{"gene":"IGF1R","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2020,"finding":"IGF1R acts as an entry receptor for respiratory syncytial virus (RSV): binding of prefusion RSV-F glycoprotein to IGF1R triggers outside-in signaling that activates protein kinase C zeta (PKCζ), which in turn recruits nucleolin from the nucleus to the plasma membrane to serve as a co-receptor for RSV entry.","method":"Co-immunoprecipitation, airway organoid cultures, PKCζ inhibition assays, RSV-infected mouse models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, organoid cultures, and in vivo mouse model all converge on the same mechanism; multiple orthogonal methods in a single rigorous study published in Nature","pmids":["32494007"],"is_preprint":false},{"year":1997,"finding":"MAD2 (hMAD2) interacts specifically with the cytoplasmic domain of the insulin receptor (IR) but NOT with IGF1R; the interaction requires the C-terminal 30 amino acids of IR, does not require IR tyrosine autophosphorylation, and is released upon receptor activation.","method":"Yeast two-hybrid, GST pulldown in vitro binding assay, co-immunoprecipitation from CHO-IR cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and in vitro pulldown in single lab; the negative finding for IGF1R is mechanistically informative (MAD2 does NOT bind IGF1R)","pmids":["9092546"],"is_preprint":false},{"year":2016,"finding":"Upon resistance to p110α-selective PI3K inhibitor BYL719, IGF1R forms a complex with IRS1/IRS2, p85 regulatory subunit, and p110β, which activates AKT/mTOR/S6K signaling and mediates resistance; co-immunoprecipitation identified this IGF1R/IRS/p85/p110β complex.","method":"Phosphotyrosine proteomics, co-immunoprecipitation, pharmacologic inhibition of complex members","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased phosphoproteomics plus Co-IP plus pharmacological validation, single lab","pmids":["27048245"],"is_preprint":false},{"year":2013,"finding":"PTP1B is a negative regulator of IGF1R-mediated signaling in hepatocytes: PTP1B deficiency maintains IGF1R-mediated signaling during APAP-induced hepatotoxicity, whereas PTP1B overexpression or siRNA knockdown respectively suppress or sustain IGF1R pathway activation.","method":"PTP1B knockout mouse model, siRNA knockdown in hepatocytes, western blotting for IGF1R signaling components","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus siRNA knockdown with defined signaling readouts, single lab","pmids":["23661004"],"is_preprint":false},{"year":2014,"finding":"DVL3 (Dishevelled homolog) forms an adaptor complex with IGF1R, Shc, Grb2, SOS, and DAB2 that links IGF1R to RAS signaling; DVL3 mediates resistance to IGF1R inhibition, and its genetic or pharmacological blockade sensitizes breast and prostate cancer cells to IGF1R inhibitors via enhanced MEK-ERK activation.","method":"Genetic screen, co-immunoprecipitation of adaptor complex, pharmacological blockade, in vivo xenograft models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex plus in vitro and in vivo validation, single lab with multiple orthogonal methods","pmids":["25168481"],"is_preprint":false},{"year":2018,"finding":"DARPP-32 physically interacts with IGF1R and promotes IGF1R phosphorylation at Y1135; this binding activates downstream SRC and STAT3 (phosphorylation at Y705), nuclear STAT3 localization, and transcription, driving gastric tumorigenesis.","method":"Proximity ligation assay, co-immunoprecipitation, knockout mouse models (TFF1 KO crossed with DARPP-32 KO), 3D organoid cultures, tissue microarrays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — PLA and Co-IP both confirm IGF1R-DARPP-32 interaction, validated in multiple mouse models and human tissues with clear mechanistic readout","pmids":["31235784"],"is_preprint":false},{"year":2011,"finding":"During resistance to the IGF1R inhibitor NVP-AEW541 in alveolar rhabdomyosarcoma, Her2 forms heterodimers with IGF1R, and IGF2 stimulation leads to Her2 phosphorylation; dual blockade of IGF1R and Her2 (lapatinib) reduces IGF1R phosphorylation and overcomes resistance.","method":"Co-immunoprecipitation of IGF1R-Her2 heterodimers in resistant primary tumor cell cultures, western blotting, combinatorial drug treatment in genetically engineered mouse model","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating heterodimer formation plus pharmacological validation, single lab","pmids":["21447712"],"is_preprint":false},{"year":2017,"finding":"Cell surface GRP78 physically interacts with IGF1R upon IGF-I stimulation (redistributing from ER to plasma membrane), promotes IGF1R phosphorylation and activation, and blocking GRP78 inhibits IGF-I-stimulated IGF1R phosphorylation, downstream PI3K/MAPK signaling, and hepatoma cell proliferation and migration.","method":"Co-immunoprecipitation, siRNA knockdown of GRP78, antibody blocking, western blotting, cell proliferation and migration assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus siRNA knockdown plus antibody blocking, single lab with multiple orthogonal methods","pmids":["28389416"],"is_preprint":false},{"year":2013,"finding":"Upon blockade of IGF-1R by anti-IGF-1R antibody cixutumumab, IGF-1 binds integrin β3, activating a β3-Src signaling cascade that leads to Akt activation and mediates resistance to cixutumumab; combined targeting of integrin β3 or Src with cixutumumab overcomes this resistance in HNSCC and NSCLC models.","method":"Ligand blotting, immunoprecipitation, immunofluorescence, cell adhesion assays, ELISA, in vivo xenograft and patient-derived xenograft tumors","journal":"Journal of the National Cancer Institute","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays plus in vivo validation, single lab","pmids":["24092920"],"is_preprint":false},{"year":2013,"finding":"Estrogen receptor (ER) rapidly associates with IGF1R in response to both E2 and IGF-I stimulation in MCF-7 cells; this ER-IGF1R interaction is required for non-genomic ER signaling, activating ERK1/2 and AKT phosphorylation, and potentiating cell growth.","method":"Co-immunoprecipitation, transfection of antisense IGF1R cDNA (reducing receptor ~50%), transient ERα transfection into NIH3T3-IGF1R cells, cell growth assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP across multiple cell lines plus gain/loss of function, single lab","pmids":["23704881"],"is_preprint":false},{"year":2006,"finding":"Aldosterone directly transactivates the IGF-1R in renal epithelial A6 cells: 10-min aldosterone exposure increases phosphorylation of IGF-1R, IRS-1, and Akt; this requires aldosterone binding to the mineralocorticoid/glucocorticoid receptor, does not require transcription, and activates PI3-K (blocked by LY-294002).","method":"Phosphorylation assays in A6 cells, PI3-K inhibitor (LY-294002) treatment, mineralocorticoid receptor dependence testing","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological and receptor-blocking experiments, single lab, no direct receptor binding assay","pmids":["17190911"],"is_preprint":false},{"year":2021,"finding":"IGF1R controls mechanosignaling in pulmonary myofibroblasts required for alveologenesis: postnatal deletion of Igf1r impairs contractile properties of lung myofibroblasts, inhibits myosin light chain (MLC) phosphorylation and nuclear YAP mechanotransductive activity; AKT, p-MLC, and nuclear YAP activation in myofibroblasts are dependent on IGF1R.","method":"Conditional Igf1r knockout mice (postnatal), pharmacologic AKT activation, lung histology, western blotting for MLC phosphorylation and YAP localization","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined cellular phenotype plus pharmacologic rescue in vivo, multiple orthogonal readouts","pmids":["33591952"],"is_preprint":false},{"year":2018,"finding":"IGF1R signaling drives antiestrogen resistance through PAK2 and PIX (PAK-interacting exchange factors): phospho-proteomics identified PAK2 and PIXα/β as downstream targets of IGF1R signaling independent of PI3K/AKT and MAPK/ERK; PAK2/PIX modulate IGF1R-driven cell scattering, and silencing PAK2 or targeting PIXα/β re-sensitizes cells to tamoxifen and fulvestrant.","method":"Kinome siRNA screen, phospho-proteomics, PAK2/PIX silencing, functional cell scattering assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased kinome screen plus phosphoproteomics plus functional validation, single lab with multiple methods","pmids":["29353882"],"is_preprint":false},{"year":2015,"finding":"PAPP-AA, an extracellular metalloprotease, promotes habituation learning by increasing local IGF bioavailability to activate IGF1R: metalloprotease-inactive PAPP-AA fails to restore habituation in pappaa mutant zebrafish; acute IGF1R inhibition in wild-type fish reduces habituation, while activation of IGF1R downstream effectors in pappaa mutants restores habituation.","method":"Genome-wide genetic screen with whole-genome sequencing, rescue with metalloprotease-dead mutant, acute pharmacological IGF1R inhibition, epistasis (activation of downstream effectors)","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with pharmacologic validation and dominant-negative rescue across multiple orthogonal experiments in zebrafish","pmids":["25754827"],"is_preprint":false},{"year":2020,"finding":"ALKBH5 (m6A RNA demethylase) demethylates IGF1R mRNA, enhancing its stability and translation, thereby activating IGF1R signaling and promoting endometrial cancer proliferation and invasion.","method":"m6A methylation analysis, western blotting, ALKBH5 knockdown/overexpression, functional proliferation and invasion assays","journal":"Journal of Cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method for the key mechanistic claim (m6A demethylation of IGF1R mRNA), limited orthogonal validation of direct molecular mechanism","pmids":["32913456"],"is_preprint":false},{"year":2022,"finding":"IGF2BP2 (m6A reader protein) binds m6A methylation sites in IGF1R mRNA and increases IGF1R expression, thereby activating the IGF1R-RhoA-ROCK signaling pathway to promote gastric cancer proliferation and metastasis.","method":"RIP (RNA immunoprecipitation) and RNA pulldown assays confirming IGF2BP2-IGF1R mRNA binding, IGF2BP2 silencing/IGF1R overexpression rescue experiments, in vivo xenograft models","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and RNA pulldown confirm direct binding, plus epistasis rescue experiments, single lab","pmids":["35306138"],"is_preprint":false},{"year":2023,"finding":"Nuclear IGF1R phosphorylates PYCR1 at Tyrosine 135 under hypoxia; this phosphorylation promotes PYCR1 binding to ELK4 and recruitment to ELK4-targeted gene promoters, stimulating PYCR1-catalyzed NAD+ production that activates Sirt7 deacetylase activity on H3K18ac to repress gene transcription and maintain tumor growth.","method":"Nuclear IGF1R activity assays, phospho-site identification (Y135), co-immunoprecipitation of PYCR1-ELK4 complex, chromatin recruitment assays, Sirt7 deacetylation assays, in vivo tumor growth experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-site identification plus Co-IP plus functional enzymatic assays plus in vivo data, single lab","pmids":["37777542"],"is_preprint":false},{"year":2022,"finding":"GIGYF1 regulates recycling of IGF1R to the cell surface; GIGYF1 knockout reduces IGF1R surface levels, thereby disrupting IGF1R/ERK signaling and causing social impairments in mice consistent with autism.","method":"Gigyf1 conditional KO mouse model, cell surface IGF1R measurement, ERK phosphorylation assays, behavioral testing","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined molecular readout (surface IGF1R levels and ERK phosphorylation), single lab","pmids":["35917186"],"is_preprint":false},{"year":2021,"finding":"IGFBP7 prolongs surface retention of IGF1R under insulin/IGF1 stimulation, resulting in sustained IGF1R, IRS-1, AKT, and ERK phosphorylation; in the presence of IGFBP7, insulin activates IGF1R at concentrations >100-fold lower than normally required, while the insulin receptor is readily internalized despite IGFBP7 addition.","method":"IGFBP7 knockdown and antibody neutralization, surface receptor retention assays, phosphorylation time-course western blotting, in vivo leukemia progression model","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IGFBP7 knockdown and antibody neutralization with phosphorylation kinetics assays and in vivo validation, single lab","pmids":["34438446"],"is_preprint":false},{"year":2024,"finding":"Follistatin (FST) directly binds IGF1R (confirmed by biolayer interferometry and co-immunoprecipitation) via its N-terminal domain; FST-IGF1R binding activates ERK and AKT signaling and Nav1.7-mediated nociceptive neuron hyperexcitability; a peptide blocking the FST N-terminal domain interaction with IGF1R attenuates neuronal hyperexcitability and neuropathic pain.","method":"Biolayer interferometry (BLI), co-immunoprecipitation, IGF1R inhibitor rescue experiments, DRG neuron electrophysiology, in vivo spinal nerve ligation mouse model, FST conditional overexpression and deletion","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding confirmed by BLI (quantitative biophysical assay) plus Co-IP plus pharmacological/genetic validation in vivo and in human DRG neurons, multiple orthogonal methods","pmids":["39413164"],"is_preprint":false},{"year":2018,"finding":"Loss of E-cadherin (CDH1) hyperactivates IGF1R signaling; in situ proximity ligation assay demonstrated a direct endogenous interaction between IGF1R and E-cadherin at cell-cell contact points, and diminished E-cadherin increases IGF1R signaling and sensitivity to anti-IGF1R/InsR therapies.","method":"In situ proximity ligation assay (PLA), E-cadherin knockdown/overexpression, western blotting for IGF1R pathway activation, xenograft tumor explant cultures","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PLA demonstrating direct endogenous IGF1R-E-cadherin interaction plus functional validation, single lab","pmids":["29941485"],"is_preprint":false},{"year":2013,"finding":"Transcription factors Ikaros isoform 1 (Ik-1) and MZF1 directly bind specific sites within the IGF1R gene promoter and suppress IGF1R transcription; decreased Ik-1 and MZF1 in NPM-ALK+ T-cell lymphoma leads to IGF1R upregulation, activating IRS-1, AKT, and NPM-ALK phosphorylation.","method":"Luciferase reporter assay, ChIP assay, forced expression of Ik-1/MZF1, western blotting, functional proliferation/migration assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter binding plus functional reporter and protein expression data, single lab","pmids":["25884514"],"is_preprint":false},{"year":2015,"finding":"In CRISPR-Cas9 screen, IGF1R overexpression promotes escape from CDK4/6 inhibitor treatment in Ewing sarcoma; elevated phospho-IGF1R was found in CDK4/6 inhibitor-resistant cell lines, and IGF1R inhibition combined with CDK4/6 inhibition more profoundly represses cell cycle and PI3K/mTOR signaling than either alone.","method":"Genome-scale ORF screen (CRISPR), resistant cell line generation, phosphoprotein analysis, small-molecule synergy screen, in vivo mouse xenograft models","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased genome-scale screen plus mechanistic validation plus in vivo data, single lab","pmids":["30397176"],"is_preprint":false},{"year":2013,"finding":"Nuclear IGF-1R expression is conserved in alveolar rhabdomyosarcoma subpopulations with high cell-surface IGF-1R; cells with high nuclear IGF-1R establish tumors more efficiently in vivo; siRNA silencing of IGF-1R in high-expressing subpopulations significantly reduces anchorage-independent colony formation, linking nuclear IGF-1R to tumorigenic capacity.","method":"FACS sorting, immunofluorescence for subcellular localization, RNA interference, anchorage-independent colony formation assay, in vivo tumor formation","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by FACS/immunofluorescence with functional consequence (tumor formation), single lab","pmids":["23928059"],"is_preprint":false},{"year":2017,"finding":"Nuclear IGF1R translocation occurs in non-malignant (normal diploid fibroblast) cells as well as cancer cells; combined use of a nuclear translocation blocker and selective IGF1R kinase inhibitors synergistically decreases cell proliferation, indicating nuclear IGF1R contributes to mitogenic signaling.","method":"Nuclear fractionation, pharmacological nuclear translocation inhibition combined with kinase inhibitors, cell proliferation assays","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibition without direct molecular mechanism of nuclear IGF1R action established, single lab, single method for nuclear localization","pmids":["28945762"],"is_preprint":false},{"year":2015,"finding":"Calcium (at moderate doses) and osteoprotegerin (OPG) regulate IGF1R expression in vascular smooth muscle cells: OPG induces IGF1R mRNA, protein, and transcription; calcium positively regulates OPG then IGF1R; IGF1R induction requires Sp1 binding at the −446 to −188 bp region of the IGF1R promoter; IGF1R activation promotes VSMC survival (Bcl2, NF-κB) and blocks calcification.","method":"Sp1 siRNA silencing, promoter deletion analysis, siRNA targeting OPG, western blotting, mineralization assays","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter deletion mapping plus siRNA validation plus functional calcification assay, single lab","pmids":["21447702"],"is_preprint":false},{"year":2020,"finding":"IGF1R inhibition induces autophagic flux; CRISPR screen identified IGF1R as a top sensitizer to lysosomal autophagy inhibition; IGF1R and ERK-MAPK inhibition converge to suppress glycolysis and enhance autophagy dependence; compensatory IGF1R phosphorylation is activated in response to chloroquine treatment in pancreatic cancer.","method":"CRISPR-Cas9 loss-of-function screen, reverse phase protein array (RPPA), autophagic flux assays, in vitro and in vivo growth suppression assays, PDAC organoids","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased CRISPR screen plus RPPA plus functional organoid and in vivo validation, single lab","pmids":["34921013"],"is_preprint":false},{"year":2015,"finding":"In resistance to EGFR inhibitors in glioblastoma, the InsR/IGF1R pathway activates AKT to maintain cell survival; concurrent inhibition of EGFR and InsR/IGF1R (with OSI-906) is required to suppress AKT and induce apoptosis; insulin and IGF1 protect EGFR-dependent glioblastoma cells from gefitinib, and this protection is absent in cells lacking IGF1R/InsR expression.","method":"Patient-derived glioblastoma xenograft (PDX) lines, RTK ligand screening, combinatorial drug treatment (gefitinib + OSI-906), western blotting for EGFR/AKT/MEK/ERK, subcutaneous xenograft tumor treatment","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PDX-based platform with pharmacological epistasis plus in vivo xenograft validation, single lab","pmids":["26561558"],"is_preprint":false},{"year":2015,"finding":"TM4SF5 and IGF1R form a membrane complex (co-immunoprecipitation) in NSCLC cells; TM4SF5 and IGF1R transcriptionally upregulate each other (bidirectional regulation); TM4SF5-IGF1R complex promotes ERK, AKT, and S6K signaling and maintains residual EGFR activity contributing to EGFR inhibitor resistance.","method":"Co-immunoprecipitation of TM4SF5-IGF1R complex, IGF1R siRNA knockdown, TM4SF5 overexpression, 2D/3D cell viability assays, western blotting","journal":"Lung cancer (Amsterdam, Netherlands)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP plus siRNA rescue, single lab, limited mechanistic detail on bidirectional transcriptional regulation","pmids":["26190015"],"is_preprint":false},{"year":2016,"finding":"In BRAF-mutant melanoma resistant to trametinib/dabrafenib, IGF1R and insulin receptor (INSR) are upregulated; RTK arrays show increased p-IGF1R and p-IR; siRNA dual knockdown of IGF1R and INSR reduces proliferation, and IGF1R/IR inhibitor (BMS-754807) suppresses p-Akt, confirming IGF1R/IR as a resistance mechanism through AKT signaling.","method":"Receptor tyrosine kinase arrays, RNA-sequencing, siRNA knockdown, BMS-754807 pharmacological inhibition, in vivo xenograft tumor treatment","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RTK array plus RNA-seq plus siRNA plus pharmacological inhibition plus in vivo validation, single lab","pmids":["34831014"],"is_preprint":false},{"year":2023,"finding":"Inhibition of IGF1R by lorlatinib sensitizes melanoma to ferroptosis (GPX4 inhibition) by suppressing the PI3K/AKT/mTOR signaling axis and its downstream target SCD (stearoyl-CoA desaturase); IGF1R (not ALK or ROS1) was identified as the major mediator of lorlatinib's effect using selective target knockdown experiments.","method":"Drug synergy screen (240 FDA-approved drugs + RSL3), IGF1R-specific knockdown vs ALK/ROS1 knockdown, western blotting for PI3K/AKT/mTOR/SCD, in vivo preclinical animal models","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective target identification via siRNA knockdown plus pharmacological validation plus in vivo models, single lab","pmids":["36889082"],"is_preprint":false},{"year":2021,"finding":"IGF1R deficiency in the brain (conditional knockout) activates IR/PI3K/Akt signaling while inhibiting MAPK/ERK1/2/CREB signaling; it increases phosphorylated Tau protein levels, disrupts mitochondrial dynamics, impairs respiratory chain complex activity, and increases oxidative stress (decreased NRF2, increased H2O2).","method":"UBC-CreERT2; Igf1r conditional knockout mice, western blotting for PI3K/Akt, ERK, GSK3β, phospho-Tau, mitochondrial complex activity assays, oxidative stress assays","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with multiple defined molecular readouts, single lab","pmids":["33562061"],"is_preprint":false},{"year":2020,"finding":"IGF1R inhibition (picropodophyllin and linsitinib) induces autophagic flux and enhances ATP release from cancer cells (immunogenic cell death marker); this was identified via a phenotypic screen of 65,000 compounds and confirmed as on-target through IGF1R kinase inhibition; IGF1R phosphorylation in human triple-negative breast cancer correlates with reduced autophagy.","method":"Phenotypic autophagy discovery screen (65,000 compounds), on-target validation with selective IGF1R inhibitors, ATP release assays, in vivo chemoimmunotherapy mouse models","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large-scale phenotypic screen with on-target confirmation and in vivo validation, single lab","pmids":["34110249"],"is_preprint":false},{"year":2018,"finding":"MDA-9/Syntenin physically interacts with IGF1R following IGFBP2 treatment, and this interaction regulates downstream STAT3 phosphorylation, which drives MMP2/MMP9 expression and promotes prostate cancer invasion.","method":"Co-immunoprecipitation of MDA-9/Syntenin-IGF1R complex, CRISPR/Cas9 knockout of MDA-9/Syntenin, loss-of-function/gain-of-function cell lines, western blotting, invasion assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus CRISPR KO plus functional invasion assays, single lab","pmids":["29572229"],"is_preprint":false}],"current_model":"IGF1R is a transmembrane tyrosine kinase receptor that, upon binding IGF1/IGF2 (or non-canonical ligands such as follistatin), undergoes autophosphorylation to activate PI3K/AKT, MAPK/ERK, and PAK2/PIX downstream signaling cascades; its activity is modulated by physical interactions with multiple partners including E-cadherin (which restrains it at cell-cell contacts), MDA-9/Syntenin, DARPP-32, GRP78, DVL3-Shc-Grb2-SOS adaptor complexes, and IGFBP7 (which prolongs receptor surface retention); receptor internalization, nuclear translocation (where it phosphorylates substrates such as PYCR1 to regulate transcription), ubiquitination-mediated degradation, and recycling (regulated by GIGYF1) collectively determine the spatiotemporal wiring of its signaling output, with the endosomal/nuclear compartments emerging as important platforms for non-canonical IGF1R functions beyond classical plasma-membrane kinase signaling."},"narrative":{"mechanistic_narrative":"IGF1R is a transmembrane receptor tyrosine kinase that, upon ligand binding, drives PI3K/AKT and MAPK/ERK signaling to control cell survival, proliferation, and tissue morphogenesis across normal and malignant contexts [PMID:33591952, PMID:26561558]. Beyond its canonical ligands, IGF1R is activated through diverse non-classical inputs: extracellular metalloprotease PAPP-AA increases local IGF bioavailability to engage IGF1R during habituation learning [PMID:25754827], aldosterone transactivates the receptor via the mineralocorticoid receptor to stimulate PI3K [PMID:17190911], and follistatin binds IGF1R directly through its N-terminal domain to activate ERK/AKT and drive nociceptive neuron hyperexcitability and neuropathic pain [PMID:39413164]. The receptor also serves as an entry receptor for respiratory syncytial virus, where prefusion RSV-F binding triggers PKCζ-dependent recruitment of nucleolin as a co-receptor [PMID:32494007]. IGF1R signaling output is shaped by a network of physical partners that modulate its activity and surface dynamics: E-cadherin restrains the receptor at cell-cell contacts [PMID:29941485], cell-surface GRP78 and DARPP-32 promote its phosphorylation and downstream SRC/STAT3 activation [PMID:31235784, PMID:28389416], IGFBP7 prolongs surface retention to sensitize the receptor to low ligand concentrations [PMID:34438446], and GIGYF1 controls its recycling back to the plasma membrane [PMID:35917186]. Receptor abundance is set transcriptionally by Ikaros/MZF1 and Sp1 at the IGF1R promoter [PMID:25884514, PMID:21447702] and post-transcriptionally through m6A-dependent regulation of IGF1R mRNA by IGF2BP2 [PMID:35306138]. A non-canonical nuclear pool of IGF1R contributes to mitogenic and tumorigenic capacity [PMID:23928059], and nuclear IGF1R phosphorylates PYCR1 at Tyr135 under hypoxia to drive an ELK4/Sirt7-dependent transcriptional program supporting tumor growth [PMID:37777542]. IGF1R is a recurrent mediator of therapeutic resistance: it forms compensatory complexes and heterodimers (with IRS/p85/p110β, Her2, TM4SF5, DVL3-Shc-Grb2-SOS, MDA-9/Syntenin, and integrin β3) and is upregulated alongside the insulin receptor to sustain AKT signaling against PI3K, CDK4/6, EGFR, and BRAF/MEK inhibitors [PMID:27048245, PMID:25168481, PMID:21447712, PMID:24092920, PMID:30397176, PMID:26561558, PMID:34831014, PMID:29572229]. IGF1R activity additionally suppresses autophagic flux and protects cancer cells from ferroptosis, linking it to metabolic and cell-death control [PMID:34921013, PMID:36889082, PMID:34110249]. PTP1B acts as a negative regulator of IGF1R signaling [PMID:23661004].","teleology":[{"year":1997,"claim":"Established receptor specificity by distinguishing IGF1R from the insulin receptor at the level of cytoplasmic-domain partner binding, showing MAD2 binds IR but not IGF1R.","evidence":"Yeast two-hybrid, GST pulldown, and Co-IP comparing IR and IGF1R cytoplasmic domains","pmids":["9092546"],"confidence":"Medium","gaps":["Negative result for IGF1R; does not identify the analogous IGF1R adaptor","Functional consequence of MAD2-IR binding not extended to IGF1R biology"]},{"year":2006,"claim":"Showed IGF1R can be activated by a non-canonical, transcription-independent input, with aldosterone transactivating the receptor via the mineralocorticoid receptor to stimulate PI3K.","evidence":"Phosphorylation assays in A6 renal cells with PI3-K inhibitor and receptor-blocking experiments","pmids":["17190911"],"confidence":"Medium","gaps":["No direct receptor binding assay","Mechanism linking MR to IGF1R phosphorylation not resolved"]},{"year":2013,"claim":"Identified PTP1B as a negative regulator that limits IGF1R signaling, and uncovered ER-IGF1R association as a node for non-genomic estrogen action, defining bidirectional modulation of the receptor.","evidence":"PTP1B KO mouse and siRNA in hepatocytes; Co-IP and gain/loss of IGF1R in MCF-7/NIH3T3 cells","pmids":["23661004","23704881"],"confidence":"Medium","gaps":["Whether PTP1B dephosphorylates IGF1R directly versus pathway intermediates not distinguished","ER-IGF1R interaction not shown to be direct"]},{"year":2013,"claim":"Defined IGF1R as a hub for adaptive resistance, showing it activates compensatory signaling via integrin β3-Src upon antibody blockade and that a nuclear IGF1R pool correlates with tumorigenic capacity.","evidence":"Ligand blotting, IP, adhesion assays, and xenografts (cixutumumab); FACS sorting, immunofluorescence, and tumor formation assays (nuclear IGF1R)","pmids":["24092920","23928059"],"confidence":"Medium","gaps":["Molecular mechanism of nuclear IGF1R action not defined at this stage","How antibody blockade redirects ligand to integrin β3 unresolved"]},{"year":2014,"claim":"Resolved a specific adaptor architecture linking IGF1R to RAS signaling, identifying the DVL3-Shc-Grb2-SOS-DAB2 complex as a determinant of IGF1R-inhibitor resistance.","evidence":"Genetic screen, Co-IP of the adaptor complex, pharmacologic blockade, and xenografts","pmids":["25168481"],"confidence":"Medium","gaps":["Stoichiometry and direct contacts within the adaptor complex not mapped","Generality across tumor types beyond breast/prostate untested"]},{"year":2015,"claim":"Demonstrated physiological IGF1R signaling in vivo, showing PAPP-AA-dependent IGF bioavailability activates IGF1R to enable habituation learning, and defined promoter-level transcriptional control of IGF1R.","evidence":"Genetic screen and pharmacologic epistasis in zebrafish; ChIP, reporter, and promoter-deletion mapping (Ikaros/MZF1, Sp1) plus EGFR-resistance PDX models","pmids":["25754827","25884514","21447702","26561558"],"confidence":"High","gaps":["Downstream effectors of IGF1R in habituation neurons not fully defined","Promoter regulators studied in specific disease contexts only"]},{"year":2016,"claim":"Generalized IGF1R as a convergent resistance receptor across kinase-inhibitor therapies, forming the IRS/p85/p110β complex and being upregulated with the insulin receptor to sustain AKT.","evidence":"Phosphoproteomics and Co-IP (PI3K inhibitor); RTK arrays, RNA-seq, siRNA, and xenografts (BRAF/MEK inhibitor)","pmids":["27048245","34831014"],"confidence":"Medium","gaps":["Whether complex formation is cause or consequence of resistance not fully separated","Direct kinase substrate landscape under resistance untested"]},{"year":2017,"claim":"Identified cell-surface partners that positively gate IGF1R activation, with GRP78 redistributing from ER to plasma membrane to promote IGF1R phosphorylation, and characterized nuclear IGF1R as contributing to mitogenic signaling.","evidence":"Co-IP, siRNA, antibody blocking (GRP78); nuclear fractionation with translocation-blocker plus kinase-inhibitor synergy","pmids":["28389416","28945762"],"confidence":"Medium","gaps":["Direct GRP78-IGF1R contact interface not mapped","Nuclear IGF1R study (Low) used single localization method without molecular nuclear function"]},{"year":2018,"claim":"Expanded the IGF1R interactome to scaffolds and adhesion molecules that bidirectionally tune output—DARPP-32 and MDA-9/Syntenin driving SRC/STAT3, E-cadherin restraining the receptor—and identified PAK2/PIX as a PI3K/MAPK-independent effector branch.","evidence":"PLA and Co-IP with KO mouse models (DARPP-32); Co-IP/CRISPR KO (MDA-9/Syntenin); in situ PLA (E-cadherin); kinome screen and phosphoproteomics (PAK2/PIX)","pmids":["31235784","29572229","29941485","29353882"],"confidence":"High","gaps":["How E-cadherin physically restrains IGF1R kinase activity not resolved","PAK2/PIX activation mechanism downstream of IGF1R not fully defined"]},{"year":2020,"claim":"Revealed a non-signaling-receptor role of IGF1R as an RSV entry receptor and established IGF1R as a regulator of autophagy and metabolic dependency in cancer.","evidence":"Co-IP, airway organoids, PKCζ inhibition, and RSV mouse models; CRISPR screen, RPPA, and autophagic flux/ATP-release assays plus organoids","pmids":["32494007","34921013","34110249"],"confidence":"High","gaps":["Whether kinase activity is required for RSV co-receptor recruitment not addressed","Mechanism coupling IGF1R inhibition to autophagic flux not fully defined"]},{"year":2021,"claim":"Defined developmental and homeostatic IGF1R functions in vivo—mechanosignaling in lung myofibroblasts via MLC/YAP, brain neuroprotection against Tau and mitochondrial dysfunction—and showed IGFBP7 prolongs receptor surface retention.","evidence":"Conditional Igf1r KO mice with pharmacologic rescue (lung); conditional KO with signaling/oxidative readouts (brain); knockdown and antibody neutralization with phospho-kinetics (IGFBP7)","pmids":["33591952","33562061","34438446"],"confidence":"High","gaps":["Direct link from IGF1R to YAP mechanotransduction beyond AKT not mapped","How IGFBP7 selectively retains IGF1R but not IR not mechanistically resolved"]},{"year":2022,"claim":"Established post-transcriptional and trafficking control of IGF1R, with m6A reader IGF2BP2 binding IGF1R mRNA to raise expression, and GIGYF1 governing receptor recycling to the surface.","evidence":"RIP and RNA pulldown with rescue and xenografts (IGF2BP2); conditional KO with surface-receptor and ERK assays plus behavior (GIGYF1)","pmids":["35306138","35917186"],"confidence":"Medium","gaps":["Whether IGF2BP2 effect is fully m6A-dependent in vivo not separated","Molecular machinery by which GIGYF1 directs IGF1R recycling unknown"]},{"year":2023,"claim":"Defined a direct nuclear enzymatic function for IGF1R, phosphorylating PYCR1 at Tyr135 to drive ELK4/Sirt7-dependent transcriptional repression under hypoxia, and extended IGF1R's role to ferroptosis control.","evidence":"Nuclear kinase assays, phospho-site mapping, Co-IP, chromatin recruitment, Sirt7 assays, and in vivo tumors; drug synergy screen with selective IGF1R knockdown (ferroptosis)","pmids":["37777542","36889082"],"confidence":"Medium","gaps":["Mechanism of IGF1R nuclear import not defined","Breadth of nuclear IGF1R substrates beyond PYCR1 unknown"]},{"year":2024,"claim":"Demonstrated a direct non-canonical ligand for IGF1R, with follistatin binding the receptor via its N-terminal domain to drive ERK/AKT signaling and neuropathic pain, validating a targetable interaction.","evidence":"Biolayer interferometry and Co-IP, DRG electrophysiology, blocking peptide, and spinal nerve ligation mouse model with FST gain/loss","pmids":["39413164"],"confidence":"High","gaps":["Whether follistatin competes with or is independent of IGF ligand binding not resolved","Structural basis of the N-terminal FST-IGF1R interface not determined"]},{"year":null,"claim":"How the many distinct IGF1R partner complexes, ligand inputs, and subcellular pools are integrated into a unified spatiotemporal signaling logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model unifying the diverse direct partners","Rules governing plasma-membrane versus nuclear versus recycling fate not established","Relative contribution of canonical IGF ligands versus follistatin/aldosterone/RSV-F inputs in vivo unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,16,7]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[13,19,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,18,20]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16,23]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,27,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[26,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,22,29]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[16,21,25]}],"complexes":["IGF1R/IRS/p85/p110β complex","IGF1R-Her2 heterodimer","DVL3-Shc-Grb2-SOS-DAB2 adaptor complex","TM4SF5-IGF1R complex"],"partners":["GRP78","DARPP-32","CDH1","IGFBP7","GIGYF1","SDCBP","FST","PYCR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P08069","full_name":"Insulin-like growth factor 1 receptor","aliases":["Insulin-like growth factor I receptor","IGF-I receptor"],"length_aa":1367,"mass_kda":154.8,"function":"Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P08069/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IGF1R","classification":"Not Classified","n_dependent_lines":247,"n_total_lines":1208,"dependency_fraction":0.20447019867549668},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000140443","cell_line_id":"CID000878","localizations":[{"compartment":"membrane","grade":3},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000878","total_profiled":1310},"omim":[{"mim_id":"619489","title":"SHORT STATURE, DAUBER-ARGENTE TYPE; SSDA","url":"https://www.omim.org/entry/619489"},{"mim_id":"619212","title":"IGF1R ANTISENSE IMPRINTED NONCODING RNA; IRAIN","url":"https://www.omim.org/entry/619212"},{"mim_id":"619089","title":"GIPC PDZ DOMAIN-CONTAINING FAMILY, MEMBER 2; GIPC2","url":"https://www.omim.org/entry/619089"},{"mim_id":"618905","title":"SILVER-RUSSELL SYNDROME 2; SRS2","url":"https://www.omim.org/entry/618905"},{"mim_id":"617372","title":"SHC TRANSFORMING PROTEIN 4; SHC4","url":"https://www.omim.org/entry/617372"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Nucleoli rim","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IGF1R"},"hgnc":{"alias_symbol":["JTK13","CD221","IGFIR","MGC18216","IGFR"],"prev_symbol":[]},"alphafold":{"accession":"P08069","domains":[{"cath_id":"3.80.20.20","chopping":"33-215","consensus_level":"high","plddt":88.1521,"start":33,"end":215},{"cath_id":"2.10.220.10","chopping":"254-328","consensus_level":"medium","plddt":85.97,"start":254,"end":328},{"cath_id":"3.80.20.20","chopping":"332-467","consensus_level":"high","plddt":89.6902,"start":332,"end":467},{"cath_id":"2.60.40.10","chopping":"491-606","consensus_level":"high","plddt":83.958,"start":491,"end":606},{"cath_id":"2.60.40.10","chopping":"616-678_775-825","consensus_level":"high","plddt":88.0443,"start":616,"end":825},{"cath_id":"2.60.40.10","chopping":"840-925","consensus_level":"high","plddt":91.6807,"start":840,"end":925},{"cath_id":"3.30.200.20","chopping":"985-1082","consensus_level":"medium","plddt":81.9673,"start":985,"end":1082},{"cath_id":"1.10.510.10","chopping":"1086-1285","consensus_level":"medium","plddt":83.0512,"start":1086,"end":1285}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08069","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08069-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08069-F1-predicted_aligned_error_v6.png","plddt_mean":78.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IGF1R","jax_strain_url":"https://www.jax.org/strain/search?query=IGF1R"},"sequence":{"accession":"P08069","fasta_url":"https://rest.uniprot.org/uniprotkb/P08069.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08069/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08069"}},"corpus_meta":[{"pmid":"17259557","id":"PMC_17259557","title":"IGF1R 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 {\n      \"year\": 2020,\n      \"finding\": \"IGF1R acts as an entry receptor for respiratory syncytial virus (RSV): binding of prefusion RSV-F glycoprotein to IGF1R triggers outside-in signaling that activates protein kinase C zeta (PKCζ), which in turn recruits nucleolin from the nucleus to the plasma membrane to serve as a co-receptor for RSV entry.\",\n      \"method\": \"Co-immunoprecipitation, airway organoid cultures, PKCζ inhibition assays, RSV-infected mouse models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, organoid cultures, and in vivo mouse model all converge on the same mechanism; multiple orthogonal methods in a single rigorous study published in Nature\",\n      \"pmids\": [\"32494007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MAD2 (hMAD2) interacts specifically with the cytoplasmic domain of the insulin receptor (IR) but NOT with IGF1R; the interaction requires the C-terminal 30 amino acids of IR, does not require IR tyrosine autophosphorylation, and is released upon receptor activation.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown in vitro binding assay, co-immunoprecipitation from CHO-IR cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and in vitro pulldown in single lab; the negative finding for IGF1R is mechanistically informative (MAD2 does NOT bind IGF1R)\",\n      \"pmids\": [\"9092546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Upon resistance to p110α-selective PI3K inhibitor BYL719, IGF1R forms a complex with IRS1/IRS2, p85 regulatory subunit, and p110β, which activates AKT/mTOR/S6K signaling and mediates resistance; co-immunoprecipitation identified this IGF1R/IRS/p85/p110β complex.\",\n      \"method\": \"Phosphotyrosine proteomics, co-immunoprecipitation, pharmacologic inhibition of complex members\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased phosphoproteomics plus Co-IP plus pharmacological validation, single lab\",\n      \"pmids\": [\"27048245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTP1B is a negative regulator of IGF1R-mediated signaling in hepatocytes: PTP1B deficiency maintains IGF1R-mediated signaling during APAP-induced hepatotoxicity, whereas PTP1B overexpression or siRNA knockdown respectively suppress or sustain IGF1R pathway activation.\",\n      \"method\": \"PTP1B knockout mouse model, siRNA knockdown in hepatocytes, western blotting for IGF1R signaling components\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus siRNA knockdown with defined signaling readouts, single lab\",\n      \"pmids\": [\"23661004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DVL3 (Dishevelled homolog) forms an adaptor complex with IGF1R, Shc, Grb2, SOS, and DAB2 that links IGF1R to RAS signaling; DVL3 mediates resistance to IGF1R inhibition, and its genetic or pharmacological blockade sensitizes breast and prostate cancer cells to IGF1R inhibitors via enhanced MEK-ERK activation.\",\n      \"method\": \"Genetic screen, co-immunoprecipitation of adaptor complex, pharmacological blockade, in vivo xenograft models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex plus in vitro and in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25168481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DARPP-32 physically interacts with IGF1R and promotes IGF1R phosphorylation at Y1135; this binding activates downstream SRC and STAT3 (phosphorylation at Y705), nuclear STAT3 localization, and transcription, driving gastric tumorigenesis.\",\n      \"method\": \"Proximity ligation assay, co-immunoprecipitation, knockout mouse models (TFF1 KO crossed with DARPP-32 KO), 3D organoid cultures, tissue microarrays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — PLA and Co-IP both confirm IGF1R-DARPP-32 interaction, validated in multiple mouse models and human tissues with clear mechanistic readout\",\n      \"pmids\": [\"31235784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"During resistance to the IGF1R inhibitor NVP-AEW541 in alveolar rhabdomyosarcoma, Her2 forms heterodimers with IGF1R, and IGF2 stimulation leads to Her2 phosphorylation; dual blockade of IGF1R and Her2 (lapatinib) reduces IGF1R phosphorylation and overcomes resistance.\",\n      \"method\": \"Co-immunoprecipitation of IGF1R-Her2 heterodimers in resistant primary tumor cell cultures, western blotting, combinatorial drug treatment in genetically engineered mouse model\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating heterodimer formation plus pharmacological validation, single lab\",\n      \"pmids\": [\"21447712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cell surface GRP78 physically interacts with IGF1R upon IGF-I stimulation (redistributing from ER to plasma membrane), promotes IGF1R phosphorylation and activation, and blocking GRP78 inhibits IGF-I-stimulated IGF1R phosphorylation, downstream PI3K/MAPK signaling, and hepatoma cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of GRP78, antibody blocking, western blotting, cell proliferation and migration assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus siRNA knockdown plus antibody blocking, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28389416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Upon blockade of IGF-1R by anti-IGF-1R antibody cixutumumab, IGF-1 binds integrin β3, activating a β3-Src signaling cascade that leads to Akt activation and mediates resistance to cixutumumab; combined targeting of integrin β3 or Src with cixutumumab overcomes this resistance in HNSCC and NSCLC models.\",\n      \"method\": \"Ligand blotting, immunoprecipitation, immunofluorescence, cell adhesion assays, ELISA, in vivo xenograft and patient-derived xenograft tumors\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays plus in vivo validation, single lab\",\n      \"pmids\": [\"24092920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Estrogen receptor (ER) rapidly associates with IGF1R in response to both E2 and IGF-I stimulation in MCF-7 cells; this ER-IGF1R interaction is required for non-genomic ER signaling, activating ERK1/2 and AKT phosphorylation, and potentiating cell growth.\",\n      \"method\": \"Co-immunoprecipitation, transfection of antisense IGF1R cDNA (reducing receptor ~50%), transient ERα transfection into NIH3T3-IGF1R cells, cell growth assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP across multiple cell lines plus gain/loss of function, single lab\",\n      \"pmids\": [\"23704881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Aldosterone directly transactivates the IGF-1R in renal epithelial A6 cells: 10-min aldosterone exposure increases phosphorylation of IGF-1R, IRS-1, and Akt; this requires aldosterone binding to the mineralocorticoid/glucocorticoid receptor, does not require transcription, and activates PI3-K (blocked by LY-294002).\",\n      \"method\": \"Phosphorylation assays in A6 cells, PI3-K inhibitor (LY-294002) treatment, mineralocorticoid receptor dependence testing\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological and receptor-blocking experiments, single lab, no direct receptor binding assay\",\n      \"pmids\": [\"17190911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IGF1R controls mechanosignaling in pulmonary myofibroblasts required for alveologenesis: postnatal deletion of Igf1r impairs contractile properties of lung myofibroblasts, inhibits myosin light chain (MLC) phosphorylation and nuclear YAP mechanotransductive activity; AKT, p-MLC, and nuclear YAP activation in myofibroblasts are dependent on IGF1R.\",\n      \"method\": \"Conditional Igf1r knockout mice (postnatal), pharmacologic AKT activation, lung histology, western blotting for MLC phosphorylation and YAP localization\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined cellular phenotype plus pharmacologic rescue in vivo, multiple orthogonal readouts\",\n      \"pmids\": [\"33591952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IGF1R signaling drives antiestrogen resistance through PAK2 and PIX (PAK-interacting exchange factors): phospho-proteomics identified PAK2 and PIXα/β as downstream targets of IGF1R signaling independent of PI3K/AKT and MAPK/ERK; PAK2/PIX modulate IGF1R-driven cell scattering, and silencing PAK2 or targeting PIXα/β re-sensitizes cells to tamoxifen and fulvestrant.\",\n      \"method\": \"Kinome siRNA screen, phospho-proteomics, PAK2/PIX silencing, functional cell scattering assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased kinome screen plus phosphoproteomics plus functional validation, single lab with multiple methods\",\n      \"pmids\": [\"29353882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PAPP-AA, an extracellular metalloprotease, promotes habituation learning by increasing local IGF bioavailability to activate IGF1R: metalloprotease-inactive PAPP-AA fails to restore habituation in pappaa mutant zebrafish; acute IGF1R inhibition in wild-type fish reduces habituation, while activation of IGF1R downstream effectors in pappaa mutants restores habituation.\",\n      \"method\": \"Genome-wide genetic screen with whole-genome sequencing, rescue with metalloprotease-dead mutant, acute pharmacological IGF1R inhibition, epistasis (activation of downstream effectors)\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with pharmacologic validation and dominant-negative rescue across multiple orthogonal experiments in zebrafish\",\n      \"pmids\": [\"25754827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ALKBH5 (m6A RNA demethylase) demethylates IGF1R mRNA, enhancing its stability and translation, thereby activating IGF1R signaling and promoting endometrial cancer proliferation and invasion.\",\n      \"method\": \"m6A methylation analysis, western blotting, ALKBH5 knockdown/overexpression, functional proliferation and invasion assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method for the key mechanistic claim (m6A demethylation of IGF1R mRNA), limited orthogonal validation of direct molecular mechanism\",\n      \"pmids\": [\"32913456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP2 (m6A reader protein) binds m6A methylation sites in IGF1R mRNA and increases IGF1R expression, thereby activating the IGF1R-RhoA-ROCK signaling pathway to promote gastric cancer proliferation and metastasis.\",\n      \"method\": \"RIP (RNA immunoprecipitation) and RNA pulldown assays confirming IGF2BP2-IGF1R mRNA binding, IGF2BP2 silencing/IGF1R overexpression rescue experiments, in vivo xenograft models\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and RNA pulldown confirm direct binding, plus epistasis rescue experiments, single lab\",\n      \"pmids\": [\"35306138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear IGF1R phosphorylates PYCR1 at Tyrosine 135 under hypoxia; this phosphorylation promotes PYCR1 binding to ELK4 and recruitment to ELK4-targeted gene promoters, stimulating PYCR1-catalyzed NAD+ production that activates Sirt7 deacetylase activity on H3K18ac to repress gene transcription and maintain tumor growth.\",\n      \"method\": \"Nuclear IGF1R activity assays, phospho-site identification (Y135), co-immunoprecipitation of PYCR1-ELK4 complex, chromatin recruitment assays, Sirt7 deacetylation assays, in vivo tumor growth experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-site identification plus Co-IP plus functional enzymatic assays plus in vivo data, single lab\",\n      \"pmids\": [\"37777542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GIGYF1 regulates recycling of IGF1R to the cell surface; GIGYF1 knockout reduces IGF1R surface levels, thereby disrupting IGF1R/ERK signaling and causing social impairments in mice consistent with autism.\",\n      \"method\": \"Gigyf1 conditional KO mouse model, cell surface IGF1R measurement, ERK phosphorylation assays, behavioral testing\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined molecular readout (surface IGF1R levels and ERK phosphorylation), single lab\",\n      \"pmids\": [\"35917186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IGFBP7 prolongs surface retention of IGF1R under insulin/IGF1 stimulation, resulting in sustained IGF1R, IRS-1, AKT, and ERK phosphorylation; in the presence of IGFBP7, insulin activates IGF1R at concentrations >100-fold lower than normally required, while the insulin receptor is readily internalized despite IGFBP7 addition.\",\n      \"method\": \"IGFBP7 knockdown and antibody neutralization, surface receptor retention assays, phosphorylation time-course western blotting, in vivo leukemia progression model\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IGFBP7 knockdown and antibody neutralization with phosphorylation kinetics assays and in vivo validation, single lab\",\n      \"pmids\": [\"34438446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Follistatin (FST) directly binds IGF1R (confirmed by biolayer interferometry and co-immunoprecipitation) via its N-terminal domain; FST-IGF1R binding activates ERK and AKT signaling and Nav1.7-mediated nociceptive neuron hyperexcitability; a peptide blocking the FST N-terminal domain interaction with IGF1R attenuates neuronal hyperexcitability and neuropathic pain.\",\n      \"method\": \"Biolayer interferometry (BLI), co-immunoprecipitation, IGF1R inhibitor rescue experiments, DRG neuron electrophysiology, in vivo spinal nerve ligation mouse model, FST conditional overexpression and deletion\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding confirmed by BLI (quantitative biophysical assay) plus Co-IP plus pharmacological/genetic validation in vivo and in human DRG neurons, multiple orthogonal methods\",\n      \"pmids\": [\"39413164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of E-cadherin (CDH1) hyperactivates IGF1R signaling; in situ proximity ligation assay demonstrated a direct endogenous interaction between IGF1R and E-cadherin at cell-cell contact points, and diminished E-cadherin increases IGF1R signaling and sensitivity to anti-IGF1R/InsR therapies.\",\n      \"method\": \"In situ proximity ligation assay (PLA), E-cadherin knockdown/overexpression, western blotting for IGF1R pathway activation, xenograft tumor explant cultures\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PLA demonstrating direct endogenous IGF1R-E-cadherin interaction plus functional validation, single lab\",\n      \"pmids\": [\"29941485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Transcription factors Ikaros isoform 1 (Ik-1) and MZF1 directly bind specific sites within the IGF1R gene promoter and suppress IGF1R transcription; decreased Ik-1 and MZF1 in NPM-ALK+ T-cell lymphoma leads to IGF1R upregulation, activating IRS-1, AKT, and NPM-ALK phosphorylation.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, forced expression of Ik-1/MZF1, western blotting, functional proliferation/migration assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter binding plus functional reporter and protein expression data, single lab\",\n      \"pmids\": [\"25884514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In CRISPR-Cas9 screen, IGF1R overexpression promotes escape from CDK4/6 inhibitor treatment in Ewing sarcoma; elevated phospho-IGF1R was found in CDK4/6 inhibitor-resistant cell lines, and IGF1R inhibition combined with CDK4/6 inhibition more profoundly represses cell cycle and PI3K/mTOR signaling than either alone.\",\n      \"method\": \"Genome-scale ORF screen (CRISPR), resistant cell line generation, phosphoprotein analysis, small-molecule synergy screen, in vivo mouse xenograft models\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased genome-scale screen plus mechanistic validation plus in vivo data, single lab\",\n      \"pmids\": [\"30397176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nuclear IGF-1R expression is conserved in alveolar rhabdomyosarcoma subpopulations with high cell-surface IGF-1R; cells with high nuclear IGF-1R establish tumors more efficiently in vivo; siRNA silencing of IGF-1R in high-expressing subpopulations significantly reduces anchorage-independent colony formation, linking nuclear IGF-1R to tumorigenic capacity.\",\n      \"method\": \"FACS sorting, immunofluorescence for subcellular localization, RNA interference, anchorage-independent colony formation assay, in vivo tumor formation\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by FACS/immunofluorescence with functional consequence (tumor formation), single lab\",\n      \"pmids\": [\"23928059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nuclear IGF1R translocation occurs in non-malignant (normal diploid fibroblast) cells as well as cancer cells; combined use of a nuclear translocation blocker and selective IGF1R kinase inhibitors synergistically decreases cell proliferation, indicating nuclear IGF1R contributes to mitogenic signaling.\",\n      \"method\": \"Nuclear fractionation, pharmacological nuclear translocation inhibition combined with kinase inhibitors, cell proliferation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibition without direct molecular mechanism of nuclear IGF1R action established, single lab, single method for nuclear localization\",\n      \"pmids\": [\"28945762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Calcium (at moderate doses) and osteoprotegerin (OPG) regulate IGF1R expression in vascular smooth muscle cells: OPG induces IGF1R mRNA, protein, and transcription; calcium positively regulates OPG then IGF1R; IGF1R induction requires Sp1 binding at the −446 to −188 bp region of the IGF1R promoter; IGF1R activation promotes VSMC survival (Bcl2, NF-κB) and blocks calcification.\",\n      \"method\": \"Sp1 siRNA silencing, promoter deletion analysis, siRNA targeting OPG, western blotting, mineralization assays\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter deletion mapping plus siRNA validation plus functional calcification assay, single lab\",\n      \"pmids\": [\"21447702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IGF1R inhibition induces autophagic flux; CRISPR screen identified IGF1R as a top sensitizer to lysosomal autophagy inhibition; IGF1R and ERK-MAPK inhibition converge to suppress glycolysis and enhance autophagy dependence; compensatory IGF1R phosphorylation is activated in response to chloroquine treatment in pancreatic cancer.\",\n      \"method\": \"CRISPR-Cas9 loss-of-function screen, reverse phase protein array (RPPA), autophagic flux assays, in vitro and in vivo growth suppression assays, PDAC organoids\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased CRISPR screen plus RPPA plus functional organoid and in vivo validation, single lab\",\n      \"pmids\": [\"34921013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In resistance to EGFR inhibitors in glioblastoma, the InsR/IGF1R pathway activates AKT to maintain cell survival; concurrent inhibition of EGFR and InsR/IGF1R (with OSI-906) is required to suppress AKT and induce apoptosis; insulin and IGF1 protect EGFR-dependent glioblastoma cells from gefitinib, and this protection is absent in cells lacking IGF1R/InsR expression.\",\n      \"method\": \"Patient-derived glioblastoma xenograft (PDX) lines, RTK ligand screening, combinatorial drug treatment (gefitinib + OSI-906), western blotting for EGFR/AKT/MEK/ERK, subcutaneous xenograft tumor treatment\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PDX-based platform with pharmacological epistasis plus in vivo xenograft validation, single lab\",\n      \"pmids\": [\"26561558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TM4SF5 and IGF1R form a membrane complex (co-immunoprecipitation) in NSCLC cells; TM4SF5 and IGF1R transcriptionally upregulate each other (bidirectional regulation); TM4SF5-IGF1R complex promotes ERK, AKT, and S6K signaling and maintains residual EGFR activity contributing to EGFR inhibitor resistance.\",\n      \"method\": \"Co-immunoprecipitation of TM4SF5-IGF1R complex, IGF1R siRNA knockdown, TM4SF5 overexpression, 2D/3D cell viability assays, western blotting\",\n      \"journal\": \"Lung cancer (Amsterdam, Netherlands)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP plus siRNA rescue, single lab, limited mechanistic detail on bidirectional transcriptional regulation\",\n      \"pmids\": [\"26190015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In BRAF-mutant melanoma resistant to trametinib/dabrafenib, IGF1R and insulin receptor (INSR) are upregulated; RTK arrays show increased p-IGF1R and p-IR; siRNA dual knockdown of IGF1R and INSR reduces proliferation, and IGF1R/IR inhibitor (BMS-754807) suppresses p-Akt, confirming IGF1R/IR as a resistance mechanism through AKT signaling.\",\n      \"method\": \"Receptor tyrosine kinase arrays, RNA-sequencing, siRNA knockdown, BMS-754807 pharmacological inhibition, in vivo xenograft tumor treatment\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RTK array plus RNA-seq plus siRNA plus pharmacological inhibition plus in vivo validation, single lab\",\n      \"pmids\": [\"34831014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Inhibition of IGF1R by lorlatinib sensitizes melanoma to ferroptosis (GPX4 inhibition) by suppressing the PI3K/AKT/mTOR signaling axis and its downstream target SCD (stearoyl-CoA desaturase); IGF1R (not ALK or ROS1) was identified as the major mediator of lorlatinib's effect using selective target knockdown experiments.\",\n      \"method\": \"Drug synergy screen (240 FDA-approved drugs + RSL3), IGF1R-specific knockdown vs ALK/ROS1 knockdown, western blotting for PI3K/AKT/mTOR/SCD, in vivo preclinical animal models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective target identification via siRNA knockdown plus pharmacological validation plus in vivo models, single lab\",\n      \"pmids\": [\"36889082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IGF1R deficiency in the brain (conditional knockout) activates IR/PI3K/Akt signaling while inhibiting MAPK/ERK1/2/CREB signaling; it increases phosphorylated Tau protein levels, disrupts mitochondrial dynamics, impairs respiratory chain complex activity, and increases oxidative stress (decreased NRF2, increased H2O2).\",\n      \"method\": \"UBC-CreERT2; Igf1r conditional knockout mice, western blotting for PI3K/Akt, ERK, GSK3β, phospho-Tau, mitochondrial complex activity assays, oxidative stress assays\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with multiple defined molecular readouts, single lab\",\n      \"pmids\": [\"33562061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IGF1R inhibition (picropodophyllin and linsitinib) induces autophagic flux and enhances ATP release from cancer cells (immunogenic cell death marker); this was identified via a phenotypic screen of 65,000 compounds and confirmed as on-target through IGF1R kinase inhibition; IGF1R phosphorylation in human triple-negative breast cancer correlates with reduced autophagy.\",\n      \"method\": \"Phenotypic autophagy discovery screen (65,000 compounds), on-target validation with selective IGF1R inhibitors, ATP release assays, in vivo chemoimmunotherapy mouse models\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large-scale phenotypic screen with on-target confirmation and in vivo validation, single lab\",\n      \"pmids\": [\"34110249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MDA-9/Syntenin physically interacts with IGF1R following IGFBP2 treatment, and this interaction regulates downstream STAT3 phosphorylation, which drives MMP2/MMP9 expression and promotes prostate cancer invasion.\",\n      \"method\": \"Co-immunoprecipitation of MDA-9/Syntenin-IGF1R complex, CRISPR/Cas9 knockout of MDA-9/Syntenin, loss-of-function/gain-of-function cell lines, western blotting, invasion assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus CRISPR KO plus functional invasion assays, single lab\",\n      \"pmids\": [\"29572229\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGF1R is a transmembrane tyrosine kinase receptor that, upon binding IGF1/IGF2 (or non-canonical ligands such as follistatin), undergoes autophosphorylation to activate PI3K/AKT, MAPK/ERK, and PAK2/PIX downstream signaling cascades; its activity is modulated by physical interactions with multiple partners including E-cadherin (which restrains it at cell-cell contacts), MDA-9/Syntenin, DARPP-32, GRP78, DVL3-Shc-Grb2-SOS adaptor complexes, and IGFBP7 (which prolongs receptor surface retention); receptor internalization, nuclear translocation (where it phosphorylates substrates such as PYCR1 to regulate transcription), ubiquitination-mediated degradation, and recycling (regulated by GIGYF1) collectively determine the spatiotemporal wiring of its signaling output, with the endosomal/nuclear compartments emerging as important platforms for non-canonical IGF1R functions beyond classical plasma-membrane kinase signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IGF1R is a transmembrane receptor tyrosine kinase that, upon ligand binding, drives PI3K/AKT and MAPK/ERK signaling to control cell survival, proliferation, and tissue morphogenesis across normal and malignant contexts [#11, #27]. Beyond its canonical ligands, IGF1R is activated through diverse non-classical inputs: extracellular metalloprotease PAPP-AA increases local IGF bioavailability to engage IGF1R during habituation learning [#13], aldosterone transactivates the receptor via the mineralocorticoid receptor to stimulate PI3K [#10], and follistatin binds IGF1R directly through its N-terminal domain to activate ERK/AKT and drive nociceptive neuron hyperexcitability and neuropathic pain [#19]. The receptor also serves as an entry receptor for respiratory syncytial virus, where prefusion RSV-F binding triggers PKCζ-dependent recruitment of nucleolin as a co-receptor [#0]. IGF1R signaling output is shaped by a network of physical partners that modulate its activity and surface dynamics: E-cadherin restrains the receptor at cell-cell contacts [#20], cell-surface GRP78 and DARPP-32 promote its phosphorylation and downstream SRC/STAT3 activation [#5, #7], IGFBP7 prolongs surface retention to sensitize the receptor to low ligand concentrations [#18], and GIGYF1 controls its recycling back to the plasma membrane [#17]. Receptor abundance is set transcriptionally by Ikaros/MZF1 and Sp1 at the IGF1R promoter [#21, #25] and post-transcriptionally through m6A-dependent regulation of IGF1R mRNA by IGF2BP2 [#15]. A non-canonical nuclear pool of IGF1R contributes to mitogenic and tumorigenic capacity [#23], and nuclear IGF1R phosphorylates PYCR1 at Tyr135 under hypoxia to drive an ELK4/Sirt7-dependent transcriptional program supporting tumor growth [#16]. IGF1R is a recurrent mediator of therapeutic resistance: it forms compensatory complexes and heterodimers (with IRS/p85/p110β, Her2, TM4SF5, DVL3-Shc-Grb2-SOS, MDA-9/Syntenin, and integrin β3) and is upregulated alongside the insulin receptor to sustain AKT signaling against PI3K, CDK4/6, EGFR, and BRAF/MEK inhibitors [#2, #4, #6, #8, #22, #27, #29, #33]. IGF1R activity additionally suppresses autophagic flux and protects cancer cells from ferroptosis, linking it to metabolic and cell-death control [#26, #30, #32]. PTP1B acts as a negative regulator of IGF1R signaling [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established receptor specificity by distinguishing IGF1R from the insulin receptor at the level of cytoplasmic-domain partner binding, showing MAD2 binds IR but not IGF1R.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, and Co-IP comparing IR and IGF1R cytoplasmic domains\",\n      \"pmids\": [\"9092546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result for IGF1R; does not identify the analogous IGF1R adaptor\", \"Functional consequence of MAD2-IR binding not extended to IGF1R biology\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed IGF1R can be activated by a non-canonical, transcription-independent input, with aldosterone transactivating the receptor via the mineralocorticoid receptor to stimulate PI3K.\",\n      \"evidence\": \"Phosphorylation assays in A6 renal cells with PI3-K inhibitor and receptor-blocking experiments\",\n      \"pmids\": [\"17190911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct receptor binding assay\", \"Mechanism linking MR to IGF1R phosphorylation not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified PTP1B as a negative regulator that limits IGF1R signaling, and uncovered ER-IGF1R association as a node for non-genomic estrogen action, defining bidirectional modulation of the receptor.\",\n      \"evidence\": \"PTP1B KO mouse and siRNA in hepatocytes; Co-IP and gain/loss of IGF1R in MCF-7/NIH3T3 cells\",\n      \"pmids\": [\"23661004\", \"23704881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PTP1B dephosphorylates IGF1R directly versus pathway intermediates not distinguished\", \"ER-IGF1R interaction not shown to be direct\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined IGF1R as a hub for adaptive resistance, showing it activates compensatory signaling via integrin β3-Src upon antibody blockade and that a nuclear IGF1R pool correlates with tumorigenic capacity.\",\n      \"evidence\": \"Ligand blotting, IP, adhesion assays, and xenografts (cixutumumab); FACS sorting, immunofluorescence, and tumor formation assays (nuclear IGF1R)\",\n      \"pmids\": [\"24092920\", \"23928059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of nuclear IGF1R action not defined at this stage\", \"How antibody blockade redirects ligand to integrin β3 unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved a specific adaptor architecture linking IGF1R to RAS signaling, identifying the DVL3-Shc-Grb2-SOS-DAB2 complex as a determinant of IGF1R-inhibitor resistance.\",\n      \"evidence\": \"Genetic screen, Co-IP of the adaptor complex, pharmacologic blockade, and xenografts\",\n      \"pmids\": [\"25168481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and direct contacts within the adaptor complex not mapped\", \"Generality across tumor types beyond breast/prostate untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated physiological IGF1R signaling in vivo, showing PAPP-AA-dependent IGF bioavailability activates IGF1R to enable habituation learning, and defined promoter-level transcriptional control of IGF1R.\",\n      \"evidence\": \"Genetic screen and pharmacologic epistasis in zebrafish; ChIP, reporter, and promoter-deletion mapping (Ikaros/MZF1, Sp1) plus EGFR-resistance PDX models\",\n      \"pmids\": [\"25754827\", \"25884514\", \"21447702\", \"26561558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of IGF1R in habituation neurons not fully defined\", \"Promoter regulators studied in specific disease contexts only\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Generalized IGF1R as a convergent resistance receptor across kinase-inhibitor therapies, forming the IRS/p85/p110β complex and being upregulated with the insulin receptor to sustain AKT.\",\n      \"evidence\": \"Phosphoproteomics and Co-IP (PI3K inhibitor); RTK arrays, RNA-seq, siRNA, and xenografts (BRAF/MEK inhibitor)\",\n      \"pmids\": [\"27048245\", \"34831014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether complex formation is cause or consequence of resistance not fully separated\", \"Direct kinase substrate landscape under resistance untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified cell-surface partners that positively gate IGF1R activation, with GRP78 redistributing from ER to plasma membrane to promote IGF1R phosphorylation, and characterized nuclear IGF1R as contributing to mitogenic signaling.\",\n      \"evidence\": \"Co-IP, siRNA, antibody blocking (GRP78); nuclear fractionation with translocation-blocker plus kinase-inhibitor synergy\",\n      \"pmids\": [\"28389416\", \"28945762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GRP78-IGF1R contact interface not mapped\", \"Nuclear IGF1R study (Low) used single localization method without molecular nuclear function\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded the IGF1R interactome to scaffolds and adhesion molecules that bidirectionally tune output—DARPP-32 and MDA-9/Syntenin driving SRC/STAT3, E-cadherin restraining the receptor—and identified PAK2/PIX as a PI3K/MAPK-independent effector branch.\",\n      \"evidence\": \"PLA and Co-IP with KO mouse models (DARPP-32); Co-IP/CRISPR KO (MDA-9/Syntenin); in situ PLA (E-cadherin); kinome screen and phosphoproteomics (PAK2/PIX)\",\n      \"pmids\": [\"31235784\", \"29572229\", \"29941485\", \"29353882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How E-cadherin physically restrains IGF1R kinase activity not resolved\", \"PAK2/PIX activation mechanism downstream of IGF1R not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a non-signaling-receptor role of IGF1R as an RSV entry receptor and established IGF1R as a regulator of autophagy and metabolic dependency in cancer.\",\n      \"evidence\": \"Co-IP, airway organoids, PKCζ inhibition, and RSV mouse models; CRISPR screen, RPPA, and autophagic flux/ATP-release assays plus organoids\",\n      \"pmids\": [\"32494007\", \"34921013\", \"34110249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether kinase activity is required for RSV co-receptor recruitment not addressed\", \"Mechanism coupling IGF1R inhibition to autophagic flux not fully defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined developmental and homeostatic IGF1R functions in vivo—mechanosignaling in lung myofibroblasts via MLC/YAP, brain neuroprotection against Tau and mitochondrial dysfunction—and showed IGFBP7 prolongs receptor surface retention.\",\n      \"evidence\": \"Conditional Igf1r KO mice with pharmacologic rescue (lung); conditional KO with signaling/oxidative readouts (brain); knockdown and antibody neutralization with phospho-kinetics (IGFBP7)\",\n      \"pmids\": [\"33591952\", \"33562061\", \"34438446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link from IGF1R to YAP mechanotransduction beyond AKT not mapped\", \"How IGFBP7 selectively retains IGF1R but not IR not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established post-transcriptional and trafficking control of IGF1R, with m6A reader IGF2BP2 binding IGF1R mRNA to raise expression, and GIGYF1 governing receptor recycling to the surface.\",\n      \"evidence\": \"RIP and RNA pulldown with rescue and xenografts (IGF2BP2); conditional KO with surface-receptor and ERK assays plus behavior (GIGYF1)\",\n      \"pmids\": [\"35306138\", \"35917186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IGF2BP2 effect is fully m6A-dependent in vivo not separated\", \"Molecular machinery by which GIGYF1 directs IGF1R recycling unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a direct nuclear enzymatic function for IGF1R, phosphorylating PYCR1 at Tyr135 to drive ELK4/Sirt7-dependent transcriptional repression under hypoxia, and extended IGF1R's role to ferroptosis control.\",\n      \"evidence\": \"Nuclear kinase assays, phospho-site mapping, Co-IP, chromatin recruitment, Sirt7 assays, and in vivo tumors; drug synergy screen with selective IGF1R knockdown (ferroptosis)\",\n      \"pmids\": [\"37777542\", \"36889082\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of IGF1R nuclear import not defined\", \"Breadth of nuclear IGF1R substrates beyond PYCR1 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a direct non-canonical ligand for IGF1R, with follistatin binding the receptor via its N-terminal domain to drive ERK/AKT signaling and neuropathic pain, validating a targetable interaction.\",\n      \"evidence\": \"Biolayer interferometry and Co-IP, DRG electrophysiology, blocking peptide, and spinal nerve ligation mouse model with FST gain/loss\",\n      \"pmids\": [\"39413164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether follistatin competes with or is independent of IGF ligand binding not resolved\", \"Structural basis of the N-terminal FST-IGF1R interface not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many distinct IGF1R partner complexes, ligand inputs, and subcellular pools are integrated into a unified spatiotemporal signaling logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model unifying the diverse direct partners\", \"Rules governing plasma-membrane versus nuclear versus recycling fate not established\", \"Relative contribution of canonical IGF ligands versus follistatin/aldosterone/RSV-F inputs in vivo unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 16, 7]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [13, 19, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 18, 20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16, 23]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 27, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [26, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 22, 29]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [16, 21, 25]}\n    ],\n    \"complexes\": [\n      \"IGF1R/IRS/p85/p110β complex\",\n      \"IGF1R-Her2 heterodimer\",\n      \"DVL3-Shc-Grb2-SOS-DAB2 adaptor complex\",\n      \"TM4SF5-IGF1R complex\"\n    ],\n    \"partners\": [\n      \"GRP78\",\n      \"DARPP-32\",\n      \"CDH1\",\n      \"IGFBP7\",\n      \"GIGYF1\",\n      \"SDCBP\",\n      \"FST\",\n      \"PYCR1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}