Affinage

IRS1

Insulin receptor substrate 1 · UniProt P35568

Round 2 corrected
Length
1242 aa
Mass
131.6 kDa
Annotated
2026-04-28
130 papers in source corpus 48 papers cited in narrative 47 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRS1 is the principal cytoplasmic docking scaffold for insulin and IGF-1 receptor tyrosine kinases, coupling receptor activation to PI3K/Akt-dependent metabolic signaling (glucose uptake, lipogenesis, gluconeogenic gene suppression) and GRB2/Ras-dependent mitogenic signaling (PMID:1648180, PMID:1380456, PMID:8491186, PMID:8396927). Upon receptor activation, IRS1 is tyrosine-phosphorylated at YMXM motifs, creating docking sites for SH2-domain effectors including the p85 subunit of PI3K, GRB2, Fyn, and SHP-2; its PH and PTB domains, together with an adjacent PIR region, cooperatively mediate binding to the activated insulin receptor, with the PIR domain contacting the IR kinase N-lobe and hinge region (PMID:1312712, PMID:8798677, PMID:38625937). IRS1 activity is negatively regulated by inhibitory serine/threonine phosphorylation at convergent sites (notably Ser307/Ser312) by JNK, IKKβ, PKCθ, and mTOR/S6K, which disrupts PTB-PIR–IR interaction and attenuates downstream signaling, and by ubiquitin-dependent proteasomal degradation mediated by SOCS1/3–elongin BC, MG53/UBE2H, KLHL9/KLHL13/CUL3, and cathepsin K (PMID:10722755, PMID:12351658, PMID:15364919, PMID:15380067, PMID:12228220, PMID:23965929, PMID:31515271). IRS1-knockout mice exhibit growth retardation and impaired glucose tolerance with compensatory IRS-2 upregulation, and tissue-specific IRS1/IRS2 deletion reveals complementary roles in hepatic glucose/lipid metabolism and cardiac function (PMID:7526222, PMID:15711641, PMID:16374520, PMID:24159000).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1991 High

    Identification of IRS-1 as the major insulin receptor kinase substrate solved the longstanding question of how cytoplasmic signals are relayed from the activated insulin receptor, establishing IRS-1 as a multisite tyrosine-phosphorylated docking protein for SH2-domain effectors.

    Evidence Molecular cloning and in vitro kinase assays with the insulin receptor

    PMID:1648180

    Open questions at the time
    • No downstream effector binding sites mapped at this stage
    • Serine/threonine phosphorylation role unresolved
  2. 1992 High

    Demonstration that PI3K p85 binds IRS-1 via SH2 domain recognition of phospho-YMXM motifs, and that the insulin receptor phosphorylates IRS-1 exclusively on tyrosine residues, established the molecular logic of the IRS-1 scaffold: receptor-catalyzed tyrosine phosphorylation creates specific docking sites for downstream enzymes.

    Evidence Co-immunoprecipitation, in vitro reconstitution with recombinant proteins, synthetic peptide competition, and baculovirus-produced IRS-1 kinase assays

    PMID:1312712 PMID:1332046 PMID:1380456 PMID:1385403

    Open questions at the time
    • Other SH2 partners beyond PI3K not yet identified
    • Functional consequence of individual YMXM sites not resolved
  3. 1993 High

    Discovery that GRB2 binds IRS-1 at distinct phosphotyrosines simultaneously with PI3K established IRS-1 as a multieffector signaling hub linking insulin to both metabolic (PI3K) and mitogenic (Ras) pathways, while identification of casein kinase II-mediated serine phosphorylation introduced the concept of inhibitory serine modification.

    Evidence Co-immunoprecipitation, yeast two-hybrid, 2D phosphopeptide mapping, Edman degradation; insulin-stimulated degradation by pulse-chase labeling

    PMID:8349691 PMID:8382493 PMID:8396927 PMID:8491186

    Open questions at the time
    • Specific serine kinases responsible for inhibitory phosphorylation in vivo unknown
    • Mechanism of IRS-1 protein degradation not defined
  4. 1994 High

    IRS-1 knockout mice demonstrated in vivo essentiality for normal growth and glucose homeostasis and revealed the existence of the compensatory substrate IRS-2, establishing genetic redundancy within the IRS family.

    Evidence Targeted gene disruption in mice with PI3K activity assay, glucose tolerance, and insulin-stimulated uptake measurements

    PMID:7526222

    Open questions at the time
    • Tissue-specific contributions of IRS-1 versus IRS-2 unresolved
    • Mechanism of IRS-2 compensatory upregulation unknown
  5. 1996 High

    Systematic domain analysis revealed that the PH and PTB domains cooperatively couple IRS-1 to the insulin receptor, and discovery of Fyn kinase as an IRS-1-binding SH2 partner expanded the signaling repertoire beyond PI3K and GRB2.

    Evidence Deletion mutagenesis in 32D cells, expression library screening with radiolabeled IRS-1 probe, reciprocal co-immunoprecipitation

    PMID:8631859 PMID:8798677

    Open questions at the time
    • Structural basis for PH/PTB cooperativity not determined
    • Functional role of Fyn phosphorylation of IRS-1 in vivo unclear
  6. 2000 High

    Identification of JNK as the kinase that phosphorylates IRS-1 Ser307 and the demonstration that this disrupts PTB domain–insulin receptor interaction provided the first molecular mechanism for inflammatory cytokine (TNFα)-induced insulin resistance.

    Evidence In vitro kinase assay, S307A mutagenesis, co-immunoprecipitation, TNFα stimulation; yeast tri-hybrid showing disrupted IR–PTB interaction

    PMID:10722755 PMID:11160134 PMID:11606564

    Open questions at the time
    • Additional inhibitory serine sites not yet mapped
    • Relative contribution of JNK versus other kinases at Ser307 in vivo uncertain
  7. 2002 High

    Convergent discoveries established that IKKβ also phosphorylates IRS-1 Ser312, SOCS1/3 target IRS-1 for ubiquitin-mediated proteasomal degradation, and JNK functions in a direct PI3K-dependent feedback loop, revealing a multi-layered negative regulatory network governing IRS-1.

    Evidence Recombinant kinase assays, IKK-KO cells, SOCS box mutants blocking elongin BC recruitment, JNK1/2 double-KO MEFs

    PMID:12228220 PMID:12351658 PMID:12417588

    Open questions at the time
    • Complete catalog of E3 ubiquitin ligases for IRS-1 unknown
    • Relative importance of serine phosphorylation versus degradation not quantified
  8. 2004 High

    PKCθ was shown to phosphorylate IRS-1 at Ser1101, and the mTOR/S6K pathway was found to downregulate IRS-1/IRS-2 protein levels, establishing lipid-activated kinase and nutrient-sensing feedback as additional inhibitory inputs converging on IRS-1.

    Evidence In vitro kinase assay with recombinant PKCθ and S1101A mutagenesis; TSC1/TSC2 deletion and ectopic Rheb expression with pathway specificity controls; PTP1B phosphatase assay

    PMID:10660596 PMID:15364919 PMID:15380067

    Open questions at the time
    • Integration hierarchy among JNK, IKK, PKCθ, and mTOR on IRS-1 in vivo unresolved
    • Structural basis for Ser1101 inhibition unknown
  9. 2005 High

    Hepatic knockdown and conditional knockout studies dissected complementary roles of IRS-1 (gluconeogenesis suppression) and IRS-2 (lipogenesis regulation) in liver, while human muscle biopsy data linked mitochondrial dysfunction to IRS-1 inhibitory serine phosphorylation in insulin-resistant offspring of diabetic parents.

    Evidence Adenoviral shRNA and Cre-lox conditional KO in mouse liver; human muscle biopsies with phosphospecific antibodies and hyperinsulinemic clamp

    PMID:15711641 PMID:16284649 PMID:16374520

    Open questions at the time
    • Precise serine kinase(s) activated by mitochondrial dysfunction in human muscle not identified
    • Whether IRS-1/IRS-2 complementarity generalizes across all insulin-responsive tissues unclear
  10. 2013 High

    Identification of MG53/UBE2H as an E3/E2 ubiquitin ligase pair for IRS-1, with MG53-KO mice showing protection from diet-induced insulin resistance, provided the first genetically validated ubiquitin ligase regulating IRS-1 stability in vivo.

    Evidence Reconstituted ubiquitination assay, E3-ligase domain mutants, MG53-/- mice on high-fat diet

    PMID:23965929

    Open questions at the time
    • Tissue specificity of MG53-mediated IRS-1 degradation not fully delineated
    • Substrate selectivity of MG53 for IRS-1 versus IRS-2 not tested
  11. 2014 High

    Direct biochemical demonstration that PTEN dephosphorylates IRS-1 tyrosines, validated by genetic epistasis (NEDD4-KO rescued by PTEN ablation), identified PTEN as a major IRS-1 phosphatase beyond the well-known PTP1B.

    Evidence In vitro phosphatase assay with recombinant PTEN and phospho-IRS-1, NEDD4-KO and PTEN-KO genetic rescue

    PMID:24814346

    Open questions at the time
    • Relative contributions of PTEN versus PTP1B toward IRS-1 dephosphorylation in specific tissues unclear
    • Structural basis for PTEN recognition of IRS-1 unknown
  12. 2019 High

    Discovery of the KLHL9/KLHL13/CUL3 E3 ligase complex targeting IRS-1 and of transcriptional control of IRS1 by TAZ/c-Jun/Tead4 in muscle and by β-catenin/TCF expanded the regulatory framework to include both a new degradation pathway and tissue-specific transcriptional inputs.

    Evidence BioID proximity labeling with co-IP and siRNA validation in ATG16L1-KO MEFs; muscle-specific TAZ-KO mice with IRS1 promoter reporter assays

    PMID:19843521 PMID:30679431 PMID:31515271

    Open questions at the time
    • Whether KLHL9/13/CUL3 and MG53/UBE2H act on different IRS-1 pools is unknown
    • Transcription factor hierarchy at the IRS1 locus across metabolic tissues not established
  13. 2024 High

    Biophysical characterization of the PIR domain adjacent to the PTB domain revealed that serine phosphorylation at Ser307/312/315/323 directly abrogates IR kinase binding (SPR), and HDX-MS mapped the PIR contact surface on the IR kinase N-lobe, providing the first structural explanation for how inhibitory serine phosphorylation disrupts IRS-1–IR interaction.

    Evidence Surface plasmon resonance, hydrogen-deuterium exchange mass spectrometry, phosphomimetic mutagenesis with cellular signaling readouts

    PMID:38625937

    Open questions at the time
    • Full atomic-resolution structure of PTB-PIR bound to the IR kinase domain not yet available
    • Whether PIR-mediated IR protection from PTP1B occurs in vivo is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • A complete structural model of full-length IRS-1 in complex with the insulin receptor, the integration hierarchy among multiple inhibitory serine kinases in physiological tissues, and the relative quantitative contributions of distinct E3 ligases to IRS-1 turnover remain unresolved.
  • No full-length IRS-1 structure exists
  • Quantitative in vivo contribution of each serine kinase and E3 ligase to IRS-1 regulation is not established
  • Tissue-specific regulation of IRS-1 versus IRS-2 signaling selectivity is incompletely understood

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 12 R-HSA-1643685 Disease 6 R-HSA-1430728 Metabolism 5 R-HSA-392499 Metabolism of proteins 5
Partners
FYNGRB2INSRMAPK8PIK3R1PTENRAB5ATRIM72

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 IRS-1 was cloned and identified as the principal cytoplasmic substrate of the insulin receptor tyrosine kinase. It contains over ten potential tyrosine phosphorylation sites (six in Tyr-Met-X-Met motifs), undergoes multisite tyrosine phosphorylation upon insulin stimulation, and acts as a multisite 'docking' protein that binds PI3K and other signaling molecules containing SH2 and SH3 domains. Molecular cloning, in vitro kinase assays, co-immunoprecipitation Nature High 1648180
1992 PI3K (p85 subunit) is activated by binding via its SH2 domains to tyrosine-phosphorylated YXXM motifs on IRS-1. This interaction requires IRS-1 tyrosine phosphorylation and is competitively inhibited by phosphopeptides containing YXXM sequences. Overexpression of IRS-1 potentiates insulin-stimulated PI3K activation. Co-immunoprecipitation, in vitro reconstitution with recombinant proteins, synthetic peptide competition, overexpression in CHO cells The EMBO Journal High 1332046 1380456
1992 The YMXM motif defines substrate specificity for the insulin receptor kinase within IRS-1. Six YMXM-containing peptides are phosphorylated with greatest efficiency (Km 24–92 µM), with a strong preference for methionine at the Y+1 and Y+3 positions. Phosphorylated YMXM sequences serve as recognition motifs for SH2 domain-containing proteins. In vitro kinase assay with synthetic peptides, site-directed mutagenesis of peptide sequences Proceedings of the National Academy of Sciences of the United States of America High 1312712
1992 Insulin receptor directly phosphorylates IRS-1 exclusively on tyrosine residues in vitro. IRS-1 is basally phosphorylated on serine/threonine residues before insulin stimulation. IRS-1 associates with the insulin receptor and with PI3K during insulin stimulation in a manner that is both insulin-sensitive and overexpression-responsive. In vitro kinase assay with baculovirus-produced IRS-1, immunofluorescence, co-immunoprecipitation in CHO cells The Journal of biological chemistry High 1385403
1993 GRB2 (SH2/SH3 adaptor) forms a stable complex with tyrosine-phosphorylated IRS-1 after insulin stimulation via its SH2 domain binding to a YV/IN motif on IRS-1. Both GRB2 and PI3K can simultaneously bind distinct phosphotyrosine regions on the same IRS-1 molecule, suggesting IRS-1 serves as a core for a large signaling complex linking insulin to Ras activation. Co-immunoprecipitation, yeast two-hybrid, in vitro binding assays The EMBO Journal High 8491186
1993 IRS-1 tyrosine phosphorylation and PI3K activity are required in the signaling pathway leading to insulin-stimulated GLUT4 translocation. Mutation of insulin receptor Tyr972 reduces IRS-1 tyrosine phosphorylation and GLUT4 translocation; PI3K inhibitor wortmannin blocks insulin-stimulated PI3K activity and GLUT4 translocation. Stable expression of mutant insulin receptor, wortmannin inhibition, GLUT4 surface detection assay Biochemical and biophysical research communications High 8396927
1993 Casein kinase II phosphorylates IRS-1 on serine residues in vitro and in cells, with Thr-502 identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. Approximately 22% of casein kinase II sites on IRS-1 overlap with insulin-sensitive phosphopeptides in intact cells. In vitro kinase assay, 2D phosphopeptide mapping, Edman degradation, automated amino acid sequencing, phosphoamino acid analysis The Journal of biological chemistry High 8349691
1993 Insulin stimulates the degradation of IRS-1 protein in 3T3-L1 adipocytes at a rate approximately 10-fold faster than basal cells. This degradation is post-transcriptional (IRS-1 mRNA is unchanged), occurs in a cycloheximide- and actinomycin D-insensitive manner, and is not inhibited by chloroquine, suggesting extra-lysosomal proteolysis. 35S-Met pulse-chase labeling, northern blot, chloroquine/cycloheximide treatment, 3T3-L1 adipocytes Biochemical and biophysical research communications Medium 8382493
1994 IRS-1-deficient mice (IRS-1 knockout) show no IRS-1 phosphorylation or IRS-1-associated PI3K activity, exhibit 50% intrauterine growth reduction, impaired glucose tolerance, and decreased insulin/IGF-1-stimulated glucose uptake. A compensatory alternative substrate, IRS-2, was discovered in these mice as a new tyrosine-phosphorylated protein that binds PI3K. Targeted gene disruption in mice, immunoprecipitation, PI3K activity assay, glucose tolerance and uptake measurements Nature High 7526222
1994 IRS-1 is widely distributed in neurons throughout the adult rat CNS (cortex, hippocampus, hypothalamus, basal ganglia, cerebellum), where it co-localizes with insulin receptor, IGF-I receptor, and PI3K, establishing that IRS-1-based insulin/IGF-1 signaling operates in brain neurons. Immunoprecipitation, Western blotting, immunocytochemistry in rat brain sections The Journal of neuroscience Medium 7965046
1996 The pleckstrin homology (PH) domain of IRS-1 (IH1 region) is essential for insulin-stimulated tyrosine phosphorylation and downstream PI3K/p70S6K activation, especially at low insulin receptor levels. The PTB domain (IH2 region) improves coupling but is not required at high receptor expression. Together, the PH and PTB domains cooperatively couple IRS-1 to the insulin receptor. Deletion mutagenesis, stable expression in 32D cells, immunoprecipitation, PI3K activity assay, peptide competition The Journal of biological chemistry High 8798677
1996 Fyn tyrosine kinase (p59fyn) binds IRS-1 via its SH2 domain at phosphorylated Tyr895 and Tyr1172 (in YXX(L/I) motifs), forming a distinct signaling complex during insulin stimulation. Grb-2 is largely excluded from IRS-1 complexes containing p59fyn, whereas Grb-2 and p85 co-exist in the same IRS-1 complex. Fyn phosphorylates a unique cohort of tyrosine residues on IRS-1 compared to the insulin receptor. Expression library screening with [32P]IRS-1 probe, co-immunoprecipitation, site-directed mutants, in vitro kinase assay The Journal of biological chemistry High 8631859
1996 The IGF-I receptor directly interacts with IRS-1 through its intracellular domain in a tyrosine kinase-dependent manner. IRS-1 residues 160–516 are sufficient for strong interaction with the IGF-I receptor intracellular domain. The interaction requires active receptor kinase. Yeast two-hybrid (interaction trap) system, reporter gene activation (LacZ and LEU2), Western blotting Molecular endocrinology Medium 8776723
1999 CHICO, the Drosophila homolog of vertebrate IRS1-4, is essential for cell size and organismal growth control. chico mutant flies are less than half normal size due to fewer and smaller cells, with chico-deficient cells showing autonomous growth defects. This establishes a conserved role for IRS family proteins in controlling cell size, cell number, and metabolism downstream of the insulin receptor. Genetic loss-of-function (chico mutants), mosaic analysis, cell size measurements Cell High 10399915
1999 In IRS-1 deficient brown adipocytes, insulin-stimulated IRS-1-associated PI3K activity and downstream Akt activation are absent, while IRS-2-associated PI3K activity is compensatorily enhanced. Despite this compensation, Akt activation is reduced by 92% and insulin-stimulated lipid synthesis is completely abolished, establishing IRS-1/PI3K/Akt as an essential requirement for insulin-stimulated lipid synthesis. IRS-1 knockout cell lines (immortalized brown adipocytes), PI3K activity assay, Akt kinase assay, cytosolic lipid quantification Diabetes High 10535444
2000 JNK associates directly with IRS-1 and phosphorylates Ser307 (rat/mouse; equivalent to Ser312 in human) in IRS-1. This phosphorylation is the major site mediating TNFα-induced inhibition of insulin-stimulated tyrosine phosphorylation of IRS-1. Mutation of Ser307 to alanine eliminates JNK phosphorylation and abrogates TNFα inhibitory effects on IRS-1. Co-immunoprecipitation of endogenous JNK with IRS-1, in vitro kinase assay, site-directed mutagenesis (S307A), TNFα and anisomycin stimulation The Journal of biological chemistry High 10722755
2001 Phosphorylation of IRS-1 at Ser307 (rat; Ser312 in human) by JNK1 disrupts the interaction between the insulin receptor catalytic domain and the IRS-1 PTB domain, blocking insulin-stimulated PI3K and MAPK signaling. This establishes inhibition of PTB domain function as a mechanism for serine phosphorylation-mediated insulin resistance. Yeast tri-hybrid assay, phosphospecific antibody detection, 32D myeloid cell expression system, PI3K and MAPK activation assays The Journal of biological chemistry High 11606564
2001 TNFα and insulin/IGF-1 stimulate phosphorylation of IRS-1 at Ser307 via distinct kinase pathways: TNFα-stimulated phosphorylation is blocked by PD98059 (MEK inhibitor), while insulin-stimulated Ser307 phosphorylation is blocked by wortmannin/LY294002 (PI3K inhibitors). This reveals both heterologous and feedback (autologous) phosphorylation converging on Ser307. Phosphospecific polyclonal antibody (αpSer307), pathway inhibitor pharmacology in 3T3-L1 cells and muscle tissue, hyperinsulinemic clamp in humans The Journal of clinical investigation High 11160134
2002 SOCS1 and SOCS3 bind IRS-1 and IRS-2 and target them for ubiquitin-mediated proteasomal degradation via the elongin BC E3 ubiquitin ligase complex. Mutations in the SOCS box that abolish elongin BC interaction prevent IRS-1/2 ubiquitination and degradation. Adenoviral SOCS1 expression in mouse liver dramatically reduces hepatic IRS-1/2 protein and causes glucose intolerance. Co-immunoprecipitation of endogenous proteins, ubiquitination assay, SOCS box mutants, adenoviral overexpression in mouse liver, glucose tolerance testing The Journal of biological chemistry High 12228220
2002 IRS-1 and IRS-3 play complementary roles in adipogenesis; mice with combined IRS-1/IRS-3 deficiency develop severe early-onset lipoatrophy with hyperglycemia and insulin resistance, whereas IRS-1/IRS-4 double knockouts are no different from IRS-1 knockouts. Adenoviral leptin delivery reverses the metabolic phenotype. Double knockout mouse generation, glucose/insulin measurements, adenoviral leptin rescue Genes & development High 12502742
2002 JNK mediates feedback inhibition of insulin signaling through direct binding to IRS-1 and phosphorylating Ser307. Insulin-stimulated JNK activation requires PI3K and Grb2 signaling. Direct JNK-IRS-1 interaction (not just activation) is required for Ser307 phosphorylation; cells lacking JNK1/JNK2 show 80% reduction in Ser307 phosphorylation and enhanced insulin-stimulated AKT activation and glucose uptake. JNK1/JNK2 double-knockout MEFs, cell-permeable JNK-binding peptide, co-immunoprecipitation, phosphospecific antibodies, glucose uptake assay The Journal of biological chemistry High 12417588
2002 BCR-ABL tyrosine kinase constitutively associates with and phosphorylates IRS-1 in K562 leukemia cells, leading to IRS-1/PI3K and IRS-1/Grb2 complex formation. Treatment with imatinib markedly attenuates BCR-ABL/IRS-1 association and IRS-1-stimulated PI3K activity. Co-immunoprecipitation, PI3K activity assay, imatinib treatment in K562 cells FEBS letters Medium 12560071
2002 IKK complex directly phosphorylates IRS-1 at Ser312 (human; rat Ser307) and additional serine sites, as shown by in vitro kinase assay with recombinant IRS-1. IKK and IRS-1 interact in intact cells; IKK activation reduces this interaction while increasing IRS-1 serine phosphorylation. IKK inhibitor 15d-PGJ2 and IKK-KO cells block TNFα-induced Ser312 phosphorylation. In vitro kinase assay with recombinant IRS-1 and IKK, co-immunoprecipitation, phosphospecific antibodies, IKK-KO cells, pharmacological inhibition The Journal of biological chemistry High 12351658
2003 Nuclear translocation of IRS-1 (and insulin receptor) occurs in osteoblast-like UMR-106 cells in a time-dependent, insulin-stimulated manner. IRS-1 in the nucleus associates with the nuclear matrix, and insulin stimulates tyrosine phosphorylation of multiple nuclear proteins, suggesting a role in nuclear signaling. Subcellular fractionation, Western blotting, confocal laser scanning microscopy Biochemical and biophysical research communications Medium 12821126
2004 PKCθ phosphorylates IRS-1 at Ser1101, blocking IRS-1 tyrosine phosphorylation and downstream Akt pathway activation. Mutation of Ser1101 to alanine makes IRS-1 insensitive to PKCθ and restores insulin signaling in culture cells. In vitro kinase assay with recombinant PKCθ and IRS-1, site-directed mutagenesis (S1101A), co-immunoprecipitation, phosphospecific antibody The Journal of biological chemistry High 15364919
2004 Constitutive activation of the Rheb/mTOR/S6K cassette (via TSC1 or TSC2 deletion, or ectopic Rheb expression) downregulates IRS-1 and IRS-2 protein levels, causing insulin resistance. This renders Akt completely refractory to activation by IRS-dependent pathways (insulin, IGF-I) but not IRS-independent pathways (PDGF). TSC1/TSC2 genetic deletion, ectopic Rheb expression, immunoprecipitation, Akt activation assays, PI3K assays Current biology High 15380067
2004 PTP1B has the highest specific activity of candidate phosphatases for dephosphorylating tyrosine-phosphorylated IRS-1 in vitro. GRB2 strongly promotes formation of a stable ternary complex between phospho-IRS-1 and catalytically inactive PTP1B, and increases the rate of IRS-1 dephosphorylation by active PTP1B by 2.7–3.9-fold. In vitro dephosphorylation assay with recombinant phosphatases, co-immunoprecipitation, overlay blots with SH2 domain probes The Journal of biological chemistry High 10660596
2005 Hepatic IRS-1 and IRS-2 have complementary roles: IRS-1 knockdown in liver upregulates gluconeogenic enzymes (G6Pase, PEPCK) and HNF4α while decreasing glucokinase; IRS-2 knockdown upregulates lipogenic enzymes (SREBP-1c, FAS) and increases hepatic lipid. Combined IRS-1/IRS-2 knockdown causes systemic insulin resistance, glucose intolerance, and hepatic steatosis with defective Akt-FoxO1 signaling. Adenovirus-mediated shRNA knockdown in mouse liver, gene expression profiling, glucose tolerance testing, hepatic lipid measurements The Journal of clinical investigation High 15711641
2005 Combined liver-specific deletion of IRS-2 on an Irs1-/- background (LKO::Irs1-/-) completely abolishes hepatic Akt-FoxO1 insulin signaling and causes immediate postnatal hyperglycemia and hyperinsulinemia. IRS-1 and IRS-2 together regulate hundreds of hepatic genes governing glucose homeostasis and systemic growth. Conditional knockout mice, Cre-lox system, Western blot for pathway components, hepatic gene expression profiling, metabolic measurements The Journal of clinical investigation High 16374520
2005 Mitochondrial density is 38% lower in muscle of insulin-resistant offspring of type 2 diabetic parents, associated with 50% increases in IRS-1 Ser312 and Ser636 phosphorylation and ~60% reduction in insulin-stimulated Akt activation. This links mitochondrial dysfunction → intramyocellular lipid accumulation → serine kinase cascade → IRS-1 inhibitory phosphorylation. Electron microscopy of muscle biopsies, hyperinsulinemic-euglycemic clamp, phosphospecific antibodies for IRS-1 Ser312/Ser636, Akt kinase assay The Journal of clinical investigation High 16284649
2006 Myo1c (myosin motor protein) and its receptor NEMO/IKKγ cooperatively facilitate TNFα-induced phosphorylation of IRS-1 at Ser307. NEMO accumulates in membrane ruffles and interacts with IRS-1 in an insulin-, actin-, and Myo1c-dependent manner. Dominant-inhibitory Myo1c or NEMO lacking the IKKβ-binding domain blocks TNFα-induced Ser307 phosphorylation. Co-immunoprecipitation, dominant-negative Myo1c expression, NEMO deletion mutants, siRNA knockdown, glucose uptake assay The Journal of cell biology Medium 16754954
2006 IRS-1 suppression in PyV-MT mammary tumors developing in Irs1-/- mice enhances metastatic spread in a cell-autonomous manner, associated with elevated IRS-2 function and enhanced PI3K/Akt/mTOR activity. IRS-1 loss also increases VEGF expression and tumor microvessel density. In wild-type metastatic tumors, IRS-1 is inactivated by serine phosphorylation, identifying IRS-1 as a metastasis suppressor. Irs1-/- transgenic mouse model, orthotopic transplant, siRNA-mediated IRS-2 knockdown rescue, phosphospecific antibodies, VEGF ELISA, microvessel density quantification Molecular and cellular biology High 17030605
2009 Inhibition of PTP1B (genetic or pharmacological with resveratrol) in IRS2-/- mice restores IRS-1-mediated PI3K/Akt/FoxO1 signaling in liver, demonstrating that PTP1B controls the phosphorylation state of the insulin receptor and thereby determines sensitivity to insulin and the relative contributions of IRS-1 vs IRS-2. IRS2-/-/PTP1B-/- double knockout mice, resveratrol treatment, co-immunoprecipitation of PTP1B with IR, PI3K/Akt/FoxO1 signaling in isolated hepatocytes Diabetes High 20028942
2009 IRS1 transcription is directly activated by β-catenin/TCF signaling via TCF consensus binding elements in the IRS1 first intron and downstream of the transcriptional start site. IRS1 function is required for efficient de novo neoplastic transformation by β-catenin in RK3E cells. Microarray-based expression profiling, reporter assay for β-catenin/TCF binding elements, shRNA-mediated IRS1 knockdown, transformation assay The Journal of biological chemistry Medium 19843521
2011 Constitutive IRS-1 expression in L6 myoblasts blocks myogenic differentiation by maintaining sustained PI3K/Akt activation that phosphorylates FoxO1, excluding it from the nucleus. Nuclear FoxO1 localization is required for the myogenic program; a dominant-interfering FoxO1 mutant also blocks differentiation. Stable expression of IRS-1 in L6 cells, PI3K/Akt/FoxO1 phosphorylation assays, confocal microscopy of FoxO1 localization, dominant-interfering FoxO1 construct PloS one Medium 21991327
2012 MEMO1 (mediator of ErbB2-driven cell motility 1) directly binds IRS-1 and activates downstream PI3K/Akt signaling, leading to upregulation of Snail1 and induction of epithelial-mesenchymal transition. MEMO1 overexpression also promotes anchorage-independent growth and metastatic potential. Co-immunoprecipitation, knockdown and overexpression studies, EMT marker expression, soft-agar assay Oncogene Medium 22824790
2013 MG53 is a RING-domain ubiquitin E3 ligase that ubiquitinates IRS-1 with the help of E2-conjugating enzyme UBE2H, negatively regulating skeletal myogenesis and insulin signaling. Disruption of MG53 E3-ligase function abolishes IRS-1 ubiquitination and enhances myogenesis. MG53-/- mice have elevated IRS-1 and are protected from high-fat diet-induced insulin resistance. Ubiquitination assay with MG53 and UBE2H, E3-ligase domain mutants, MG53-/- mice, co-immunoprecipitation, high-fat diet challenge Nature communications High 23965929
2013 Heart-specific IRS1/IRS2 double knockout (H-DKO) mice develop cardiac apoptosis, fibrosis, and failure with diminished Akt-FoxO1 signaling and impaired cardiac metabolic gene expression. Chronic insulin exposure in cardiomyocytes reduces IRS1 and IRS2 protein via activation of p38α MAPK, establishing p38α as a mediator of cardiac IRS1/2 degradation during insulin resistance. Heart-specific conditional double KO mice, neonatal rat cardiomyocyte culture, p38α inhibitor, echocardiography, cardiac gene expression profiling Diabetes High 24159000
2013 Nexilin (F-actin binding protein) preferentially associates with IRS-1 (not IRS-2) under basal conditions in L6 myotubes, tethering IRS-1 to actin-rich structures. Insulin induces disassembly of the nexilin-IRS-1 complex. Nexilin silencing enhances p85 recruitment to IRS-1, increases PI(3,4,5)P3 formation, and augments AKT activation and glucose uptake; nexilin overexpression has opposite effects. Co-immunoprecipitation, siRNA knockdown, overexpression, latrunculin B treatment, PI3K activity assay, glucose uptake measurement PloS one Medium 23383252
2014 PTEN is a protein tyrosine phosphatase that selectively dephosphorylates IRS-1. NEDD4 (a PTEN ubiquitin ligase) supports IGF/insulin signaling by promoting PTEN degradation; NEDD4 deletion causes defective IRS-1 and AKT phosphorylation that is rescued by PTEN ablation. Direct biochemical analysis and cellular reconstitution confirm PTEN's IRS-1 phosphatase activity. Direct in vitro phosphatase assay with recombinant PTEN and IRS-1, NEDD4 knockout and PTEN knockout genetic rescue, cellular reconstitution Nature structural & molecular biology High 24814346
2019 ATG16L1 deficiency causes proteasomal IRS1 degradation via the KLHL9/KLHL13/CUL3 E3 ubiquitin ligase complex, leading to insulin resistance. KLHL9 and KLHL13 (Kelch-like proteins) interact with IRS1 and, with CUL3, promote its ubiquitination. Knockdown of Klhl9, Klhl13, or Cul3 restores IRS1 expression and insulin signaling in ATG16L1 KO cells. BioID proximity labeling, co-immunoprecipitation, siRNA knockdown, proteasome inhibitor treatment, ATG16L1 KO MEFs The Journal of biological chemistry High 31515271
2019 TAZ (transcriptional coactivator with PDZ-binding motif) upregulates IRS1 transcription by physically interacting with c-Jun and Tead4 to form a transcriptional complex at the IRS1 promoter. Muscle-specific TAZ knockout mice show significantly decreased IRS1 expression and insulin sensitivity. Wnt signaling induces IRS1 expression via TAZ in muscle cells. Muscle-specific TAZ KO mice, co-immunoprecipitation of TAZ/c-Jun/Tead4 complex, IRS1 promoter reporter assay, glucose uptake measurement, GLUT4 translocation assay Nature communications High 30679431
2019 PGC1A determines the IRS1:IRS2 ratio in hepatocytes by simultaneously driving IRS2 expression (via CREB downstream of glucagon) and suppressing IRS1 expression. This IRS1/IRS2 ratio shift modulates insulin-stimulated AKT phosphorylation and glucose production, revealing PGC1A as a counterregulatory factor in hepatic insulin signaling. Gain- and loss-of-function PGC1A adenoviral models in primary mouse hepatocytes, CREB inhibition, glucose production assay, IRS1/IRS2 protein/mRNA quantification Proceedings of the National Academy of Sciences of the United States of America Medium 30770439
2020 Rab5a (endosome biogenesis regulator) directly interacts with IRS-1 in a GTP-dependent manner, with interaction enhanced upon IGF-1 activation. Critical interaction residues are Arg207/Arg222 of IRS-1 and Tyr82/Tyr89/Tyr90 of Rab5a. Rab5a modulates IRS-1 activation by coordinating IRS-1 association with IGFR and regulating IRS-1 intracellular membrane targeting. Myogenic Rab5a deletion impairs IGF/AKT-mTOR signaling and muscle regeneration. Co-immunoprecipitation, GTP-loading assay, site-directed mutagenesis of interaction residues, conditional Rab5a KO mice, AKT-mTOR phosphorylation assays, muscle regeneration histology Cell death and differentiation High 32051546
2022 Cathepsin K (CTSK) promotes IRS-1 ubiquitination and degradation in cancer cachexia-induced muscle atrophy. CTSK selectively acts on IRS-1 in the region of amino acids 268–574, cleaves IRS-1, and causes its ubiquitination-dependent degradation. CTSK deletion mitigates IRS-1 loss and preserves skeletal muscle mass and AKT-mTOR signaling. Co-immunoprecipitation, IRS-1 domain truncation co-transfection, IRS-1 ubiquitin assay, CTSK-/- knockout mice, Lewis lung carcinoma cachexia model Journal of cachexia, sarcopenia and muscle Medium 35098692
2024 A region in human IRS-1 directly C-terminal to the PTB domain (termed the PIR domain) contains key serine phosphorylation sites (Ser307, Ser312, Ser315, Ser323). The unphosphorylated PTB-PIR binds stronger to the insulin receptor than the PTB domain alone; phosphorylation at these PIR serines abrogates IR binding as shown by surface plasmon resonance. The PIR domain contacts the N-terminal lobe and hinge region of the IR kinase domain (hydrogen-deuterium exchange MS), and may protect IR from PTP1B-mediated dephosphorylation. Surface plasmon resonance, hydrogen-deuterium exchange mass spectrometry, site-directed mutagenesis (Ser-to-Glu phosphomimetics), insulin signaling in cells expressing mutant IRS-1 Proceedings of the National Academy of Sciences of the United States of America High 38625937
2024 PYCR1 regulates IRS1 transcriptional activity via H3K18 lactylation of the IRS1 histone promoter region. PYCR1 knockout/inhibition reduces glycolysis and H3K18 lactylation at the IRS1 promoter, thereby suppressing IRS1 expression and downstream PI3K/AKT/mTOR and MAPK/ERK pathways in liver cancer cells. ChIP assay for H3K18 lactylation at IRS1 promoter, transcriptome sequencing, metabolomics, PYCR1 KO in xenograft and lung metastasis models Clinical and translational medicine Medium 39422696

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2873 20686565
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2013 Discovery and refinement of loci associated with lipid levels. Nature genetics 2409 24097068
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1991 Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 1449 1648180
2010 Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature genetics 1401 20581827
2000 The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). The Journal of biological chemistry 1179 10722755
1994 Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 1066 7526222
1992 Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. The EMBO journal 963 1380456
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
2007 Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nature biotechnology 858 17721511
2014 Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nature genetics 834 24509480
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2001 Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. The Journal of biological chemistry 779 11606564
2012 Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 776 22869320
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2002 SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. The Journal of biological chemistry 702 12228220
2005 Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 690 15733744
1993 The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. The EMBO journal 689 8491186
2004 Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Current biology : CB 669 15380067
1999 Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell 669 10399915
2012 A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nature genetics 661 22581228
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2005 Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. The Journal of clinical investigation 639 16284649
2002 Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. The Journal of biological chemistry 594 12351658
2005 A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 568 16273093
2001 Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. The Journal of clinical investigation 497 11160134
2004 Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology 471 15604215
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1992 IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. Proceedings of the National Academy of Sciences of the United States of America 433 1332046
1997 ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene 417 9174053
2012 Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. PLoS genetics 400 22479202
2003 The role of PI3K in immune cells. Nature immunology 391 12660731
2004 Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. Current biology : CB 386 15324660
1994 Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. Molecular and cellular biology 351 7935386
2002 c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. The Journal of biological chemistry 346 12417588
2000 Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein. The Journal of biological chemistry 346 10660596
2013 Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. PLoS genetics 339 23754948
1992 Expression and function of IRS-1 in insulin signal transmission. The Journal of biological chemistry 293 1385403
1994 The IRS-1 signaling system. Trends in biochemical sciences 291 8048169
1993 Insulin-stimulated GLUT4 translocation is relevant to the phosphorylation of IRS-1 and the activity of PI3-kinase. Biochemical and biophysical research communications 289 8396927
2004 Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). The Journal of biological chemistry 277 15364919
2005 Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. The Journal of clinical investigation 215 15711641
2008 The cell growth suppressor, mir-126, targets IRS-1. Biochemical and biophysical research communications 202 18834857
2005 Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. The Journal of clinical investigation 176 16374520
1992 YMXM motifs of IRS-1 define substrate specificity of the insulin receptor kinase. Proceedings of the National Academy of Sciences of the United States of America 174 1312712
2013 MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling. Nature communications 146 23965929
2013 Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38α MAPK during insulin resistance. Diabetes 142 24159000
1996 The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. The Journal of biological chemistry 141 8798677
1994 Insulin receptor substrate-1 (IRS-1) distribution in the rat central nervous system. The Journal of neuroscience : the official journal of the Society for Neuroscience 111 7965046
1996 The Fyn tyrosine kinase binds Irs-1 and forms a distinct signaling complex during insulin stimulation. The Journal of biological chemistry 110 8631859
1996 Evidence for the direct interaction of the insulin-like growth factor I receptor with IRS-1, Shc, and Grb10. Molecular endocrinology (Baltimore, Md.) 105 8776723
2014 PTEN is a protein tyrosine phosphatase for IRS1. Nature structural & molecular biology 102 24814346
2019 CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling. EMBO reports 101 31468695
2007 Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 100 17575262
2009 Inhibition of PTP1B restores IRS1-mediated hepatic insulin signaling in IRS2-deficient mice. Diabetes 99 20028942
1993 Insulin stimulates the degradation of IRS-1 in 3T3-L1 adipocytes. Biochemical and biophysical research communications 97 8382493
2002 Lipoatrophic diabetes in Irs1(-/-)/Irs3(-/-) double knockout mice. Genes & development 96 12502742
2019 PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin. Proceedings of the National Academy of Sciences of the United States of America 95 30770439
2004 Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 93 15247132
2007 Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis. Cell cycle (Georgetown, Tex.) 86 17361103
1998 Role of binding proteins to IRS-1 in insulin signalling. Molecular and cellular biochemistry 86 9609110
2012 Downregulation of miR-145 associated with cancer progression and VEGF transcriptional activation by targeting N-RAS and IRS1. Biochimica et biophysica acta 83 23201159
2018 Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers. International journal of obesity (2005) 82 29717275
1994 The IRS-1 signaling system. Current opinion in genetics & development 77 8193539
2014 MicroRNA-145 suppresses hepatocellular carcinoma by targeting IRS1 and its downstream Akt signaling. Biochemical and biophysical research communications 76 24690171
2009 Essential role for either TRS1 or IRS1 in human cytomegalovirus replication. Journal of virology 74 19211736
2006 Suppression of insulin receptor substrate 1 (IRS-1) promotes mammary tumor metastasis. Molecular and cellular biology 74 17030605
2007 GLP-1 amplifies insulin signaling by up-regulation of IRbeta, IRS-1 and Glut4 in 3T3-L1 adipocytes. Endocrine 71 17992607
1993 Phosphorylation of the insulin receptor substrate IRS-1 by casein kinase II. The Journal of biological chemistry 71 8349691
2012 MEMO1, a new IRS1-interacting protein, induces epithelial-mesenchymal transition in mammary epithelial cells. Oncogene 66 22824790
2021 Carpachromene Ameliorates Insulin Resistance in HepG2 Cells via Modulating IR/IRS1/PI3k/Akt/GSK3/FoxO1 Pathway. Molecules (Basel, Switzerland) 65 34946711
2016 miR-195 inhibits tumor growth and angiogenesis through modulating IRS1 in breast cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 62 27133044
2006 Myosin motor Myo1c and its receptor NEMO/IKK-gamma promote TNF-alpha-induced serine307 phosphorylation of IRS-1. The Journal of cell biology 57 16754954
2012 TNFα and SOCS3 regulate IRS-1 to increase retinal endothelial cell apoptosis. Cellular signalling 56 22266116
2012 Diosgenin ameliorates palmitate-induced endothelial dysfunction and insulin resistance via blocking IKKβ and IRS-1 pathways. Atherosclerosis 56 22766331
2003 IRS-1 regulation in health and disease. IUBMB life 56 14584587
2012 Nuclear IRS-1 and cancer. Journal of cellular physiology 54 22454254
2019 TNF-α Downregulation Modifies Insulin Receptor Substrate 1 (IRS-1) in Metabolic Signaling of Diabetic Insulin-Resistant Hepatocytes. Mediators of inflammation 49 30863203
2020 Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes. Scientific reports 48 32238837
2020 Pro-Inflammatory Markers Negatively Regulate IRS1 in Endometrial Cells and Endometrium from Women with Obesity and PCOS. Reproductive sciences (Thousand Oaks, Calif.) 46 32046436
1993 Immunocytochemical detection of insulin receptor substrate-1 (IRS-1) in rat brain: colocalization with phosphotyrosine. Regulatory peptides 46 7505468
2024 PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification. Clinical and translational medicine 45 39422696
2009 IRS1 regulation by Wnt/beta-catenin signaling and varied contribution of IRS1 to the neoplastic phenotype. The Journal of biological chemistry 44 19843521
1999 Insulin signaling in insulin receptor substrate (IRS)-1-deficient brown adipocytes: requirement of IRS-1 for lipid synthesis. Diabetes 44 10535444
2019 TAZ couples Hippo/Wnt signalling and insulin sensitivity through Irs1 expression. Nature communications 43 30679431
2002 Cbl, IRS-1, and IRS-2 mediate effects of rosiglitazone on PI3K, PKC-lambda, and glucose transport in 3T3/L1 adipocytes. Endocrinology 43 11956152
2004 Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signalling. Annales d'endocrinologie 42 15122091
2005 Downregulation of IRS-1 expression causes inhibition of corneal angiogenesis. Investigative ophthalmology & visual science 41 16249482
2019 MiR-30a regulates cancer cell response to chemotherapy through SNAI1/IRS1/AKT pathway. Cell death & disease 40 30770779
2019 Hesperidin ameliorates insulin resistance by regulating the IRS1-GLUT2 pathway via TLR4 in HepG2 cells. Phytotherapy research : PTR 40 31074547
2018 Cinnamaldehyde ameliorates STZ-induced rat diabetes through modulation of IRS1/PI3K/AKT2 pathway and AGEs/RAGE interaction. Naunyn-Schmiedeberg's archives of pharmacology 40 30460386
2017 MiR-30e inhibits tumor growth and chemoresistance via targeting IRS1 in Breast Cancer. Scientific reports 40 29162879
2020 Rab5a activates IRS1 to coordinate IGF-AKT-mTOR signaling and myoblast differentiation during muscle regeneration. Cell death and differentiation 39 32051546
2018 Identification of microRNA that represses IRS-1 expression in liver. PloS one 38 29364977
2023 Vitamin D supplementation alleviates insulin resistance in prediabetic rats by modifying IRS-1 and PPARγ/NF-κB expressions. Frontiers in endocrinology 37 37324274
2015 Carrageenan Inhibits Insulin Signaling through GRB10-mediated Decrease in Tyr(P)-IRS1 and through Inflammation-induced Increase in Ser(P)307-IRS1. The Journal of biological chemistry 37 25784556
2021 MicroRNA-21 deficiency suppresses prostate cancer progression through downregulation of the IRS1-SREBP-1 signaling pathway. Cancer letters 36 34610416
2017 MicroRNA-126 inhibits cell viability and invasion in a diabetic retinopathy model via targeting IRS-1. Oncology letters 36 28943945
2018 Upregulation of IRS1 Enhances IGF1 Response in Y537S and D538G ESR1 Mutant Breast Cancer Cells. Endocrinology 35 29029116
2019 Deficiency of the autophagy gene ATG16L1 induces insulin resistance through KLHL9/KLHL13/CUL3-mediated IRS1 degradation. The Journal of biological chemistry 34 31515271
2014 Insulin receptor substrate-1 (IRS-1) Gly927Arg: correlation with gestational diabetes mellitus in Saudi women. BioMed research international 34 24695443
2000 Cooperative transformation of 32D cells by the combined expression of IRS-1 and V-Ha-Ras. Oncogene 34 10918581
2017 TGFβ/Smad3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells. PloS one 30 28414818
2016 miR-144 suppresses the growth and metastasis of laryngeal squamous cell carcinoma by targeting IRS1. American journal of translational research 30 27069535
2019 Fucoidan⁻Fucoxanthin Ameliorated Cardiac Function via IRS1/GRB2/ SOS1, GSK3β/CREB Pathways and Metabolic Pathways in Senescent Mice. Marine drugs 29 30669571
2020 Berberine promotes peri-implant osteogenesis in diabetic rats by ROS-mediated IRS-1 pathway. BioFactors (Oxford, England) 28 33233028
2007 Insulin receptor substrate (IRS)-1 regulates murine embryonic stem (mES) cells self-renewal. Journal of cellular physiology 28 17620314
2003 BCR-ABL binds to IRS-1 and IRS-1 phosphorylation is inhibited by imatinib in K562 cells. FEBS letters 28 12560071
2021 miR-410-3P inhibits adipocyte differentiation by targeting IRS-1 in cancer-associated cachexia patients. Lipids in health and disease 26 34563222
2020 MiRNA-7 enhances erlotinib sensitivity of glioblastoma cells by blocking the IRS-1 and IRS-2 expression. The Journal of pharmacy and pharmacology 26 32026479
2015 MicroRNA-128 suppresses cell growth and metastasis in colorectal carcinoma by targeting IRS1. Oncology reports 26 26352220
2022 Estrogen Protects Cardiac Function and Energy Metabolism in Dilated Cardiomyopathy Induced by Loss of Cardiac IRS1 and IRS2. Circulation. Heart failure 25 35579013
2024 The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction. Proceedings of the National Academy of Sciences of the United States of America 24 38625937
2023 Esculin ameliorates obesity-induced insulin resistance by improving adipose tissue remodeling and activating the IRS1/PI3K/AKT/GLUT4 pathway. Journal of ethnopharmacology 24 37778516
2021 FoxP3-miR-150-5p/3p suppresses ovarian tumorigenesis via an IGF1R/IRS1 pathway feedback loop. Cell death & disease 24 33723215
2016 miR-628 Promotes Burn-Induced Skeletal Muscle Atrophy via Targeting IRS1. International journal of biological sciences 24 27766036
2012 Association of IRS-1 and IRS-2 genes polymorphisms with polycystic ovary syndrome: a meta-analysis. Endocrine journal 24 22523112
2003 Nuclear matrix association of insulin receptor and IRS-1 by insulin in osteoblast-like UMR-106 cells. Biochemical and biophysical research communications 24 12821126
2013 Nexilin, a cardiomyopathy-associated F-actin binding protein, binds and regulates IRS1 signaling in skeletal muscle cells. PloS one 23 23383252
2022 Cathepsin K activity controls cachexia-induced muscle atrophy via the modulation of IRS1 ubiquitination. Journal of cachexia, sarcopenia and muscle 22 35098692
2020 NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells. Signal transduction and targeted therapy 22 32296029
2020 Regulation of IRS-1, insulin signaling and glucose uptake by miR-143/145 in vascular smooth muscle cells. Biochemical and biophysical research communications 22 32560812
2018 IRS-1 increases TAZ expression and promotes osteogenic differentiation in rat bone marrow mesenchymal stem cells. Biology open 22 30530508
2012 Polymorphisms in the IRS-1 and PPAR-γ genes and their association with polycystic ovary syndrome among South Indian women. Gene 22 22575725
2012 The transcriptional coactivators p/CIP and SRC-1 control insulin resistance through IRS1 in obesity models. PloS one 22 22859932
2011 Constitutive expression of insulin receptor substrate (IRS)-1 inhibits myogenic differentiation through nuclear exclusion of Foxo1 in L6 myoblasts. PloS one 22 21991327
2010 Spontaneous Irs1 passenger mutation linked to a gene-targeted SerpinB2 allele. Proceedings of the National Academy of Sciences of the United States of America 22 20837540
2002 Variations in insulin secretion in carriers of gene variants in IRS-1 and -2. Diabetes 22 11872698
2017 IGF1 regulates RUNX1 expression via IRS1/2: Implications for antler chondrocyte differentiation. Cell cycle (Georgetown, Tex.) 21 28055425