is_preprint":false},{"pmid":"8398123","id":"PMC_8398123","title":"IGF-I and the IGF-I receptor in development of nonmammalian vertebrates.","date":"1993","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/8398123","citation_count":34,"is_preprint":false},{"pmid":"28405590","id":"PMC_28405590","title":"Therapeutic potential of IGF-I on hippocampal neurogenesis and function during aging.","date":"2016","source":"Neurogenesis (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/28405590","citation_count":34,"is_preprint":false},{"pmid":"12488244","id":"PMC_12488244","title":"Protein anabolic effects of insulin and IGF-I in the ovine fetus.","date":"2002","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/12488244","citation_count":33,"is_preprint":false},{"pmid":"10986623","id":"PMC_10986623","title":"IGF-I and osteoporosis.","date":"2000","source":"Clinics in laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10986623","citation_count":32,"is_preprint":false},{"pmid":"26821056","id":"PMC_26821056","title":"Endocrine and Local IGF-I in the Bony Fish Immune System.","date":"2016","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/26821056","citation_count":32,"is_preprint":false},{"pmid":"15998499","id":"PMC_15998499","title":"Ovarian and IGF-I axis control of mammary development in prepubertal heifers.","date":"2005","source":"Domestic animal endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15998499","citation_count":32,"is_preprint":false},{"pmid":"8853450","id":"PMC_8853450","title":"Growth hormone and IGF-I therapy in the hypercatabolic patient.","date":"1996","source":"Bailliere's clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/8853450","citation_count":32,"is_preprint":false},{"pmid":"12692589","id":"PMC_12692589","title":"IGF-I gene transfer by electroporation promotes regeneration in a muscle injury model.","date":"2003","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/12692589","citation_count":32,"is_preprint":false},{"pmid":"8708531","id":"PMC_8708531","title":"Expression of IGF-I and IGF-binding protein genes in cirrhotic liver.","date":"1996","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/8708531","citation_count":31,"is_preprint":false},{"pmid":"23704881","id":"PMC_23704881","title":"Interaction between IGF-IR and ER induced by E2 and IGF-I.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23704881","citation_count":30,"is_preprint":false},{"pmid":"18693051","id":"PMC_18693051","title":"Changes in insulin and IGF-I receptor expression during differentiation of human preadipocytes.","date":"2008","source":"Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society","url":"https://pubmed.ncbi.nlm.nih.gov/18693051","citation_count":30,"is_preprint":false},{"pmid":"26219865","id":"PMC_26219865","title":"Role of IGF-I in follistatin-induced skeletal muscle hypertrophy.","date":"2015","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26219865","citation_count":29,"is_preprint":false},{"pmid":"20133448","id":"PMC_20133448","title":"Deletion of IGF-I receptor (IGF-IR) in primary osteoblasts reduces GH-induced STAT5 signaling.","date":"2010","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/20133448","citation_count":28,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45276,"output_tokens":6676,"usd":0.117984,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15743,"output_tokens":4498,"usd":0.095583,"stage2_stop_reason":"end_turn"},"total_usd":0.213567,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"IGF-I gene knockout in mice (homologous recombination in ES cells) demonstrates IGF-I is required for normal embryonic growth: IGF-I-/- mice are <60% body weight at birth with severe muscle underdevelopment and >95% perinatal lethality, establishing IGF-I as an essential embryonic growth factor.\",\n      \"method\": \"Homologous recombination knockout mouse, histopathology\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function genetic model with specific, well-characterized phenotypic readout; foundational study widely replicated\",\n      \"pmids\": [\"8276243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Recombinant human IGF-I infusion in healthy men suppresses hepatic glucose output (rate of appearance), increases peripheral glucose disposal (rate of disappearance), suppresses beta-cell insulin secretion, and reduces leucine rate of appearance (protein catabolism), demonstrating direct insulin-like and protein-anabolic metabolic actions in vivo.\",\n      \"method\": \"Euglycemic clamp with stable isotope tracer kinetics (L-[1-13C]leucine, [3-3H]glucose) in humans\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo metabolic reconstitution with isotope tracer methodology, multiple orthogonal readouts\",\n      \"pmids\": [\"8279537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"In the pituitary, IGF-I binds its cell-surface receptor, activates intrinsic beta-subunit tyrosine kinase, phosphorylates IRS-1, and selectively inhibits GH gene transcription and secretion; the submembrane Tyr950 residue is critical for transducing the IGF-I suppression signal to the GH gene. A kinase-deficient truncated IGF-I receptor (952STOP) acts as dominant negative, blocking both GH suppression and mitogenic IGF-I signals.\",\n      \"method\": \"Stable transfection of wild-type and mutant IGF-I receptor constructs in GH-secreting cells; structure-function mutagenesis; dominant-negative receptor analysis\",\n      \"journal\": \"Recent progress in hormone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis with functional validation (GH secretion and gene transcription readouts) in a defined cell system\",\n      \"pmids\": [\"8701079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"IGF-I receptor signals through IRS-1 to activate PI3-kinase in a mitogenic/anti-apoptotic mode; in the absence of IRS-1, IGF-IR signals instead through a differentiation pathway (granulocytic differentiation in haematopoietic cells), establishing IRS-1 concentration as a switch between mitogenic/survival and differentiation outputs of the IGF-IR.\",\n      \"method\": \"Cell-based assays with IRS-1 manipulation (overexpression and loss-of-function) in R-cell (IGF-IR-null MEF) system; IGF-IR reconstitution\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cell system with receptor reconstitution and IRS-1 manipulation, single lab\",\n      \"pmids\": [\"10579905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"IGF-IR protects cells from apoptosis (anoikis, okadaic acid) more efficiently than the insulin receptor even when IRS-1 is overexpressed; moreover, IGF-IR anti-apoptotic signaling is resistant to PI3-kinase inhibitors, whereas insulin receptor anti-apoptotic signaling is PI3K-sensitive, revealing a PI3K-independent anti-apoptotic pathway unique to the IGF-IR.\",\n      \"method\": \"Stable transfection of IR into IGF-IR-null R-cells; apoptosis assays; PI3-kinase inhibitor treatment\",\n      \"journal\": \"Hormone and metabolic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean receptor-null cell system with reconstitution and pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"10226786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IGF-I is required for pubertal mammary gland development (terminal end bud formation and ductal morphogenesis): IGF-I-/- knockout mice have grossly impaired mammary development, restored by IGF-I + estradiol treatment but not by GH + estradiol, demonstrating that GH acts through locally produced IGF-I for this developmental process.\",\n      \"method\": \"IGF-I knockout mouse model; hormone replacement experiments (IGF-I vs GH + estradiol)\",\n      \"journal\": \"Journal of mammary gland biology and neoplasia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific phenotypic readout and hormone rescue experiments distinguishing direct vs GH-mediated pathway\",\n      \"pmids\": [\"10791764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IRS-1 acts as an endocytic regulator of the IGF-I receptor by interacting with the clathrin adaptor complex AP2 and inhibiting recruitment of IGF-IR into clathrin-coated structures, thereby delaying IGF-IR endocytosis after ligand stimulation and prolonging sustained Akt activation; loss of IRS-1 shifts IGF-I signaling from sustained to transient Akt activation and augments FoxO-mediated transcription.\",\n      \"method\": \"Co-immunoprecipitation (IRS-1/AP2 interaction); endocytosis assays; AP2-binding-deficient IRS-1 mutant; single-molecule imaging; IRS-1 depletion with signaling readouts\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mutant rescue, multiple orthogonal assays (imaging, signaling, transcription) in single study\",\n      \"pmids\": [\"29661273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IGF-I is an autocrine/paracrine mitogen for brain microglia: IGF-I mRNA is expressed by microglia/macrophages in ischemic brain regions, and exogenous IGF-I stimulates a 2-fold increase in DNA synthesis in purified adult brain microglial cultures, establishing IGF-I as a mitogenic signal for these cells after injury.\",\n      \"method\": \"In vitro [3H]-thymidine incorporation in purified adult brain microglia; combined immunostaining/in situ hybridization in vivo\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro proliferation assay combined with in vivo localization, single lab\",\n      \"pmids\": [\"12112378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Beta-cell-specific expression of IGF-I in transgenic mice counteracts streptozotocin-induced cytotoxicity and insulitis, promotes beta-cell neogenesis and replication, and restores normoglycemia, demonstrating that local IGF-I in pancreatic islets can regenerate beta-cell mass and protect against type 1 diabetes.\",\n      \"method\": \"Transgenic mouse overexpression (beta-cell-specific IGF-I); streptozotocin model; histomorphometry; metabolic measurements\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific transgenic gain-of-function model with defined cellular and metabolic phenotype, two genetic backgrounds tested\",\n      \"pmids\": [\"11994404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IGF-I promotes Schwann cell motility and survival via activation of Akt (phosphorylation at Ser473) downstream of PI3-kinase; dominant-negative K179M Akt transfection blocks both IGF-I-induced Akt phosphorylation and the pro-motility and anti-apoptotic effects, establishing Akt as a required effector.\",\n      \"method\": \"Dominant-negative Akt transfection; PI3-K inhibitor (LY294002); Akt phosphorylation Western blot; cell motility and survival assays\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative approach with pharmacological corroboration, single lab\",\n      \"pmids\": [\"11162904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IGF-I induces tyrosine phosphorylation of caveolin-1 at Tyr14 and causes translocation of caveolin-1 and formation of membrane patches on the plasma membrane; IGF-IR co-localizes with caveolin-1 in lipid raft-enriched fractions; this effect is IGF-I-specific and not reproduced by insulin in cells overexpressing insulin receptors.\",\n      \"method\": \"Co-fractionation/lipid raft isolation; Western blot for phospho-caveolin-1; immunofluorescence; R-cell reconstitution system\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization and phosphorylation assays with ligand specificity control, single lab\",\n      \"pmids\": [\"12135605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In embryonic rat spinal cord motor neurons, IGF-I binds IGF-IR and activates both MAPK and PI3K/Akt pathways via phosphorylation of IRS-1 and Shc (but not IRS-2); IGF-I prevents glutamate-induced DNA fragmentation and caspase-3 cleavage; neither MAPK inhibitor (PD98059) nor PI3K inhibitor (LY294002) alone blocks neuroprotection, but both together are required, demonstrating pathway redundancy in motor neuron survival.\",\n      \"method\": \"Enriched primary motor neuron culture; pathway inhibitors; Western blot for signaling intermediates and caspase-3 cleavage; DNA fragmentation assay\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined primary cell system with pharmacological pathway dissection and multiple readouts, single lab\",\n      \"pmids\": [\"15193297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IGF-I instructs multipotent adult neural progenitor cells (hippocampus-derived) to differentiate into oligodendrocytes via inhibition of bone morphogenetic protein (BMP) signaling; modeling analysis indicates the effect is instructive (fate specification) rather than selective; overexpression of IGF-I in hippocampus in vivo increases oligodendrocyte markers.\",\n      \"method\": \"Adult neural progenitor cell culture; fate mapping; BMP signaling analysis; in vivo IGF-I overexpression with immunohistochemistry\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro fate assay with mechanistic follow-up (BMP pathway) and in vivo corroboration, single lab\",\n      \"pmids\": [\"14709544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IGF-I enhances TRPV1-mediated membrane currents by both sensitizing the receptor and promoting translocation of TRPV1 from cytosol to plasma membrane; this effect requires PI3K and PKC-mediated phosphorylation of TRPV1, downstream of IGF-I receptor tyrosine kinase activation.\",\n      \"method\": \"Electrophysiology (patch-clamp) in heterologous expression systems and DRG neurons; PI3K and PKC inhibitors; immunofluorescence for TRPV1 localization\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with pharmacological pathway dissection and localization data, single lab\",\n      \"pmids\": [\"15857517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IGF-I neuroprotection in hypoxia-ischemia involves activation of Akt (PI3K pathway) and inactivation of GSK3beta: ICV IGF-I after HI increases pAkt in cytosol and pGSK3beta in both cytosol and nuclear fractions, concomitant with reduced caspase-3 and caspase-9 activity, resulting in 40% reduction in brain damage.\",\n      \"method\": \"Neonatal rat HI model; ICV IGF-I administration; Western blot for pAkt, pGSK3beta; caspase activity assays; immunohistochemistry\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with signaling pathway analysis and functional outcome, single lab\",\n      \"pmids\": [\"15845077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IGF-I specifically enhances the extent and rate of axon outgrowth of corticospinal motor neurons (CSMN) via the IGF-I receptor and downstream signaling pathways; this effect is distinct from IGF-I support of neuronal survival and distinct from BDNF, which promotes branching/arborization but not axon outgrowth.\",\n      \"method\": \"CSMN purification and culture; IGF-IR inhibition; in vivo analyses; comparison with BDNF\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — purified primary neuron system with receptor-specific inhibition and in vivo corroboration, distinct phenotypic readout separating survival from axon outgrowth\",\n      \"pmids\": [\"17057708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IGF-IR in mature osteoblasts is required for PTH anabolic effects on bone: osteoblast-specific IGF-IR knockout (IGF-IR OBKO) mice have reduced bone volume, decreased periosteal bone formation, and impaired PTH-stimulated osteoprogenitor cell proliferation and differentiation, establishing that PTH requires IGF-IR signaling in osteoblasts to exert its anabolic actions.\",\n      \"method\": \"Conditional (osteoblast-specific) IGF-IR knockout mice; PTH treatment; microCT; bone histomorphometry; BMSC culture\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with specific phenotypic readout, PTH rescue experiment, multiple structural and cellular readouts\",\n      \"pmids\": [\"17539737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IGF-I rescues diabetic cardiomyocyte dysfunction by inhibiting RhoA activation and restoring Akt phosphorylation, thereby re-coupling eNOS (reversing eNOS uncoupling indicated by NOS inhibitor-sensitive O2- accumulation), restoring NO levels, and normalizing Kv1.2 potassium channel expression and cardiomyocyte contractile parameters.\",\n      \"method\": \"IGF-I transgenic mice crossed with diabetic model; Rho kinase inhibitor (Y27632); eNOS coupler (BH4/folate); echocardiography; cardiomyocyte contractility measurements; Western blot for RhoA, pAkt, pERK, eNOS\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic gain-of-function with pharmacological mechanistic dissection (Rho kinase inhibitor, BH4), multiple pathway readouts\",\n      \"pmids\": [\"18199585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IGF-IR deletion specifically in adult neural stem cells (NSCs) increases cumulative neuroblast production and enhances neuronal integration into the olfactory bulb during aging, with differential downstream effects: Akt phosphorylation preferentially decreased in IGF-1R-/- NSCs within the niche, while ERK pathway is downregulated in differentiated neurons, demonstrating that IGF-I signaling through Akt in NSCs suppresses neurogenesis during aging.\",\n      \"method\": \"Conditional IGF-IR knockout in adult NSCs; BrdU/EdU cell fate tracing; Western blot for pAkt, pERK; olfactory behavioral testing; mathematical modeling\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO with signaling pathway analysis and behavioral outcome, single lab\",\n      \"pmids\": [\"26219530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IGF-I enhances cellular senescence in confluent primary cells (mouse, rat, human) through a ROS-p53 pathway: IGF-I induces γH2AX (DNA damage marker), increases p53 and p21, and activates SA-β-gal; ROS scavenger (NAC) suppresses senescence markers; p53-null MEFs are resistant to IGF-I-induced SA-β-gal and p21 induction, establishing that p53 is required downstream of IGF-I/ROS in this pathway.\",\n      \"method\": \"Primary cell cultures (confluent state); ROS scavenger treatment; p53-null MEFs; SA-β-gal assay; Western blot for γH2AX, p53, p21\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (p53-KO) and pharmacological (NAC) dissection in multiple cell types, single lab\",\n      \"pmids\": [\"22877754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IGF-I and IGFBP-2 coordinately stimulate osteoblast differentiation through early activation of AMPK (via their respective receptors), which drives autophagy (ULK-1 S555 phosphorylation, beclin-1 and LC3II induction); early AMPK activity is required, but subsequent AMPK down-regulation is also necessary to permit mTOR/AKT activation and completion of differentiation.\",\n      \"method\": \"Calvarial osteoblast and MC-3T3 cell cultures; AMPK inhibitors; constitutively active AMPK overexpression; receptor-blocking antibodies; Western blot for autophagy markers; differentiation assays\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic manipulation of AMPK with multiple autophagy pathway readouts, single lab\",\n      \"pmids\": [\"26556533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IGF1R directly phosphorylates a specific tyrosine residue (Y494) on the cytoplasmic domain of PTH1R in vitro; phosphorylated PTH1R localizes to barbed ends of actin filaments and increases actin polymerization during osteoblast-to-osteocyte morphological transition; disruption of Y494 reduces actin polymerization and dendrite length; conditional ablation of PTH1R in osteoblasts reduces osteocyte number and dendrites per osteocyte in vivo.\",\n      \"method\": \"In vitro kinase assay (IGF1R phosphorylation of PTH1R); site-directed mutagenesis (Y494); immunofluorescence for actin and pPTH1R; conditional PTH1R KO mice\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase reconstitution with mutagenesis, supported by in vivo conditional KO with matched phenotype\",\n      \"pmids\": [\"29507819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IGF-IR is required for acute GH-induced STAT5 signaling in osteoblasts: Cre-mediated deletion of IGF-IR in primary calvarial osteoblasts more than doubles the ED50 for GH-induced STAT5 activation and reduces maximal STAT5 activity by ~50%, while sparing GH-induced ERK; a C-terminally truncated IGF-IR lacking the kinase domain partially rescues GH-induced STAT5 activity, suggesting IGF-IR facilitates GH signaling through a kinase-independent scaffolding mechanism in addition to its role as IGF-I signal transducer.\",\n      \"method\": \"Adenoviral Cre-mediated conditional IGF-IR deletion in primary osteoblasts; STAT5 luciferase reporter; adenoviral IGF-IR re-expression and truncation mutant rescue; Western blot for pSTAT5, pERK\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic deletion with specific rescue (full-length vs kinase-dead IGF-IR), multiple orthogonal signaling readouts, domain-function dissection\",\n      \"pmids\": [\"20133448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"High extracellular calcium stimulates osteoblast DNA synthesis via an autocrine/paracrine IGF-I mechanism: elevated [Ca2+]e increases IGF-I mRNA expression and IGF-I protein secretion from MC3T3-E1 osteoblastic cells; neutralizing IGF-I antiserum completely abolishes the high [Ca2+]e-induced increase in DNA synthesis.\",\n      \"method\": \"MC3T3-E1 osteoblast cell culture; [3H]-thymidine incorporation; IGF-I neutralizing antibody; Northern blot for IGF-I mRNA; IGF-I RIA\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — neutralizing antibody functional block with matched mRNA/protein readouts, single lab\",\n      \"pmids\": [\"8203509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In thyroid eye disease (TED), IGF-IR forms a physical and functional complex with TSHR in orbital fibroblasts/fibrocytes; actions mediated through TSHR are dependent on IGF-IR activity; IGF-IR possesses kinase-independent activities and functions as a tyrosine kinase/G-protein-coupled receptor hybrid using the G-protein receptor kinase/β-arrestin system.\",\n      \"method\": \"Teprotumumab (anti-IGF-IR monoclonal antibody) attenuation of both IGF-I and TSH actions; in vitro fibrocyte assays; IGF-IR knockdown\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological IGF-IR inhibition and knockdown with functional readouts (cytokine induction), receptor complex supported by prior literature; single review synthesizing experimental evidence\",\n      \"pmids\": [\"35167695\"],\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 undergoes autophosphorylation and phosphorylates adaptor substrates IRS-1 and Shc; IRS-1 in turn activates PI3K/Akt (promoting cell survival, glucose metabolism, and protein anabolism) and the Ras/MAPK pathway (promoting proliferation), with IRS-1 concentration acting as a switch between mitogenic/survival and differentiation outputs; IRS-1 also delays IGF-IR endocytosis by competing with the AP2 clathrin adaptor, prolonging sustained Akt signaling; IGF-IR additionally phosphorylates PTH1R on Y494 to modulate actin dynamics in osteoblast-to-osteocyte transitions, and can scaffold GH-induced JAK2/STAT5 signaling in a partly kinase-independent manner; IGF-I is required for embryonic growth, postnatal somatic and skeletal development, mammary ductal morphogenesis, neural progenitor fate (oligodendrocyte specification via BMP inhibition), CSMN axon outgrowth, and beta-cell regeneration, while chronic IGF-I signaling can promote cellular senescence through a ROS/p53 pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IGF-I (IGF1) is a secreted growth factor essential for embryonic and postnatal somatic growth and a broad effector of cell survival, proliferation, differentiation, and tissue-specific anabolic programs; genetic ablation in mice produces severe growth retardation, muscle underdevelopment, and near-complete perinatal lethality [#0]. IGF-I acts through the IGF-I receptor (IGF-IR), a tyrosine kinase that upon ligand binding autophosphorylates and recruits the adaptor substrates IRS-1 and Shc; the submembrane Tyr950 residue is critical for downstream signal transduction, and kinase-dead receptor mutants act as dominant negatives [#2]. IRS-1 is the principal node that determines the output of receptor activation: it routes signaling into PI3K/Akt-driven mitogenic and anti-apoptotic responses, with IRS-1 abundance functioning as a switch between mitogenic/survival and differentiation programs [#3], and it additionally controls receptor trafficking by competing with the clathrin adaptor AP2 to delay IGF-IR endocytosis and sustain Akt activation [#6]. Akt is the required survival effector in multiple cell types, acting in part through GSK3beta inactivation and caspase suppression [#9, #14], and IGF-IR also engages anti-apoptotic outputs that are PI3K-independent [#4]. Through these pathways IGF-I directs tissue programs including pubertal mammary ductal morphogenesis as the local mediator of GH action [#5], pancreatic beta-cell regeneration and protection [#8], oligodendrocyte fate specification via BMP inhibition [#12], corticospinal motor neuron axon outgrowth [#15], and metabolic insulin-like actions including suppression of hepatic glucose output and protein catabolism [#1]. In bone, IGF-IR is required for the anabolic actions of PTH in osteoblasts [#16] and directly phosphorylates PTH1R on Tyr494 to drive actin polymerization during the osteoblast-to-osteocyte transition [#21], and it scaffolds GH-induced STAT5 signaling in a partly kinase-independent manner [#22]. Chronic IGF-I signaling can also drive cellular senescence through a ROS/p53/p21 pathway [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that IGF-I is an essential, non-redundant growth factor in vivo rather than merely a permissive systemic hormone, answering whether endogenous IGF-I is required for normal development.\",\n      \"evidence\": \"Homologous-recombination IGF-I knockout mice with histopathology\",\n      \"pmids\": [\"8276243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not separate embryonic from postnatal IGF-I requirement\",\n        \"Does not identify which tissues require autocrine vs endocrine IGF-I\",\n        \"Receptor and downstream effector not addressed\"\n      ]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstrated that IGF-I exerts direct insulin-like metabolic and protein-anabolic effects in humans, distinguishing its acute metabolic actions from chronic growth-promoting roles.\",\n      \"evidence\": \"Euglycemic clamp with stable isotope tracer kinetics in healthy men\",\n      \"pmids\": [\"8279537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not resolve whether effects are via IGF-IR or insulin receptor cross-reactivity\",\n        \"Tissue-level glucose flux mechanism not dissected\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined the receptor-proximal signaling architecture, showing IGF-IR kinase activity, IRS-1 phosphorylation, and the critical submembrane Tyr950 residue transduce IGF-I signals, with a dominant-negative receptor blocking output.\",\n      \"evidence\": \"Stable transfection of WT and mutant IGF-I receptor constructs in GH-secreting cells with structure-function mutagenesis\",\n      \"pmids\": [\"8701079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Tested mainly in pituitary GH-secreting cells\",\n        \"Does not enumerate the full set of downstream branches\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved how a single receptor produces divergent outputs by identifying IRS-1 concentration as a switch between mitogenic/survival (PI3K) and differentiation pathways, and revealing a PI3K-independent anti-apoptotic arm unique to IGF-IR.\",\n      \"evidence\": \"IGF-IR-null R-cell reconstitution with IRS-1 manipulation and PI3K-inhibitor pathway dissection\",\n      \"pmids\": [\"10579905\", \"10226786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular identity of the PI3K-independent anti-apoptotic effector not defined\",\n        \"Single-lab cell-line model, not validated in vivo\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected IGF-I to multiple tissue-specific programs—mammary ductal morphogenesis (as local mediator of GH), beta-cell regeneration, microglial proliferation, and Schwann cell survival/motility via Akt—establishing IGF-I as a broadly acting autocrine/paracrine effector.\",\n      \"evidence\": \"IGF-I KO with hormone rescue, beta-cell-specific transgenic STZ model, microglial thymidine incorporation, and dominant-negative Akt in Schwann cells\",\n      \"pmids\": [\"10791764\", \"11994404\", \"12112378\", \"11162904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Tissue-specific signaling branches not uniformly mapped\",\n        \"Microglial and Schwann cell findings are single-lab\",\n        \"Lipid-raft/caveolin-1 mechanism (12135605) not integrated into a functional output\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined neuronal mechanisms of IGF-I action, showing Akt/GSK3beta-mediated neuroprotection in hypoxia-ischemia and redundant MAPK+PI3K survival signaling in motor neurons, plus TRPV1 sensitization/trafficking.\",\n      \"evidence\": \"Neonatal HI rat model, primary motor neuron cultures with pathway inhibitors, and patch-clamp electrophysiology\",\n      \"pmids\": [\"15845077\", \"15193297\", \"15857517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Relative contribution of each pathway in vivo unresolved\",\n        \"Single-lab studies for each readout\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed IGF-I drives oligodendrocyte fate via BMP inhibition and instructs corticospinal motor neuron axon outgrowth, separating its developmental/regenerative roles from generic survival support.\",\n      \"evidence\": \"Adult neural progenitor fate assays with BMP analysis and purified CSMN cultures with IGF-IR inhibition plus in vivo corroboration\",\n      \"pmids\": [\"14709544\", \"17057708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream effectors of BMP inhibition not fully defined\",\n        \"Mechanism linking IGF-IR to axon-outgrowth machinery unmapped\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed kinase-independent and trafficking-level functions of the receptor system: IGF-IR scaffolds GH-induced STAT5 signaling independent of its kinase, and IRS-1 delays IGF-IR endocytosis via AP2 competition to sustain Akt signaling.\",\n      \"evidence\": \"Conditional IGF-IR deletion with truncation-mutant rescue in osteoblasts; reciprocal Co-IP, AP2-binding-deficient IRS-1 mutant and single-molecule imaging\",\n      \"pmids\": [\"20133448\", \"29661273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the kinase-independent scaffold not determined\",\n        \"Generality of the AP2-competition mechanism beyond the tested system unclear\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established IGF-IR as a bone anabolic hub: required for PTH anabolic action in osteoblasts, directly phosphorylating PTH1R Y494 to drive actin polymerization in the osteoblast-to-osteocyte transition, and coordinating AMPK/autophagy-dependent osteoblast differentiation.\",\n      \"evidence\": \"Osteoblast-specific IGF-IR/PTH1R conditional KO mice, in vitro kinase assay with Y494 mutagenesis, and AMPK manipulation with autophagy readouts\",\n      \"pmids\": [\"17539737\", \"29507819\", \"26556533\", \"8203509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How IGF-IR–PTH1R crosstalk integrates with canonical PTH GPCR signaling not fully defined\",\n        \"Temporal AMPK switch mechanism incompletely resolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a detrimental face of chronic IGF-I signaling—induction of cellular senescence through a ROS/p53/p21 pathway—and a suppressive role in aging neurogenesis via Akt in neural stem cells.\",\n      \"evidence\": \"Primary cells with ROS scavenger and p53-null MEFs; conditional IGF-IR deletion in adult NSCs with fate tracing\",\n      \"pmids\": [\"22877754\", \"26219530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism generating ROS downstream of IGF-I not defined\",\n        \"Reconciliation of pro-survival vs pro-senescence outputs context-dependence unresolved\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended IGF-IR function to receptor crosstalk in disease, showing it forms a physical/functional complex with TSHR in orbital fibroblasts and exerts kinase-independent, GPCR-like activity in thyroid eye disease.\",\n      \"evidence\": \"Anti-IGF-IR antibody (teprotumumab) attenuation and IGF-IR knockdown in fibrocyte assays\",\n      \"pmids\": [\"35167695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical demonstration of the TSHR–IGF-IR complex not provided in this synthesis\",\n        \"Structural basis of the hybrid receptor behavior unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IGF-I/IGF-IR signaling dynamics are decoded to select among opposing cell fates—survival, proliferation, differentiation, and senescence—across different tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unified model linking signal duration/amplitude to fate choice\",\n        \"Tissue-specific effector complements not comprehensively mapped\",\n        \"Structural mechanism of kinase-independent receptor scaffolding undetermined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 5, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 3, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [22, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 5, 8, 23]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 6, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 5, 12, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 9, 14]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IGF1R\",\n      \"IRS1\",\n      \"SHC1\",\n      \"AP2\",\n      \"CAV1\",\n      \"PTH1R\",\n      \"TSHR\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}