Affinage

IRS4

Insulin receptor substrate 4 · UniProt O14654

Length
1257 aa
Mass
133.8 kDa
Annotated
2026-06-10
43 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRS4 is a cytoplasmic insulin-receptor-substrate adaptor that couples receptor tyrosine kinase signaling to the PI3K/AKT axis, mediating metabolic and mitogenic outputs while functioning distinctly from IRS-1 and IRS-2 (PMID:10594015, PMID:10077007). Upon tyrosine phosphorylation, IRS4 recruits PI3K regulatory subunits to drive AKT activation, BAD phosphorylation, and—via Grb-2—MAPK signaling, and it suffices to stimulate PI3K-dependent GLUT4 translocation independently of insulin (PMID:10594015, PMID:10077007). The non-receptor kinase FER phosphorylates IRS4 at Tyr779 through interaction with its PH and PTB domains, enabling recruitment of PIK3R2/p85β to activate PI3K-AKT (PMID:35550247). A defining feature of IRS4 is constitutive, growth-factor-independent and feedback-insensitive PI3K/AKT activation, attributed to its lack of a SHP2-binding domain present in IRS1/2; this drives insulin/IGF1-independent proliferation, anchorage-independent growth, and tumorigenesis, synergy with ERBB2/HER2, and resistance to HER2- and EGFR-targeted therapies (PMID:27876799, PMID:33894221, PMID:42054459). IRS4 also acts as a negative regulator of IRS-1/IRS-2 signaling by reducing IRS-2 levels and impairing IGF-1-stimulated IRS-1/2 phosphorylation (PMID:11113178). IRS4 abundance is controlled by ubiquitin-dependent degradation: Asb-4 promotes IRS4 ubiquitination and degradation via its SOCS box (PMID:21955513), and CK1γ2-mediated phosphorylation at Ser859 promotes CHIP-dependent polyubiquitination and lysosomal degradation, with degradation-resistant IRS4 elevating p-AKT and proliferation (PMID:30026872). In the brain, IRS4-expressing paraventricular hypothalamic neurons are required for normal feeding and energy expenditure, IRS4 synergizes with IRS2 in non-LepRb neurons for energy balance, and loss-of-function IRS4 mutations cause isolated congenital central hypothyroidism in males via the hypothalamic-pituitary TSH axis (PMID:24567904, PMID:30061370, PMID:32218485).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 High

    Established that IRS4 transduces insulin signals to AKT/BAD and MAPK but is functionally distinct from IRS-1/2, defining it as a non-redundant adaptor.

    Evidence Retroviral expression in 32D(IR) myeloid cells with co-IP, kinase, phosphorylation, and apoptosis assays comparing IRS-1/2/4

    PMID:10594015

    Open questions at the time
    • Did not identify the receptor kinases or sites driving IRS4 phosphorylation
    • Weak p85/PI3K coupling left the basis of pathway selectivity unresolved
  2. 1999 High

    Showed IRS4 can drive a core metabolic insulin output—GLUT4 translocation—in a PI3K- and YXXM-motif-dependent manner, even without insulin.

    Evidence Cotransfection of HA-GLUT4 and IRS-4 in rat adipose cells with surface GLUT4 measurement, PI3K inhibitors, and YXXM mutagenesis

    PMID:10077007

    Open questions at the time
    • Overexpression context may not reflect endogenous stoichiometry
    • Mechanism of insulin-independent activation not defined
  3. 2001 High

    Revealed a paradoxical negative-regulatory role: IRS4 suppresses IRS-2 levels and IRS-1/2 phosphorylation while raising basal PI3K/AKT, separating its mitogenic from metabolic functions.

    Evidence Retroviral transduction into WT and IRS-1 KO 3T3 fibroblasts with immunoblot, PI3K, and MAPK assays

    PMID:11113178

    Open questions at the time
    • Mechanism by which IRS4 reduces IRS-2 not defined
    • Failure to rescue mitogenesis in IRS-1 KO left signaling output incomplete
  4. 2003 Medium

    Demonstrated cell-context-dependent PI3K coupling: in beta-cells IRS4 compensates for IRS-2 to support survival/mitogenesis, while in IGF1R-null T-lymphoma cells insulin-driven IRS4 activates PI3K/p70S6K but not Ras-MAPK.

    Evidence Adenoviral gain/loss in INS-1 cells and IP/kinase/inhibitor dissection in LB T-cell lymphoma cells

    PMID:12618213 PMID:14604813

    Open questions at the time
    • Context-dependence of MAPK coupling not mechanistically explained
    • Single-lab cell-line studies
  5. 2010 Low

    Confirmed insulin-induced IRS4 tyrosine phosphorylation and physical IRS4/PI3K association in hepatic cells, with crosstalk modulation by Angiotensin II.

    Evidence Co-IP, tyrosine phosphorylation and PI3K activity assays in HepG2 cells and rat liver membranes with AT1 receptor manipulation

    PMID:16933034 PMID:20079766

    Open questions at the time
    • Single-method phosphorylation readouts without kinase reconstitution
    • Physiological relevance of AngII crosstalk unclear
  6. 2011 High

    Identified Asb-4 as a hypothalamic regulator that ubiquitinates and degrades IRS4 via its SOCS box, establishing post-translational control of IRS4-dependent AKT signaling in feeding-relevant neurons.

    Evidence Reciprocal co-IP in HEK293 and rat hypothalamic extracts, SOCS box deletion, ubiquitination and AKT assays, in situ hybridization

    PMID:21955513

    Open questions at the time
    • Did not establish whether Asb-4-mediated degradation is proteasomal vs lysosomal definitively
    • In vivo consequence of Asb-4 loss on IRS4 not tested
  7. 2013 Medium

    Showed IRS4 drives constitutive, IRS1/2-independent PI3K/AKT/S6K activity in cancer cells and is required for their proliferation, framing IRS4 as an oncogenic driver.

    Evidence RNAi knockdown with PIP3, AKT/S6K phosphorylation, and proliferation assays in IRS4-high cancer cells

    PMID:24039912

    Open questions at the time
    • Did not explain why IRS4 dominates over co-expressed IRS1/2
    • No in vivo validation
  8. 2013 High

    Defined a brain-specific, cell-type-resolved role: Irs2/Irs4 synergize in non-LepRb hypothalamic neurons to control energy balance.

    Evidence Genetic epistasis across bIrs2/Irs4 double-knockout combinations with metabolic phenotyping in mice

    PMID:24567904

    Open questions at the time
    • Molecular signaling underlying Irs2/Irs4 synergy not resolved
    • Specific neuronal subtypes not fully defined
  9. 2016 High

    Provided the molecular basis for constitutive PI3K/AKT activation—absence of a SHP2-binding domain renders IRS4 feedback-insensitive—and demonstrated tumorigenicity and HER2-therapy resistance.

    Evidence Insertional mutagenesis screen, retroviral overexpression in mammary cells, domain mutagenesis, in vivo tumorigenesis and HER2-resistance assays

    PMID:27876799

    Open questions at the time
    • Did not identify the upstream kinase normally phosphorylating IRS4 in tumors
    • Did not address regulation of IRS4 abundance in this setting
  10. 2017 Medium

    Extended IRS4's role to BMP signaling, where it binds BMPRII, targets Smad1 for degradation, and promotes myogenesis while activating PI3K/Akt.

    Evidence Co-IP, proteasome inhibitor and Smad1 degradation assays, knockdown and differentiation assays in C2C12 myoblasts

    PMID:28821740

    Open questions at the time
    • Mechanism linking IRS4 to Smad1 degradation not defined
    • Single cell-type model
  11. 2018 High

    Identified the CK1γ2–Ser859–CHIP axis controlling IRS4 stability, linking phospho-dependent degradation to suppression of AKT signaling and tumor proliferation.

    Evidence In vitro kinase assay, mass spectrometry, cycloheximide chase, ubiquitination assays, phospho-mutant validation in vitro and xenograft

    PMID:30026872

    Open questions at the time
    • Upstream signals controlling CK1γ2 activity on IRS4 unknown
    • Relationship between CHIP and Asb-4 degradation routes not reconciled
  12. 2018 Medium

    Connected IRS4 loss-of-function to human disease, identifying it as a cause of isolated congenital central hypothyroidism via the hypothalamic-pituitary TSH axis.

    Evidence Exome/Sanger sequencing of CeH patients, human hypothalamus/pituitary expression, and Irs4 KO mouse pituitary Tshb/TSH profiling

    PMID:30061370

    Open questions at the time
    • Signaling pathway linking IRS4 to TSH regulation not defined
    • Male-restricted phenotype mechanism unexplained
  13. 2020 Medium

    Resolved the neuronal circuit: IRS4-expressing PVH/periventricular neurons are necessary and sufficient for feeding and energy expenditure control.

    Evidence Cre-dependent chemogenetic activation/silencing, neuronal tracing, and metabolic measurement in mice

    PMID:32218485

    Open questions at the time
    • Role of cell-intrinsic IRS4 signaling vs neuron identity not separated
    • Downstream hindbrain effectors not mechanistically mapped
  14. 2022 High

    Identified FER as the kinase phosphorylating IRS4 at Tyr779 through PH/PTB domain interaction to recruit p85β and activate PI3K-AKT, supplying an upstream activator of oncogenic IRS4.

    Evidence Mass spectrometry substrate ID, co-IP, BioID, in vitro kinase assay, and Y779F phospho-mutant rescue in vitro and in xenografts

    PMID:35550247

    Open questions at the time
    • Generality of FER as the activating kinase across tissues unknown
    • Other phosphosites contributing to PI3K recruitment not enumerated
  15. 2026 Medium

    Mapped IRS4 as a pan-cancer dependency whose PH/PTB domains are dispensable for PI3K-activating oncogenic function and whose tumor expression arises through enhancer-hijacking rearrangements, motivating degradation-based therapy.

    Evidence Pan-cancer dependency analysis, domain deletion with PI3K-Akt readouts, and genomic rearrangement analysis (GATA3-IRS4, ANKRD30A-IRS4)

    PMID:42054459

    Open questions at the time
    • Reconciling dispensable PH/PTB here with FER-domain dependence elsewhere unresolved
    • Degradation-based therapeutic feasibility not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IRS4's constitutive, feedback-insensitive PI3K activation is integrated with its phospho-dependent degradation, its receptor/kinase inputs across tissues, and its disease-relevant hypothalamic signaling remains incompletely unified.
  • No structural model of IRS4–p85 or IRS4–FER complexes
  • Tissue-specific upstream activators beyond FER not defined
  • Mechanism of IRS4-mediated IRS-2 suppression unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1430728 Metabolism 2 R-HSA-392499 Metabolism of proteins 2
Partners
ASB4BMPR2CSNK1G2FERGRB2PIK3R2STUB1

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 IRS-4 mediates PKB/Akt activation and BAD phosphorylation during insulin stimulation in 32D myeloid progenitor cells, but only weakly binds and activates p85-associated PI 3-kinase and fails to activate p70(s6k) or inhibit apoptosis, distinguishing it functionally from IRS-1 and IRS-2. IRS-4 also promotes Grb-2 association and MAPK activation similarly to IRS-1. Retroviral expression in 32D(IR) cells, co-immunoprecipitation, kinase assays, apoptosis assays, phosphorylation measurements Molecular and cellular biology High 10594015
2001 IRS-4 overexpression decreases IRS-2 mRNA and protein levels and impairs IGF-1-stimulated tyrosine phosphorylation of IRS-1 and IRS-2, increases basal PI 3-kinase activity and Akt phosphorylation, but fails to reconstitute the mitogenic response to IGF-1 in IRS-1 KO cells, acting as a negative regulator of IGF-1 signaling. Retroviral transduction into 3T3 fibroblasts from WT and IRS-1 KO mice, immunoblotting, PI 3-kinase activity assay, MAPK phosphorylation assay Molecular and cellular biology High 11113178
1999 IRS-4 overexpression in rat adipose cells stimulates GLUT4 translocation to the cell surface in a PI 3-kinase-dependent manner, even in the absence of insulin, demonstrating that IRS-4 can mediate insulin metabolic actions. Cotransfection of HA-tagged GLUT4 and IRS-4 in rat adipose cells, cell surface GLUT4 measurement, PI 3-kinase inhibitor studies, YXXM motif mutagenesis Molecular endocrinology (Baltimore, Md.) High 10077007
2003 IRS-4 expression in INS-1 pancreatic beta-cells compensates for IRS-2 depletion by enhancing glucose/IGF-1-induced mitogenesis and protecting against fatty acid-induced apoptosis via PKB activation and decreased caspase-9 activation. Adenoviral-mediated overexpression and antisense knockdown in INS-1 cells, PKB phosphorylation assay, caspase-9 activation assay, apoptosis assay Molecular and cellular endocrinology Medium 14604813
2003 In murine T-cell lymphoma (LB) cells lacking IGF-1 receptors, insulin stimulates tyrosine phosphorylation of IRS-4 (160 kDa), which associates with and activates PI3-kinase and downstream p70(S6K), but not the Ras-MAPK pathway; PI3-kinase (not p70S6K or MEK) is required for insulin-stimulated DNA synthesis. Immunoprecipitation, kinase assays, PI3-kinase activity assay, selective inhibitor treatment, thymidine incorporation assay Cellular signalling Medium 12618213
2006 Insulin induces tyrosine phosphorylation of IRS-4 (pp160) in rat liver membranes; Angiotensin II pre-stimulation reduces this phosphorylation in a dose-dependent manner; PI3-kinase inhibitors increase IRS-4 phosphorylation, indicating a PI3K-dependent negative feedback on IRS-4 tyrosine phosphorylation. Tyrosine phosphorylation assay in rat liver membrane preparations, inhibitor studies (okadaic acid, genistein, wortmannin, LY294002), immunoblotting with anti-IRS-4 antibody Molecular and cellular biochemistry Low 16933034
2010 In HepG2 cells, insulin induces tyrosine phosphorylation of IRS-4 and physical association between IRS-4 and PI3-kinase (co-immunoprecipitation); Angiotensin II via AT1 receptors potentiates IRS-4 tyrosine phosphorylation but does not alter IRS-4/PI3-K association or PI3-K activation. Co-immunoprecipitation, tyrosine phosphorylation assay, PI3-kinase activity measurement, PI3-K inhibitor treatment Regulatory peptides Low 20079766
2011 Asb-4 (ankyrin repeat and SOCS box containing protein 4) co-localizes with IRS4 in hypothalamic arcuate nucleus POMC and NPY neurons, physically interacts with IRS4 by co-immunoprecipitation (both in transfected HEK293 cells and in rat hypothalamic extracts), promotes IRS4 ubiquitination and proteasomal/lysosomal degradation via its SOCS box, and reduces insulin-stimulated AKT phosphorylation. In situ hybridization, co-immunoprecipitation (in HEK293 cells and rat hypothalamic extracts), ubiquitination assay, SOCS box deletion mutagenesis, AKT phosphorylation assay BMC neuroscience High 21955513
2013 IRS4 expression in cancer cells with high IRS4 levels drives constitutively elevated PIP3, Akt, and p70 S6 kinase activities even in the absence of growth factors; PI3K signaling in these cells depends on IRS4 even though IRS1/2 are co-expressed. IRS4 knockdown inhibits cell proliferation in IRS4-high cells. RNAi knockdown, PIP3 measurement, Akt and S6K phosphorylation assay, cell proliferation assay PloS one Medium 24039912
2013 Brain-specific deletion of Irs2 combined with whole-body Irs4 knockout (bIrs2−/− · Irs4−/y) causes severe obesity, decreased energy expenditure, hyperglycemia, and insulin resistance; these phenotypes are not observed with Irs4 knockout alone or with LepRb-specific Irs2 deletion plus Irs4 knockout, indicating that Irs2 and Irs4 synergize in non-LepRb hypothalamic neurons to control energy balance. Genetic epistasis using double-knockout mouse models (Cre-lox), metabolic phenotyping (body weight, energy expenditure, blood glucose, insulin tolerance) Molecular metabolism High 24567904
2016 IRS4 expression in mammary epithelial cells induces constitutive PI3K/AKT pathway hyperactivation, insulin/IGF1-independent cell proliferation, anchorage-independent growth, and in vivo tumorigenesis. The absence of a SHP2-binding domain in IRS4 (present in IRS1/2) is identified as the molecular basis for its constitutive, feedback-insensitive PI3K/AKT activation. IRS4 and ERBB2/HER2 synergistically induce tumorigenesis, and IRS4 expression confers resistance to HER2-targeted therapy. Insertional mutagenesis screen, retroviral overexpression in mammary epithelial cells, PI3K/AKT pathway phosphorylation assays, proliferation/anchorage-independent growth assays, in vivo tumorigenesis models, domain analysis/mutagenesis, HER2-targeted therapy resistance assay Nature communications High 27876799
2017 IRS4 interacts with BMP receptor BMPRII and specifically targets Smad1 for proteasomal degradation, repressing BMP/Smad signaling while concomitantly activating the PI3K/Akt axis in C2C12 myoblasts. IRS4 promotes myogenesis and its knockdown inhibits myoblast differentiation. Co-immunoprecipitation, proteasome inhibitor assays, Smad1 phosphorylation/degradation measurements, PI3K/Akt activation assay, IRS4 knockdown in C2C12 cells, myogenic differentiation assay Scientific reports Medium 28821740
2018 IRS4 is phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promotes polyubiquitination and degradation of IRS4 via the CHIP E3 ligase through the ubiquitin/lysosome pathway. A non-phosphorylatable IRS4 mutant (Ser859 mutant) shows higher p-Akt levels and faster tumor cell proliferation. In vitro kinase assay, mass spectrometry, co-immunoprecipitation, cycloheximide chase assay, ubiquitination assay, phospho-mutant overexpression, colony formation assay, xenograft mouse model Theranostics High 30026872
2018 Loss-of-function mutations in IRS4 (nonsense and frameshift) are associated with isolated congenital central hypothyroidism (CeH) in males; IRS4 mRNA is expressed in human hypothalamic nuclei (including paraventricular nucleus) and pituitary; female Irs4 knockout mice show decreased pituitary Tshb mRNA levels, linking IRS4 to TSH regulation in the hypothalamic-pituitary axis. Exome sequencing, Sanger sequencing, IRS4 expression analysis in human hypothalamus/pituitary, Irs4 knockout mouse model with pituitary Tshb mRNA measurement and serum thyroid hormone measurement, 24-hour TSH secretion profiling Journal of medical genetics Medium 30061370
2020 IRS4-expressing neurons in the paraventricular, subparaventricular, and periventricular hypothalamus are sufficient and necessary for normal feeding and energy expenditure; activation of IRS4PVH neurons suppresses feeding and increases energy expenditure, and their silencing causes obesity; IRS4PVH neurons lie within hypothalamic circuitry innervating distinct hindbrain regions. Cre-dependent viral tools for chemogenetic activation and silencing of IRS4-expressing neurons, neuronal tracing, feeding and energy expenditure measurement in mice Scientific reports Medium 32218485
2021 IRS4 knockout suppresses proliferation, colony formation, migration, invasion, and tumor growth in A549 lung cancer cells; IRS4 activates both PI3K/Akt and Ras-MAPK pathways; IRS4 depletion significantly sensitizes EGFR-TKI-resistant cells to gefitinib. CRISPR/retroviral KO and stable overexpression, proliferation/colony/migration/invasion assays, PI3K/Akt and MAPK pathway phosphorylation assays, xenograft mouse model, gefitinib sensitivity assay Experimental cell research Medium 33894221
2022 Non-receptor tyrosine kinase FER phosphorylates IRS4 at Tyr779 via its kinase domain interacting with the PH and PTB domains of IRS4; this phosphorylation enables IRS4 to recruit PIK3R2/p85β (regulatory subunit of PI3K), activating the PI3K-AKT pathway. Phosphorylation-defective IRS4 (Y779F) fails to rescue IRS4-null ovarian tumor cell proliferation in vitro and in vivo. Mass spectrometry substrate identification, co-immunoprecipitation, proximity-based tagging (BioID), in vitro kinase assay, phospho-mutant rescue experiments, in vitro and xenograft proliferation assays eLife High 35550247
2014 IRS-4 physically interacts with the copper transporter CTR1 (co-immunoprecipitation confirmed with FLAG-CTR1 and myc-CTR1); the interaction is enhanced when the CTR1 Y103A mutation is present. Proteomic analysis of CTR1-derived peptides, co-immunoprecipitation from HEK cells expressing FLAG-CTR1 or myc-CTR1 Biochemical pharmacology Low 24967972
2026 IRS4 drives cancer cell dependency through PI3K-Akt activation; domain analysis shows the PH and PTB domains are dispensable for IRS4's PI3K-activating oncogenic function, suggesting degradation-based therapeutic modalities; IRS4 expression in adult tumors is associated with enhancer hijacking rearrangements including GATA3-IRS4 and ANKRD30A-IRS4 in breast cancer. Pan-cancer dependency analysis, domain deletion analysis, PI3K-Akt pathway assays, genomic rearrangement analysis Science advances Medium 42054459
2021 PD-L1 binds to eIF3I and promotes cutaneous diabetic wound healing by downregulating IRS4; the eIF3I-PD-L1-IRS4 axis contributes to wound healing defects. PD-L1 interacting proteins were identified by co-immunoprecipitation combined with mass spectrometry. Transcriptional profiling, co-immunoprecipitation combined with mass spectrometry, coimmunoprecipitation validation, in vivo and in vitro functional assays, immunohistochemistry The Journal of investigative dermatology Low 34293353

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nature genetics 318 27869826
2001 Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. Molecular and cellular biology 78 11113178
2003 Decreasing IRS-2 expression in pancreatic beta-cells (INS-1) promotes apoptosis, which can be compensated for by introduction of IRS-4 expression. Molecular and cellular endocrinology 65 14604813
2016 IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation. Nature communications 58 27876799
2000 IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. Molecular and cellular biology 52 10594015
1999 Action of insulin receptor substrate-3 (IRS-3) and IRS-4 to stimulate translocation of GLUT4 in rat adipose cells. Molecular endocrinology (Baltimore, Md.) 50 10077007
2013 Effect of IRS4 levels on PI 3-kinase signalling. PloS one 36 24039912
2018 Mutations in IRS4 are associated with central hypothyroidism. Journal of medical genetics 32 30061370
2013 Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis. Molecular metabolism 31 24567904
2021 IRS4 promotes the progression of non-small cell lung cancer and confers resistance to EGFR-TKI through the activation of PI3K/Akt and Ras-MAPK pathways. Experimental cell research 26 33894221
2022 FER-mediated phosphorylation and PIK3R2 recruitment on IRS4 promotes AKT activation and tumorigenesis in ovarian cancer cells. eLife 24 35550247
2011 Ankyrin repeat and SOCS box containing protein 4 (Asb-4) colocalizes with insulin receptor substrate 4 (IRS4) in the hypothalamic neurons and mediates IRS4 degradation. BMC neuroscience 24 21955513
2017 Insulin receptor substrate 4 (IRS4) is a constitutive active oncogenic driver collaborating with HER2 and causing therapeutic resistance. Molecular & cellular oncology 21 28401183
2017 Downregulation of miR-493 promoted melanoma proliferation by suppressing IRS4 expression. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 21 28475006
2021 hsa_circ_0023409 Accelerates Gastric Cancer Cell Growth and Metastasis Through Regulating the IRS4/PI3K/AKT Pathway. Cell transplantation 20 33439739
2020 Paraventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance. Scientific reports 20 32218485
2005 Candida albicans IRS4 contributes to hyphal formation and virulence after the initial stages of disseminated candidiasis. Microbiology (Reading, England) 20 16151204
2004 Negative regulation of phosphatidylinositol 4,5-bisphosphate levels by the INP51-associated proteins TAX4 and IRS4. The Journal of biological chemistry 20 15265867
2018 Phosphorylation of IRS4 by CK1γ2 promotes its degradation by CHIP through the ubiquitin/lysosome pathway. Theranostics 19 30026872
2017 IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation. Scientific reports 19 28821740
2014 Molecular modulation of the copper and cisplatin transport function of CTR1 and its interaction with IRS-4. Biochemical pharmacology 19 24967972
2020 Long Noncoding RNA LINC00173 Promotes the Malignancy of Melanoma by Promoting the Expression of IRS4 Through Competitive Binding to microRNA-493. Cancer management and research 15 32440211
2018 Overexpression of IRS-4 Correlates with Procaspase 3 Levels in Tumoural Tissue of Patients with Colorectal Cancer. Journal of oncology 14 30410539
2021 Possible Role of IRS-4 in the Origin of Multifocal Hepatocellular Carcinoma. Cancers 12 34071030
2024 Evodiamine inhibits growth of vemurafenib drug-resistant melanoma via suppressing IRS4/PI3K/AKT signaling pathway. Journal of natural medicines 10 38324123
2021 PD-L1 Triggered by Binding eIF3I Contributes to the Amelioration of Diabetes-Associated Wound Healing Defects by Regulating IRS4. The Journal of investigative dermatology 10 34293353
2021 Actinomycin D Arrests Cell Cycle of Hepatocellular Carcinoma Cell Lines and Induces p53-Dependent Cell Death: A Study of the Molecular Mechanism Involved in the Protective Effect of IRS-4. Pharmaceuticals (Basel, Switzerland) 9 34577545
2014 Proliferation and migration of hepatoblastoma cells are mediated by IRS-4 via PI3K/Akt pathways. International journal of clinical and experimental medicine 9 25419430
2003 IRS-4 mediated mitogenic signalling by insulin and growth hormone in LB cells, a murine T-cell lymphoma devoid of IGF-I receptors. Cellular signalling 9 12618213
2021 Chronic venous disease patients show increased IRS-4 expression in the great saphenous vein wall. The Journal of international medical research 8 34590920
2023 Is Insulin Receptor Substrate4 (IRS4) a Platform Involved in the Activation of Several Oncogenes? Cancers 7 37760618
2011 Association between body mass index and insulin receptor substrate-4 (IRS-4) gene polymorphisms in patients with schizophrenia. Neuro endocrinology letters 6 22167131
2022 Patients with Invasive Lobular Carcinoma Show a Significant Increase in IRS-4 Expression Compared to Infiltrative Ductal Carcinoma-A Histopathological Study. Medicina (Kaunas, Lithuania) 4 35743985
2013 A competitive infection model of hematogenously disseminated candidiasis in mice redefines the role of Candida albicans IRS4 in pathogenesis. Infection and immunity 4 23429534
2006 Angiotensin II modulates tyr-phosphorylation of IRS-4, an insulin receptor substrate, in rat liver membranes. Molecular and cellular biochemistry 4 16933034
2024 HDAC inhibitors target IRS4 to enhance anti‑AR therapy in AR‑positive triple‑negative breast cancer. International journal of oncology 3 38214343
2021 Long Noncoding RNA LINC00173 Promotes the Malignancy of Melanoma by Promoting the Expression of IRS4 Through Competitive Binding to microRNA-493 [Retraction]. Cancer management and research 3 34616181
2011 The insulin receptor substrate-4 (IRS-4) gene and schizophrenia: no evidence for a main genetic factor, however one report of a single schizophrenia patient with a mutation. Neuro endocrinology letters 3 21407155
2010 Role of IRS-4 in PI3-K activation by insulin in HepG2 cells, modulation by Angiotensin II. Regulatory peptides 2 20079766
2010 Porcine insulin receptor substrate 4 (IRS4) gene: cloning, polymorphism and association study. Molecular biology reports 2 21104145
2025 Transcriptome Sequencing Identifies PCK1 and IRS4 as Key Regulators of Gestational Diabetes Mellitus in Placenta: A Pilot Study. Diabetes, metabolic syndrome and obesity : targets and therapy 1 41179578
2026 IRS4 is a PI3K-activating cancer dependency up-regulated through DNA rearrangements or epigenetic mechanisms in multiple solid tumors. Science advances 0 42054459
2025 A Novel X-Linked Variant c.1772delG (p.G591fs*20) in IRS4 in Two Related Patients with Central Hypothyroidism. Molecular syndromology 0 41048878

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