Affinage

IGF1R

Insulin-like growth factor 1 receptor · UniProt P08069

Length
1367 aa
Mass
154.8 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 Medium

    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

    PMID:9092546

    Open questions at the time
    • Negative result for IGF1R; does not identify the analogous IGF1R adaptor
    • Functional consequence of MAD2-IR binding not extended to IGF1R biology
  2. 2006 Medium

    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

    PMID:17190911

    Open questions at the time
    • No direct receptor binding assay
    • Mechanism linking MR to IGF1R phosphorylation not resolved
  3. 2013 Medium

    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

    PMID:23661004 PMID:23704881

    Open questions at the time
    • Whether PTP1B dephosphorylates IGF1R directly versus pathway intermediates not distinguished
    • ER-IGF1R interaction not shown to be direct
  4. 2013 Medium

    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)

    PMID:23928059 PMID:24092920

    Open questions at the time
    • Molecular mechanism of nuclear IGF1R action not defined at this stage
    • How antibody blockade redirects ligand to integrin β3 unresolved
  5. 2014 Medium

    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

    PMID:25168481

    Open questions at the time
    • Stoichiometry and direct contacts within the adaptor complex not mapped
    • Generality across tumor types beyond breast/prostate untested
  6. 2015 High

    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

    PMID:21447702 PMID:25754827 PMID:25884514 PMID:26561558

    Open questions at the time
    • Downstream effectors of IGF1R in habituation neurons not fully defined
    • Promoter regulators studied in specific disease contexts only
  7. 2016 Medium

    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)

    PMID:27048245 PMID:34831014

    Open questions at the time
    • Whether complex formation is cause or consequence of resistance not fully separated
    • Direct kinase substrate landscape under resistance untested
  8. 2017 Medium

    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

    PMID:28389416 PMID:28945762

    Open questions at the time
    • Direct GRP78-IGF1R contact interface not mapped
    • Nuclear IGF1R study (Low) used single localization method without molecular nuclear function
  9. 2018 High

    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)

    PMID:29353882 PMID:29572229 PMID:29941485 PMID:31235784

    Open questions at the time
    • How E-cadherin physically restrains IGF1R kinase activity not resolved
    • PAK2/PIX activation mechanism downstream of IGF1R not fully defined
  10. 2020 High

    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

    PMID:32494007 PMID:34110249 PMID:34921013

    Open questions at the time
    • Whether kinase activity is required for RSV co-receptor recruitment not addressed
    • Mechanism coupling IGF1R inhibition to autophagic flux not fully defined
  11. 2021 High

    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)

    PMID:33562061 PMID:33591952 PMID:34438446

    Open questions at the time
    • Direct link from IGF1R to YAP mechanotransduction beyond AKT not mapped
    • How IGFBP7 selectively retains IGF1R but not IR not mechanistically resolved
  12. 2022 Medium

    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)

    PMID:35306138 PMID:35917186

    Open questions at the time
    • Whether IGF2BP2 effect is fully m6A-dependent in vivo not separated
    • Molecular machinery by which GIGYF1 directs IGF1R recycling unknown
  13. 2023 Medium

    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)

    PMID:36889082 PMID:37777542

    Open questions at the time
    • Mechanism of IGF1R nuclear import not defined
    • Breadth of nuclear IGF1R substrates beyond PYCR1 unknown
  14. 2024 High

    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

    PMID:39413164

    Open questions at the time
    • Whether follistatin competes with or is independent of IGF ligand binding not resolved
    • Structural basis of the N-terminal FST-IGF1R interface not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many distinct IGF1R partner complexes, ligand inputs, and subcellular pools are integrated into a unified spatiotemporal signaling logic remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9612973 Autophagy 2
Partners
CDH1DARPP-32FSTGIGYF1GRP78IGFBP7PYCR1SDCBP
Complex memberships
DVL3-Shc-Grb2-SOS-DAB2 adaptor complexIGF1R-Her2 heterodimerIGF1R/IRS/p85/p110β complexTM4SF5-IGF1R complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 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. Co-immunoprecipitation, airway organoid cultures, PKCζ inhibition assays, RSV-infected mouse models Nature High 32494007
1997 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. Yeast two-hybrid, GST pulldown in vitro binding assay, co-immunoprecipitation from CHO-IR cells The Journal of biological chemistry Medium 9092546
2016 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. Phosphotyrosine proteomics, co-immunoprecipitation, pharmacologic inhibition of complex members Breast cancer research : BCR Medium 27048245
2013 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. PTP1B knockout mouse model, siRNA knockdown in hepatocytes, western blotting for IGF1R signaling components Cell death & disease Medium 23661004
2014 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. Genetic screen, co-immunoprecipitation of adaptor complex, pharmacological blockade, in vivo xenograft models Cancer research Medium 25168481
2018 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. Proximity ligation assay, co-immunoprecipitation, knockout mouse models (TFF1 KO crossed with DARPP-32 KO), 3D organoid cultures, tissue microarrays Oncogene High 31235784
2011 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. Co-immunoprecipitation of IGF1R-Her2 heterodimers in resistant primary tumor cell cultures, western blotting, combinatorial drug treatment in genetically engineered mouse model Molecular cancer therapeutics Medium 21447712
2017 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. Co-immunoprecipitation, siRNA knockdown of GRP78, antibody blocking, western blotting, cell proliferation and migration assays Cellular signalling Medium 28389416
2013 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. Ligand blotting, immunoprecipitation, immunofluorescence, cell adhesion assays, ELISA, in vivo xenograft and patient-derived xenograft tumors Journal of the National Cancer Institute Medium 24092920
2013 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. Co-immunoprecipitation, transfection of antisense IGF1R cDNA (reducing receptor ~50%), transient ERα transfection into NIH3T3-IGF1R cells, cell growth assays PloS one Medium 23704881
2006 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). Phosphorylation assays in A6 cells, PI3-K inhibitor (LY-294002) treatment, mineralocorticoid receptor dependence testing American journal of physiology. Renal physiology Medium 17190911
2021 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. Conditional Igf1r knockout mice (postnatal), pharmacologic AKT activation, lung histology, western blotting for MLC phosphorylation and YAP localization JCI insight High 33591952
2018 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. Kinome siRNA screen, phospho-proteomics, PAK2/PIX silencing, functional cell scattering assays Oncogene Medium 29353882
2015 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. Genome-wide genetic screen with whole-genome sequencing, rescue with metalloprotease-dead mutant, acute pharmacological IGF1R inhibition, epistasis (activation of downstream effectors) Neuron High 25754827
2020 ALKBH5 (m6A RNA demethylase) demethylates IGF1R mRNA, enhancing its stability and translation, thereby activating IGF1R signaling and promoting endometrial cancer proliferation and invasion. m6A methylation analysis, western blotting, ALKBH5 knockdown/overexpression, functional proliferation and invasion assays Journal of Cancer Low 32913456
2022 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. RIP (RNA immunoprecipitation) and RNA pulldown assays confirming IGF2BP2-IGF1R mRNA binding, IGF2BP2 silencing/IGF1R overexpression rescue experiments, in vivo xenograft models Cellular signalling Medium 35306138
2023 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. 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 Nature communications Medium 37777542
2022 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. Gigyf1 conditional KO mouse model, cell surface IGF1R measurement, ERK phosphorylation assays, behavioral testing The Journal of clinical investigation Medium 35917186
2021 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. IGFBP7 knockdown and antibody neutralization, surface receptor retention assays, phosphorylation time-course western blotting, in vivo leukemia progression model Blood advances Medium 34438446
2024 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. Biolayer interferometry (BLI), co-immunoprecipitation, IGF1R inhibitor rescue experiments, DRG neuron electrophysiology, in vivo spinal nerve ligation mouse model, FST conditional overexpression and deletion Science translational medicine High 39413164
2018 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. In situ proximity ligation assay (PLA), E-cadherin knockdown/overexpression, western blotting for IGF1R pathway activation, xenograft tumor explant cultures Clinical cancer research Medium 29941485
2013 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. Luciferase reporter assay, ChIP assay, forced expression of Ik-1/MZF1, western blotting, functional proliferation/migration assays Molecular cancer Medium 25884514
2015 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. Genome-scale ORF screen (CRISPR), resistant cell line generation, phosphoprotein analysis, small-molecule synergy screen, in vivo mouse xenograft models Clinical cancer research Medium 30397176
2013 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. FACS sorting, immunofluorescence for subcellular localization, RNA interference, anchorage-independent colony formation assay, in vivo tumor formation Molecular cancer research : MCR Medium 23928059
2017 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. Nuclear fractionation, pharmacological nuclear translocation inhibition combined with kinase inhibitors, cell proliferation assays PloS one Low 28945762
2015 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. Sp1 siRNA silencing, promoter deletion analysis, siRNA targeting OPG, western blotting, mineralization assays Cardiovascular research Medium 21447702
2020 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. CRISPR-Cas9 loss-of-function screen, reverse phase protein array (RPPA), autophagic flux assays, in vitro and in vivo growth suppression assays, PDAC organoids Cancer research Medium 34921013
2015 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. 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 Clinical cancer research Medium 26561558
2015 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. Co-immunoprecipitation of TM4SF5-IGF1R complex, IGF1R siRNA knockdown, TM4SF5 overexpression, 2D/3D cell viability assays, western blotting Lung cancer (Amsterdam, Netherlands) Low 26190015
2016 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. Receptor tyrosine kinase arrays, RNA-sequencing, siRNA knockdown, BMS-754807 pharmacological inhibition, in vivo xenograft tumor treatment Cancers Medium 34831014
2023 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. 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 Redox biology Medium 36889082
2021 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). UBC-CreERT2; Igf1r conditional knockout mice, western blotting for PI3K/Akt, ERK, GSK3β, phospho-Tau, mitochondrial complex activity assays, oxidative stress assays Biomedicines Medium 33562061
2020 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. Phenotypic autophagy discovery screen (65,000 compounds), on-target validation with selective IGF1R inhibitors, ATP release assays, in vivo chemoimmunotherapy mouse models Autophagy Medium 34110249
2018 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. 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 Cancer research Medium 29572229

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 IGF1R signalling and its inhibition. Endocrine-related cancer 236 17259557
2020 IGF1R is an entry receptor for respiratory syncytial virus. Nature 154 32494007
2015 Role of IGF1R in Breast Cancer Subtypes, Stemness, and Lineage Differentiation. Frontiers in endocrinology 154 25964777
2013 IGF-1R as an anti-cancer target--trials and tribulations. Chinese journal of cancer 152 23601239
2008 Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. Journal of mammary gland biology and neoplasia 145 19003523
2014 Can we unlock the potential of IGF-1R inhibition in cancer therapy? Cancer treatment reviews 111 25123819
2014 MiR-143 and MiR-145 regulate IGF1R to suppress cell proliferation in colorectal cancer. PloS one 110 25474488
2020 Disorders of IGFs and IGF-1R signaling pathways. Molecular and cellular endocrinology 107 32941924
2015 IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas. PloS one 93 26173023
2012 Targeting the insulin-like growth factor 1 receptor (IGF1R) signaling pathway for cancer therapy. Expert opinion on therapeutic targets 93 22239439
2019 Ginsenoside F1 promotes angiogenesis by activating the IGF-1/IGF1R pathway. Pharmacological research 81 31048033
2013 Protein tyrosine phosphatase 1B modulates GSK3β/Nrf2 and IGFIR signaling pathways in acetaminophen-induced hepatotoxicity. Cell death & disease 79 23661004
2018 A Combination CDK4/6 and IGF1R Inhibitor Strategy for Ewing Sarcoma. Clinical cancer research : an official journal of the American Association for Cancer Research 77 30397176
2015 A genome-wide screen identifies PAPP-AA-mediated IGFR signaling as a novel regulator of habituation learning. Neuron 77 25754827
2011 IGF1R mutations as cause of SGA. Best practice & research. Clinical endocrinology & metabolism 76 21396585
2022 Drugging IGF-1R in cancer: New insights and emerging opportunities. Genes & diseases 71 37013053
2015 InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 70 26561558
2018 Loss of E-cadherin Enhances IGF1-IGF1R Pathway Activation and Sensitizes Breast Cancers to Anti-IGF1R/InsR Inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research 64 29941485
2016 Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition. Breast cancer research : BCR 64 27048245
2021 IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R. Cell death & disease 56 34075028
2016 MicroRNA-133a Inhibits Osteosarcoma Cells Proliferation and Invasion via Targeting IGF-1R. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 56 26845446
2011 Evasion mechanisms to Igf1r inhibition in rhabdomyosarcoma. Molecular cancer therapeutics 55 21447712
2009 Combined inhibition of IGFR enhances the effects of gefitinib in H1650: a lung cancer cell line with EGFR mutation and primary resistance to EGFR-TK inhibitors. Cancer chemotherapy and pharmacology 52 19921194
2005 CD221 (IGF-1R) is aberrantly expressed in multiple myeloma, in relation to disease severity. Haematologica 52 15921396
2019 Investigational IGF1R inhibitors in early stage clinical trials for cancer therapy. Expert opinion on investigational drugs 50 31731883
2016 The TGFβ pathway stimulates ovarian cancer cell proliferation by increasing IGF1R levels. International journal of cancer 49 27299695
2022 Targeting insulin-like growth factor-1 receptor (IGF1R) for brain delivery of biologics. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 47 35192204
2022 Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors. Cancer research 46 34921013
2018 The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer Invasion. Cancer research 46 29572229
2011 Calcium and osteoprotegerin regulate IGF1R expression to inhibit vascular calcification. Cardiovascular research 43 21447702
2014 Vertical blockade of the IGFR- PI3K/Akt/mTOR pathway for the treatment of hepatocellular carcinoma: the role of survivin. Molecular cancer 42 24387108
2013 Combating resistance to anti-IGFR antibody by targeting the integrin β3-Src pathway. Journal of the National Cancer Institute 41 24092920
2020 ALKBH5 regulates IGF1R expression to promote the Proliferation and Tumorigenicity of Endometrial Cancer. Journal of Cancer 40 32913456
1997 Interaction of MAD2 with the carboxyl terminus of the insulin receptor but not with the IGFIR. Evidence for release from the insulin receptor after activation. The Journal of biological chemistry 40 9092546
2020 IGF-1R inhibition induces MEK phosphorylation to promote survival in colon carcinomas. Signal transduction and targeted therapy 39 32843616
2019 Below the Surface: IGF-1R Therapeutic Targeting and Its Endocytic Journey. Cells 39 31600876
2014 Crosstalk between IGF-1R and other tumor promoting pathways. Current pharmaceutical design 39 23944361
2010 Elevated IGFIR expression regulating VEGF and VEGF-C predicts lymph node metastasis in human colorectal cancer. BMC cancer 39 20459642
2022 Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2. Theranostics 38 35154476
2017 Cell surface GRP78 facilitates hepatoma cells proliferation and migration by activating IGF-IR. Cellular signalling 38 28389416
2013 Insulin-like growth factor 1 receptor (IGF1R) expression and survival in operable squamous-cell laryngeal cancer. PloS one 38 23365645
2023 IGF-1R targeting in cancer - does sub-cellular localization matter? Journal of experimental & clinical cancer research : CR 36 37858153
2016 IGF1R and c-met as therapeutic targets for colorectal cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 27470393
2013 Expression and significance of IGF-1 and IGF-1R in thyroid nodules. Endocrine 36 23288662
2022 Hypoxia-induced ELF3 promotes tumor angiogenesis through IGF1/IGF1R. EMBO reports 35 35695065
2011 R1507, an anti-insulin-like growth factor-1 receptor (IGF-1R) antibody, and EWS/FLI-1 siRNA in Ewing's sarcoma: convergence at the IGF/IGFR/Akt axis. PloS one 35 22022506
2022 IGF2BP2 promotes gastric cancer progression by regulating the IGF1R-RhoA-ROCK signaling pathway. Cellular signalling 34 35306138
2018 IGF1R signaling drives antiestrogen resistance through PAK2/PIX activation in luminal breast cancer. Oncogene 34 29353882
2018 Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/β-Catenin/IGFR-IR Signaling Axis. Frontiers in oncology 33 30406034
2017 miR-422a Inhibits Glioma Proliferation and Invasion by Targeting IGF1 and IGF1R. Oncology research 32 28277190
2017 Molecular Imaging of IGF-1R in Cancer. Molecular imaging 31 29169312
2020 New Insights from IGF-IR Stimulating Activity Analyses: Pathological Considerations. Cells 30 32252327
2013 Interaction between IGF-IR and ER induced by E2 and IGF-I. PloS one 30 23704881
2001 Increased IGFR activity and glucose transport in cultured skeletal muscle from insulin receptor null mice. American journal of physiology. Endocrinology and metabolism 30 11404219
2023 Inhibiting SCD expression by IGF1R during lorlatinib therapy sensitizes melanoma to ferroptosis. Redox biology 29 36889082
2021 IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis. Biomedicines 29 33562061
2019 Activation of IGF1R by DARPP-32 promotes STAT3 signaling in gastric cancer cells. Oncogene 29 31235784
2017 Alpinia oxyphylla Miq. fruit extract activates IGFR-PI3K/Akt signaling to induce Schwann cell proliferation and sciatic nerve regeneration. BMC complementary and alternative medicine 29 28359314
2013 Dynamic and nuclear expression of PDGFRα and IGF-1R in alveolar Rhabdomyosarcoma. Molecular cancer research : MCR 29 23928059
2023 Effects and potential mechanisms of IGF1/IGF1R in the liver fibrosis: A review. International journal of biological macromolecules 28 37567540
2015 MiR-100 Inhibits Osteosarcoma Cell Proliferation, Migration, and Invasion and Enhances Chemosensitivity by Targeting IGFIR. Technology in cancer research & treatment 28 26306402
2014 Dsh homolog DVL3 mediates resistance to IGFIR inhibition by regulating IGF-RAS signaling. Cancer research 28 25168481
2020 NCK1-AS1 enhances glioma cell proliferation, radioresistance and chemoresistance via miR-22-3p/IGF1R ceRNA pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 27 32887025
2019 ReishiMax inhibits mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells. Signal transduction and targeted therapy 27 31637001
2021 IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma. Cancers 26 34831014
2019 Increasing knowledge in IGF1R defects: lessons from 35 new patients. Journal of medical genetics 26 31586944
2015 Metformin down-regulates endometrial carcinoma cell secretion of IGF-1 and expression of IGF-1R. Asian Pacific journal of cancer prevention : APJCP 26 25640355
2023 IGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia. Nature communications 25 37777542
2021 Autophagy induction by IGF1R inhibition with picropodophyllin and linsitinib. Autophagy 25 34110249
2016 IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis. Endocrine-related cancer 25 27185872
2021 IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis. JCI insight 24 33591952
2018 Role of IGF-1R in ameliorating apoptosis of GNE deficient cells. Scientific reports 24 29743626
2017 Nuclear insulin-like growth factor-1 receptor (IGF1R) displays proliferative and regulatory activities in non-malignant cells. PloS one 24 28945762
2019 IGF-1R Inhibition Suppresses Cell Proliferation and Increases Radiosensitivity in Nasopharyngeal Carcinoma Cells. Mediators of inflammation 22 31467485
2022 GIGYF1 disruption associates with autism and impaired IGF-1R signaling. The Journal of clinical investigation 21 35917186
2020 Exercise training restores IGFIR survival signaling in d-galactose induced-aging rats to suppress cardiac apoptosis. Journal of advanced research 21 33364043
2015 The transcription factors Ik-1 and MZF1 downregulate IGF-IR expression in NPM-ALK⁺ T-cell lymphoma. Molecular cancer 21 25884514
2015 Inhibition of IGF1-R overcomes IGFBP7-induced chemotherapy resistance in T-ALL. BMC cancer 21 26450156
2006 Transactivation of the IGF-1R by aldosterone. American journal of physiology. Renal physiology 21 17190911
2023 Aloin and CPT-11 combination activates miRNA-133b and downregulates IGF1R- PI3K/AKT/mTOR and MEK/ERK pathways to inhibit colorectal cancer progression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 20 38000359
2020 IGF1R Axis Inhibition Restores Dendritic Cell Antitumor Response in Ovarian Cancer. Translational oncology 20 32428851
2017 Relation of the IGF/IGF1R system to autophagy in colitis and colorectal cancer. World journal of gastroenterology 20 29290648
2016 Chapter Seven - When Phosphorylation Encounters Ubiquitination: A Balanced Perspective on IGF-1R Signaling. Progress in molecular biology and translational science 19 27378760
2013 Novel mechanisms of regulation of IGF-1R action: functional and therapeutic implications. Pediatric endocrinology reviews : PER 19 23957198
2012 Expression pattern and targeting of HER family members and IGF-IR in pancreatic cancer. Frontiers in bioscience (Landmark edition) 19 22652808
2009 IGF-IR in neuroprotection and brain tumors. Frontiers in bioscience (Landmark edition) 19 19273072
2009 Insulin receptor and IGF1R are not required for oocyte growth, differentiation, and maturation in mice. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 19 19851056
2021 Physiologic IGFBP7 levels prolong IGF1R activation in acute lymphoblastic leukemia. Blood advances 18 34438446
2024 Follistatin drives neuropathic pain in mice through IGF1R signaling in nociceptive neurons. Science translational medicine 17 39413164
2023 Decreased IGF1R attenuates senescence and improves function in pancreatic β-cells. Frontiers in endocrinology 17 37441495
2019 IGF2 and IGF1R mRNAs Are Detectable in Human Spermatozoa. The world journal of men's health 17 31496145
2016 Co-inhibition of EGFR and IGF1R synergistically impacts therapeutically on adrenocortical carcinoma. Oncotarget 17 27105537
2023 EGFR/IGF1R Signaling Modulates Relaxation in Hypertrophic Cardiomyopathy. Circulation research 16 37477020
2022 Recent developments in the structural characterisation of the IR and IGF1R: implications for the design of IR-IGF1R hybrid receptor modulators. RSC medicinal chemistry 15 35647546
2020 Is There Evidence for IGF1R-Stimulating Abs in Graves' Orbitopathy Pathogenesis? International journal of molecular sciences 15 32911689
2018 Targeting IGF1R pathway in cancer with microRNAs: How close are we? RNA biology 15 28613101
2018 Berberine promotes nerve regeneration through IGFR‑mediated JNK‑AKT signal pathway. Molecular medicine reports 15 30272344
2015 Bidirectional signaling between TM4SF5 and IGF1R promotes resistance to EGFR kinase inhibitors. Lung cancer (Amsterdam, Netherlands) 15 26190015
2015 Cabozantinib Inhibits Abiraterone's Upregulation of IGFIR Phosphorylation and Enhances Its Anti-Prostate Cancer Activity. Clinical cancer research : an official journal of the American Association for Cancer Research 15 26289068
2014 Genetic variations in the IGF-IGFR-IGFBP axis confer susceptibility to lung and esophageal cancer. Genetics and molecular research : GMR 15 24615087

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