Affinage

IRS1

Insulin receptor substrate 1 · UniProt P35568

Length
1242 aa
Mass
131.6 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRS-1 is a cytoplasmic scaffold/adaptor protein that serves as the principal proximal substrate of the insulin and IGF-1 receptor tyrosine kinases, coupling receptor activation to PI3K-driven metabolic and mitogenic signaling (PMID:1385403, PMID:1380456, PMID:1332046). Following receptor engagement, IRS-1 is phosphorylated exclusively on tyrosines within YMXM motifs that define insulin-receptor substrate specificity; these phosphotyrosines then dock the SH2 domains of the p85 regulatory subunit to recruit and activate PI3K, and also engage Grb2 and SHP-2 to relay downstream signals (PMID:1380456, PMID:1332046, PMID:1312712, PMID:11147812). Receptor coupling depends on the N-terminal PH domain (essential at physiological receptor levels, with the PTB domain enhancing binding) and on a serine-rich PIR region C-terminal to the PTB domain that, together with PTB, mediates high-affinity insulin-receptor binding (PMID:8798677, PMID:38625937). Because IRS-1 sequesters a limited pool of Grb2 from Shc, its abundance helps partition signaling between metabolic and MAP-kinase outputs (PMID:7983051). IRS-1 signaling output is constrained by a dense regulatory network: inhibitory serine/threonine phosphorylation — at Ser307 by ERK- and PI3K-dependent kinases and JNK, at Ser1101 by PKCθ, and within the PIR domain — disrupts receptor coupling and blocks downstream Akt activation (PMID:11160134, PMID:15364919, PMID:38625937); tyrosine dephosphorylation by PTEN (antagonized by NEDD4) and receptor dephosphorylation by PTP1B reverse activating marks (PMID:24814346, PMID:20028942); and IRS-1 protein levels are set by ubiquitin-mediated proteasomal degradation through SOCS1/3–elongin BC, the MG53–UBE2H E3/E2 pair, and cathepsin K–triggered cleavage and degradation (PMID:12228220, PMID:23965929, PMID:35098692). IRS-1 also functions beyond signal transmission: it binds the AP2 clathrin adaptor to delay IGF-IR endocytosis and sustain surface receptor signaling, and interacts with GTP-bound Rab5a to control its membrane targeting and IGF-receptor association (PMID:29661273, PMID:32051546). Genetically, IRS-1 defines an IRS-1-dependent branch of insulin/IGF-1 signaling distinct from IRS-2, with tissue-specific roles in skeletal muscle regeneration, myogenic differentiation, epidermal differentiation, and β-cell ER-stress responses (PMID:7526222, PMID:32051546, PMID:21852229, PMID:17508357, PMID:27378176). IRS1 transcription is controlled by a TAZ/c-Jun/Tead4 complex and by PYCR1-driven H3K18 lactylation at its promoter (PMID:30679431, PMID:39422696).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1992 High

    Established that IRS-1 is a direct insulin-receptor kinase substrate whose tyrosine-phosphorylated YMXM motifs recruit and activate PI3K via p85 SH2 domains, defining the core insulin-signaling relay.

    Evidence In vitro kinase assays with purified IR and recombinant IRS-1, synthetic phosphopeptide competition, SH2 pulldown, PI3K activity assay, and overexpression in CHO cells across independent labs

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

    Open questions at the time
    • Did not enumerate which of the multiple IRS-1 tyrosines are physiologically engaged in vivo
    • Did not resolve stoichiometry of PI3K versus other SH2 effectors on a single IRS-1 molecule
  2. 1994 High

    Genetic knockout separated IRS-1-dependent from IRS-1-independent signaling, showing a paralog (IRS-2) sustains residual PI3K coupling.

    Evidence Targeted IRS-1 knockout mice with PI3K activity assays and glucose uptake measurements

    PMID:7526222

    Open questions at the time
    • Did not define which tissues rely preferentially on IRS-1 versus IRS-2
    • Mechanism of functional redundancy at the molecular level unresolved
  3. 1994 Medium

    Demonstrated that IRS-1 competes with Shc for a limited Grb2 pool, providing a mechanism for partitioning insulin signaling between metabolic and MAP-kinase/mitogenic outputs.

    Evidence Transfection overexpression, reciprocal co-IP, MAP kinase gel-shift, and c-fos reporter assays in a single lab

    PMID:7983051

    Open questions at the time
    • Based on overexpression which may exaggerate competition
    • In vivo relevance of Grb2 sequestration not established
  4. 1996 High

    Mapped the receptor-coupling determinants to the N-terminal PH and PTB domains, with the PH domain essential at physiological receptor levels.

    Evidence Domain deletion mutagenesis and functional reconstitution in 32D cells with PI3K and p70S6K readouts

    PMID:8798677

    Open questions at the time
    • Structural basis of PH-domain receptor coupling not resolved
    • Identity of any PH-domain lipid/protein ligand not defined
  5. 2001 High

    Identified Ser307 as an inhibitory phosphosite engaged by distinct ERK- and PI3K-dependent pathways (and JNK), establishing feedback/cross-talk suppression of IRS-1.

    Evidence Phosphospecific antibody detection in cells, rodent muscle, and human hyperinsulinemic clamp with kinase-inhibitor dissection

    PMID:11160134

    Open questions at the time
    • Precise kinase responsible in each context not fully isolated
    • Quantitative contribution of Ser307 to whole-cell insulin resistance not defined
  6. 2002 High

    Showed IRS-1 abundance is controlled by SOCS1/3-directed ubiquitin-proteasome degradation via the elongin BC ligase, linking cytokine signaling to IRS-1 turnover.

    Evidence Co-IP, ubiquitination assays, SOCS box mutants, and adenoviral expression in mouse liver with glucose tolerance testing

    PMID:12228220

    Open questions at the time
    • Identity of the catalytic E3/E2 components beyond elongin BC scaffolding not fully defined here
    • Lysine acceptor sites on IRS-1 not mapped
  7. 2004 High

    Defined Ser1101 as a PKCθ inhibitory site, providing a lipid/diacylglycerol-responsive route to IRS-1 inactivation.

    Evidence In vitro PKCθ kinase assay, S1101A mutagenesis with functional rescue of insulin signaling in cells

    PMID:15364919

    Open questions at the time
    • Upstream signals activating PKCθ toward IRS-1 in vivo not delineated
    • Interplay with other inhibitory serines not addressed
  8. 2003 Medium

    Connected oncogenic tyrosine kinases to IRS-1, showing BCR-ABL binds and constitutively phosphorylates IRS-1 to drive PI3K and Grb2 complexes.

    Evidence Co-IP, PI3K activity assay, and imatinib treatment in K562 cells

    PMID:12560071

    Open questions at the time
    • Single cell line, single lab
    • Direct versus indirect BCR-ABL–IRS-1 interaction not distinguished
  9. 2001 Medium

    Extended IRS-1 effector coupling to neurotrophin/oncogenic TRK kinases, with IRS-1 required for TRK-T1-driven DNA synthesis.

    Evidence Co-IP, PI3K assay, yeast two-hybrid, and IRS-1-null fibroblast reconstitution

    PMID:11147812

    Open questions at the time
    • Physiological relevance in neuronal contexts not tested
    • Single lab
  10. 2006 Medium

    Linked IRS-1 hyperactivity to tumorigenesis and identified β-catenin as a binding partner in the mammary gland.

    Evidence Mammary-targeted transgenic mice with in vitro and in vivo co-IP for β-catenin

    PMID:17030631

    Open questions at the time
    • Mechanism by which IRS-1–β-catenin binding drives transformation unresolved
    • Overexpression model may not reflect endogenous biology
  11. 2007 Medium

    Distinguished IRS-1 from IRS-2 in epidermal differentiation, showing IRS-1 is specifically required for keratinocyte differentiation.

    Evidence IRS-1 and IRS-2 KO mice with histology and K1 marker analysis

    PMID:17508357

    Open questions at the time
    • Molecular basis of paralog specificity in skin not defined
    • Single lab
  12. 2009 Medium

    Showed PTP1B sets IRS-1 signaling indirectly by dephosphorylating the insulin receptor, with deletion/inhibition restoring hepatic IRS-1 signaling.

    Evidence IRS2-KO/PTP1B-KO double-KO mice, resveratrol inhibition, and hepatic signaling Westerns

    PMID:20028942

    Open questions at the time
    • Action is on the receptor, not IRS-1 directly
    • Single lab
  13. 2011 Medium

    Placed IRS-1 downstream of the Rheb-mTOR/raptor axis in myogenesis via suppression of IRS-1 protein and Ser307 phosphorylation.

    Evidence siRNA epistasis (raptor/Rheb/IRS-1) in C2C12 myoblasts with differentiation and Akt readouts

    PMID:21852229

    Open questions at the time
    • Direct kinase mediating Ser307 in this axis not identified
    • Single cell model
  14. 2013 High

    Identified MG53 as an E3 ligase using UBE2H to ubiquitinate IRS-1, controlling IRS-1 levels in skeletal muscle and insulin signaling.

    Evidence In vitro ubiquitination reconstitution with E2/E3, E3-dead mutant, and MG53-KO mice on metabolic challenge

    PMID:23965929

    Open questions at the time
    • IRS-1 ubiquitin acceptor sites not mapped
    • Tissue selectivity of MG53 action not fully defined
  15. 2013 Medium

    Revealed nexilin as a basal IRS-1 (not IRS-2) binding partner that restrains p85 recruitment, disassembled by insulin.

    Evidence Reciprocal co-IP plus gain/loss of function with PIP3, AKT, and glucose uptake readouts in L6 myotubes

    PMID:23383252

    Open questions at the time
    • Structural basis of nexilin–IRS-1 selectivity unknown
    • Single lab, single cell model
  16. 2013 Medium

    Demonstrated p38α MAPK reduces cardiac IRS-1/IRS-2 protein during chronic insulin exposure, with combined loss causing dilated cardiomyopathy.

    Evidence Heart-specific IRS1/IRS2 double-KO mice, cardiomyocyte chronic insulin treatment, p38 inhibition, echocardiography

    PMID:24159000

    Open questions at the time
    • Mechanism of p38-driven IRS protein loss not detailed
    • Single lab
  17. 2014 High

    Established PTEN as a direct IRS-1 protein-tyrosine phosphatase antagonized by NEDD4, adding a phosphatase arm to IRS-1 regulation.

    Evidence Direct dephosphorylation assay, cellular reconstitution, NEDD4-KO cells, and PTEN-ablation rescue

    PMID:24814346

    Open questions at the time
    • Which IRS-1 phosphotyrosines PTEN targets not mapped
    • Balance between PTEN lipid- and protein-phosphatase activities in vivo unresolved
  18. 2016 Medium

    Detailed an IRS-1 scaffolding role in osteoblasts assembling PKCζ (via p62) and vimentin to drive PTEN tyrosine phosphorylation and AKT-dependent differentiation.

    Evidence Multi-protein co-IP, in vitro kinase assay from immunoprecipitates, and disrupting peptides in primary calvarial osteoblasts

    PMID:26773517

    Open questions at the time
    • Generality beyond osteoblasts not tested
    • Single lab
  19. 2016 Medium

    Showed IRS-1 loss protects β-cells from ER stress apoptosis by reducing spliced XBP-1, attenuating translation, and preserving ER calcium.

    Evidence IRS1-KO and IRS2-KO β-cells with XBP-1 fractionation, polysome profiling, eEF2 phosphorylation, and ER calcium measurements

    PMID:27378176

    Open questions at the time
    • Direct molecular link between IRS-1 and XBP-1 stability not defined
    • Single lab
  20. 2018 High

    Uncovered a non-canonical role: IRS-1 binds AP2 to delay IGF-IR clathrin-mediated endocytosis, converting transient into sustained Akt signaling.

    Evidence Reciprocal co-IP, live-cell imaging of clathrin structures, AP2-binding mutant rescue, and Akt/FoxO readouts

    PMID:29661273

    Open questions at the time
    • AP2-binding motif on IRS-1 not precisely mapped
    • Generality to insulin receptor versus IGF-IR not addressed
  21. 2019 Medium

    Identified transcriptional control of IRS1 by a TAZ/c-Jun/Tead4 complex governing muscle insulin sensitivity downstream of Wnt/APC.

    Evidence Muscle-specific TAZ-KO and APC/TAZ double-KO mice, ChIP/co-IP, promoter reporter, and glucose uptake

    PMID:30679431

    Open questions at the time
    • Direct TAZ binding element on IRS1 promoter not finely mapped
    • Single lab
  22. 2020 High

    Showed GTP-bound Rab5a directly binds IRS-1 to coordinate its membrane targeting and IGF-receptor association, controlling AKT-mTOR signaling in muscle regeneration.

    Evidence Co-IP, GTP-dependent binding, interface-residue mutagenesis, and myogenic Rab5a-KO mice

    PMID:32051546

    Open questions at the time
    • Spatial dynamics of IRS-1 membrane targeting not directly visualized
    • Relationship to AP2-mediated trafficking unresolved
  23. 2022 Medium

    Defined cathepsin K as a protease that cleaves IRS-1 (aa 268–574) to trigger its ubiquitination and degradation, driving muscle cachexia.

    Evidence Co-IP, truncation mapping, ubiquitination assay, and CTSK KO/overexpression in C2C12 and an in vivo tumor model

    PMID:35098692

    Open questions at the time
    • Coupling between cleavage and ubiquitination machinery not detailed
    • Single lab
  24. 2024 High

    Defined the PTB-adjacent PIR domain (Ser307/312/315/323) as a high-affinity receptor-binding module whose serine phosphorylation disrupts IR coupling, unifying inhibitory phosphorylation into a structural mechanism.

    Evidence SPR binding, HDX-MS, and phosphomimetic mutagenesis with signaling readouts in insulin-responsive cells

    PMID:38625937

    Open questions at the time
    • Endogenous kinases acting on individual PIR serines in vivo not fully assigned
    • Structure of the full PTB-PIR–receptor complex not solved
  25. 2024 Medium

    Linked metabolic enzyme PYCR1 to epigenetic activation of IRS1 transcription via H3K18 lactylation in liver cancer.

    Evidence ChIP for H3K18la at the IRS1 promoter, PYCR1 KO, metabolomics, and pathway Westerns

    PMID:39422696

    Open questions at the time
    • Direct enzymology connecting PYCR1 to promoter lactylation not established
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the full set of activating tyrosine and inhibitory serine modifications, phosphatases, ubiquitin ligases, and trafficking partners are integrated on a single IRS-1 molecule in real time remains unresolved.
  • No integrated structural model of IRS-1 with bound receptor and effectors
  • Quantitative hierarchy among competing regulatory inputs undefined
  • Tissue-specific determinants of IRS-1 versus IRS-2 usage incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
AP2GRB2IGF1RINSRPIK3R1PTENRAB5ASOCS1

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 IRS-1 undergoes tyrosine phosphorylation at YXXM motifs upon insulin stimulation and activates PI3K by binding to the SH2 domains of the p85 regulatory subunit; phosphorylated YXXM-containing peptides block this interaction in vitro, and tyrosyl-phosphorylated IRS-1 activates PI3K in anti-p85 immunoprecipitates. In vitro kinase assay, SH2-domain fusion protein pulldown, synthetic phosphopeptide competition, co-immunoprecipitation, PI3K activity assay The EMBO journal / PNAS High 1332046 1380456
1992 YMXM motifs in IRS-1 define substrate specificity of the insulin receptor kinase; the insulin receptor kinase preferentially phosphorylates peptides containing YMXM sequences (with methionine at Y+1 and Y+3), and when phosphorylated these motifs serve as recognition sites for SH2-domain-containing signaling proteins. In vitro peptide substrate kinase assay with synthetic peptides corresponding to IRS-1 tyrosine sites; structure-activity analysis with substituted YMXM peptides Proceedings of the National Academy of Sciences of the United States of America High 1312712
1992 IRS-1 is a direct physiological substrate of the insulin receptor kinase: purified insulin receptor phosphorylates baculovirus-produced IRS-1 exclusively on tyrosine residues in vitro; IRS-1 associates with the insulin receptor during insulin stimulation; and co-expression of insulin receptor and IRS-1 strongly amplifies insulin-stimulated PI3K association and DNA synthesis. In vitro kinase assay with purified IR and recombinant IRS-1, co-immunoprecipitation, immunofluorescence localization, overexpression in CHO cells The Journal of biological chemistry High 1385403
1994 Genetic disruption of IRS-1 in mice abolishes IRS-1 phosphorylation and IRS-1-associated PI3K activity; residual insulin/IGF-1 signaling is mediated by a distinct IRS-2 protein that binds PI3K, establishing IRS-1-dependent and IRS-1-independent pathways. Targeted gene knockout in mice, immunoprecipitation/PI3K activity assay, glucose uptake assays in vivo and in vitro Nature High 7526222
1996 The pleckstrin homology (PH) domain at the IRS-1 N-terminus is the principal link coupling IRS-1 to the insulin receptor; the PTB domain improves coupling but is not essential at high receptor levels, whereas the PH domain is essential at physiological low receptor levels for insulin-stimulated IRS-1 tyrosine phosphorylation, PI3K activity, and p70S6K phosphorylation. Domain deletion mutagenesis, peptide competition binding assays, reconstitution in 32D cells with insulin receptor and IRS-1 deletion mutants, PI3K activity assay The Journal of biological chemistry High 8798677
1994 IRS-1 and Shc compete for a limited cellular pool of Grb2; overexpression of IRS-1 sequesters Grb2 away from Shc, reducing insulin-stimulated MAP kinase activation and c-fos transcription, which proceed predominantly through the Shc-Grb2 pathway. Transfection overexpression, indirect co-immunoprecipitation, MAP kinase gel-shift assay, c-fos transcriptional reporter assay The Journal of biological chemistry Medium 7983051
2001 TNF-α and insulin/IGF-1 stimulate phosphorylation of IRS-1 at Ser307 via distinct kinase pathways: TNF-α acts through a PD98059-sensitive (ERK) pathway, while insulin acts through a PI3K-dependent (LY294002/wortmannin-sensitive) pathway; Ser307 phosphorylation inhibits insulin-stimulated IRS-1 tyrosine phosphorylation. Phosphospecific antibody (αpSer307) detection in cell lines and in vivo (muscle from insulin-injected rodents and human hyperinsulinemic clamp), kinase inhibitor dissection The Journal of clinical investigation High 11160134
2002 SOCS1 and SOCS3 target IRS-1 and IRS-2 for ubiquitin-mediated proteasomal degradation via the elongin BC ubiquitin-ligase complex; SOCS1 binds IRS-1/2 directly, and mutations in the SOCS box (which disrupt elongin BC binding) abrogate ubiquitination and degradation without affecting IRS binding. Co-immunoprecipitation (recombinant and endogenous proteins), ubiquitination assay, SOCS box mutant analysis, adenoviral expression in mouse liver with glucose tolerance testing The Journal of biological chemistry High 12228220
2004 PKCθ phosphorylates IRS-1 at Ser1101, blocking IRS-1 tyrosine phosphorylation and downstream Akt activation; mutation of Ser1101 to alanine makes IRS-1 insensitive to PKCθ and restores insulin signaling. In vitro kinase assay (PKCθ phosphorylation of IRS-1), site-directed mutagenesis (S1101A), overexpression/inhibition in cultured cells, Western blot for tyrosine phosphorylation and Akt activation The Journal of biological chemistry High 15364919
2006 IRS-1 overexpression in the mammary gland causes constitutive IRS-1 phosphorylation, progressive mammary hyperplasia, tumorigenesis, and metastasis in transgenic mice; IRS-1 binds β-catenin in vitro and in vivo, implicating β-catenin signaling in IRS-1-driven tumorigenesis. Mammary-targeted transgenic mice, in vitro and in vivo co-immunoprecipitation for β-catenin binding, histological analysis of tumor phenotype Molecular and cellular biology Medium 17030631
2013 MG53 is an E3 ubiquitin ligase that induces IRS-1 ubiquitination using UBE2H as the E2-conjugating enzyme; disruption of MG53's E3 ligase activity abolishes IRS-1 ubiquitination and enhances skeletal myogenesis and insulin signaling. E3 ligase activity assay, ubiquitination assay with UBE2H, MG53 E3-ligase-dead mutant, MG53 knockout mice (elevated IRS-1 levels), high-fat/high-sucrose diet challenge Nature communications High 23965929
2014 PTEN acts as a protein tyrosine phosphatase that selectively dephosphorylates IRS-1; NEDD4, a PTEN ubiquitin ligase, antagonizes PTEN to support IGF/insulin signaling through IRS-1; ablation of PTEN rescues defective IRS-1 and AKT phosphorylation caused by NEDD4 deletion. Direct biochemical dephosphorylation assay (PTEN acting on IRS-1), cellular reconstitution, NEDD4 knockout cells, PTEN ablation rescue experiments Nature structural & molecular biology High 24814346
2018 IRS-1 interacts with the clathrin adaptor complex AP2 and delays AP2-mediated IGF-IR endocytosis after ligand stimulation by inhibiting recruitment of IGF-IR into clathrin-coated structures; this prolongs IGF-IR surface activity and shifts downstream signaling from transient to sustained Akt activation. An AP2-binding-deficient IRS-1 mutant fails to delay endocytosis. Co-immunoprecipitation (IRS-1/AP2), live-cell imaging, IRS-1 depletion/reconstitution with AP2-binding mutant, clathrin-coated structure tracking, Akt phosphorylation kinetics, FoxO transcriptional reporter eLife High 29661273
2020 Rab5a directly interacts with IRS-1 in a GTP-dependent manner (enhanced by IGF-1 and myogenic differentiation); Rab5a modulates IRS-1 activation by coordinating the IRS-1/IGF receptor association and regulating intracellular membrane targeting of IRS-1, thereby controlling AKT-mTOR signaling and muscle regeneration. Co-immunoprecipitation (endogenous and overexpressed), GTP-dependent binding assay, site-directed mutagenesis (R207/R222 on IRS-1; Y82/Y89/Y90 on Rab5a), myogenic Rab5a-KO mice, AKT-mTOR signaling assays Cell death and differentiation High 32051546
2024 Serine phosphorylations within a region of IRS-1 directly C-terminal to the PTB domain (designated the PIR domain, encompassing Ser307, Ser312, Ser315, and Ser323) abrogate IRS-1 binding to the insulin receptor; the PTB-PIR module binds IR more strongly than PTB alone (by surface plasmon resonance), and PIR phosphomimetic mutations (S→E) decrease IR, IRS-1, and AKT phosphorylation in cells. Surface plasmon resonance (SPR) binding assays, hydrogen-deuterium exchange mass spectrometry (HDX-MS), phosphomimetic mutagenesis (S307E/S312E/S315E/S323E), Western blot of signaling in insulin-responsive cells Proceedings of the National Academy of Sciences of the United States of America High 38625937
2003 BCR-ABL binds to IRS-1 and constitutively phosphorylates it in K562 cells; this is associated with IRS-1/PI3K and IRS-1/Grb2 complex formation; imatinib treatment markedly attenuates BCR-ABL/IRS-1 association and IRS-1-associated PI3K activity. Co-immunoprecipitation, PI3K activity assay, imatinib treatment FEBS letters Medium 12560071
2001 IRS-1 and IRS-2 are tyrosine-phosphorylated substrates of both TrkA and the TRK-T1 oncogene; this phosphorylation recruits p85-PI3K, SHP-2, and Grb2 to IRS-1 and increases PI3K activity; TRK-T1 stimulates DNA synthesis in wild-type but not IRS-1−/− fibroblasts, and yeast two-hybrid analysis shows direct TRK–IRS interaction. Co-immunoprecipitation, PI3K activity assay, yeast two-hybrid, IRS-1 KO fibroblast reconstitution, DNA synthesis assay Journal of cellular physiology Medium 11147812
2011 The Rheb-mTOR/raptor axis negatively regulates myogenic differentiation by suppressing IRS-1 protein levels and increasing Ser307 phosphorylation on IRS-1; IRS-1 knockdown eliminates the enhanced differentiation seen with raptor or Rheb knockdown, placing IRS-1 downstream of raptor/Rheb in myogenesis. siRNA knockdown of raptor, Rheb, and IRS-1 in C2C12 myoblasts, overexpression constructs, Akt phosphorylation and differentiation assays, Western blot for IRS-1 protein levels and Ser307 phosphorylation The Journal of biological chemistry Medium 21852229
2013 Nexilin, an F-actin binding protein, preferentially binds IRS-1 (but not IRS-2) under basal conditions in L6 myotubes and the complex is disassembled by insulin; nexilin silencing has no effect on IRS-1 tyrosine phosphorylation but enhances p85 recruitment to IRS-1, PI(3,4,5)P3 formation, AKT activation, and glucose uptake; nexilin overexpression inhibits IRS-1→AKT signaling. Co-immunoprecipitation (nexilin/IRS-1/p85), siRNA knockdown, nexilin overexpression, PI(3,4,5)P3 assay, AKT phosphorylation, glucose uptake assay in L6 myotubes PloS one Medium 23383252
2013 p38α MAPK activation during chronic insulin exposure reduces cardiac IRS-1 and IRS-2 protein levels, preventing subsequent insulin action; heart-specific IRS1/IRS2 double-KO mice develop dilated cardiomyopathy with impaired Akt→FoxO1 signaling and reduced ATP content. Heart-specific double-KO mice, neonatal rat ventricular cardiomyocyte chronic insulin treatment, p38 inhibitor experiments, echocardiography, Akt/FoxO1 signaling Western blot Diabetes Medium 24159000
2016 IRS-1 acts as a molecular scaffold in osteoblasts: IGF-I stimulates IRS-1 phosphorylation and co-recruitment of PKCζ (via the p62 adaptor) and vimentin to phospho-IRS-1; activated PKCζ directly phosphorylates vimentin, enabling downstream RPTPβ inactivation, PTEN tyrosine phosphorylation, and AKT activation required for osteoblast differentiation. Immunoprecipitation of IRS-1 complexes containing PKCζ and vimentin, in vitro kinase assay (PKCζ phosphorylating vimentin from IRS-1 immunoprecipitates), disrupting peptides for p62/PKCζ and p62/IRS-1 interactions, primary mouse calvarial osteoblasts Journal of bone and mineral research Medium 26773517
2022 Cathepsin K (CTSK) selectively cleaves IRS-1 in the region of amino acids 268–574, causing IRS-1 ubiquitination and degradation; CTSK knockout prevents IRS-1 degradation and preserves AKT-mTOR signaling in cachectic muscle; CTSK overexpression accelerates IRS-1 ubiquitination even without pro-cachectic stimulus. Co-immunoprecipitation, truncation mapping of IRS-1–CTSK interaction, ubiquitination assay, CTSK KO and overexpression in C2C12 cells and in vivo LLC tumor model, Western blot for IRS-1/Akt/mTOR Journal of cachexia, sarcopenia and muscle Medium 35098692
2019 TAZ transcriptionally upregulates IRS1 expression by physically interacting with c-Jun and Tead4 to induce IRS1 transcription; muscle-specific TAZ-KO mice show decreased IRS1 expression and insulin sensitivity; Wnt/APC signaling requires TAZ for IRS1-dependent insulin signaling in muscle. Muscle-specific TAZ-KO mice, APC/TAZ double-KO mice, ChIP/co-immunoprecipitation (TAZ with c-Jun and Tead4), IRS1 promoter reporter assay, glucose uptake assay Nature communications Medium 30679431
2007 IRS-1 (but not IRS-2) is required for normal epidermal differentiation: IRS-1-null mouse skin is thinner due to reduced spinous layer, with impaired keratinocyte differentiation marker K1 induction; IRS-2-null skin appears normal, establishing distinct roles for the two paralogs in epidermis. IRS-1 and IRS-2 KO mice, histological analysis, primary skin cell differentiation assays, K1 marker expression Journal of cellular physiology Medium 17508357
2016 IRS-1 deficiency in β-cells protects against ER stress-induced apoptosis by reducing nuclear accumulation of spliced XBP-1 (via proteasomal degradation), attenuating general translation (increased eEF2 phosphorylation), and maintaining elevated ER calcium levels. IRS1-KO and IRS2-KO β-cells, ER stress induction, nuclear fractionation for XBP-1, polyribosomal profiling, eEF2 phosphorylation assay, ER calcium measurement Scientific reports Medium 27378176
2024 PYCR1 promotes IRS1 transcription in liver cancer by increasing H3K18 lactylation at the IRS1 promoter; knockout or inhibition of PYCR1 reduces glycolysis, lowers H3K18 lactylation at the IRS1 promoter, and decreases IRS1 expression and downstream PI3K/AKT/mTOR signaling. ChIP assay (H3K18 lactylation at IRS1 promoter), PYCR1 KO, metabolomics, transcriptome sequencing, Western blot for IRS1 and pathway components Clinical and translational medicine Medium 39422696
2009 PTP1B dephosphorylates the insulin receptor and thereby determines IRS-1-mediated PI3K/Akt/FoxO1 signaling in liver; in IRS2-deficient mice (which develop hyperglycemia), elevated PTP1B impairs IRS1 signaling, and deletion or pharmacological inhibition of PTP1B restores IRS1-dependent hepatic insulin signaling. IRS2-KO / PTP1B-KO double-KO mice, resveratrol pharmacological PTP1B inhibition, hepatic insulin signaling Western blots, isolated hepatocytes Diabetes Medium 20028942

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 1068 7526222
1992 Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. The EMBO journal 963 1380456
2012 Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 788 22869320
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 693 15733744
1999 Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell 669 10399915
2001 Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. The Journal of clinical investigation 499 11160134
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
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
2004 Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). The Journal of biological chemistry 279 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 179 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
2010 Insulin receptor substrates Irs1 and Irs2 coordinate skeletal muscle growth and metabolism via the Akt and AMPK pathways. Molecular and cellular biology 150 21135130
2013 MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling. Nature communications 148 23965929
2013 Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38α MAPK during insulin resistance. Diabetes 143 24159000
1996 The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. The Journal of biological chemistry 141 8798677
2006 Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2. Molecular and cellular biology 140 17030631
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
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
2009 Inhibition of PTP1B restores IRS1-mediated hepatic insulin signaling in IRS2-deficient mice. Diabetes 99 20028942
1994 Insulin receptor substrate-1 (IRS1) and Shc compete for a limited pool of Grb2 in mediating insulin downstream signaling. The Journal of biological chemistry 99 7983051
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 97 30770439
2002 Lipoatrophic diabetes in Irs1(-/-)/Irs3(-/-) double knockout mice. Genes & development 96 12502742
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
2001 Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. Molecular and cellular biology 78 11113178
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 75 19211736
1994 Insulin receptor substrate-1 (IRS-1) expression in rat brain. Endocrinology 75 7511094
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
2019 LncRNA-XIST/microRNA-126 sponge mediates cell proliferation and glucose metabolism through the IRS1/PI3K/Akt pathway in glioma. Journal of cellular biochemistry 70 31680298
2021 Carpachromene Ameliorates Insulin Resistance in HepG2 Cells via Modulating IR/IRS1/PI3k/Akt/GSK3/FoxO1 Pathway. Molecules (Basel, Switzerland) 69 34946711
2003 The role of insulin receptor substrate-1 gene (IRS1) in type 2 diabetes in Pima Indians. Diabetes 68 14633864
1996 Insulin receptor substrate 1 and 2 (IRS1 and IRS2): what a tangled web we weave. Trends in cell biology 67 15157524
2016 miR-195 inhibits tumor growth and angiogenesis through modulating IRS1 in breast cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 62 27133044
2008 Selective regulation of heme oxygenase-1 expression and function by insulin through IRS1/phosphoinositide 3-kinase/Akt-2 pathway. The Journal of biological chemistry 61 18854316
2001 The G972R variant of the insulin receptor substrate-1 (IRS-1) gene, body fat distribution and insulin-resistance. Diabetologia 60 11317670
2012 TNFα and SOCS3 regulate IRS-1 to increase retinal endothelial cell apoptosis. Cellular signalling 58 22266116
2018 IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling. eLife 56 29661273
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
2024 PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification. Clinical and translational medicine 51 39422696
2012 The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer. PloS one 51 22558377
2019 TNF-α Downregulation Modifies Insulin Receptor Substrate 1 (IRS-1) in Metabolic Signaling of Diabetic Insulin-Resistant Hepatocytes. Mediators of inflammation 50 30863203
2006 Refeeding and insulin activate the AKT/p70S6 kinase pathway without affecting IRS1 tyrosine phosphorylation in chicken muscle. Domestic animal endocrinology 49 17029674
2020 Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes. Scientific reports 48 32238837
2019 Panax notoginseng saponins alleviate skeletal muscle insulin resistance by regulating the IRS1-PI3K-AKT signaling pathway and GLUT4 expression. FEBS open bio 48 30945455
2020 Pro-Inflammatory Markers Negatively Regulate IRS1 in Endometrial Cells and Endometrium from Women with Obesity and PCOS. Reproductive sciences (Thousand Oaks, Calif.) 47 32046436
2019 TAZ couples Hippo/Wnt signalling and insulin sensitivity through Irs1 expression. Nature communications 43 30679431
2018 Cinnamaldehyde ameliorates STZ-induced rat diabetes through modulation of IRS1/PI3K/AKT2 pathway and AGEs/RAGE interaction. Naunyn-Schmiedeberg's archives of pharmacology 43 30460386
1998 Nutritional state regulates insulin receptor and IRS-1 phosphorylation and expression in chicken. The American journal of physiology 43 9486163
2004 Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signalling. Annales d'endocrinologie 42 15122091
2020 Rab5a activates IRS1 to coordinate IGF-AKT-mTOR signaling and myoblast differentiation during muscle regeneration. Cell death and differentiation 41 32051546
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
2018 Identification of microRNA that represses IRS-1 expression in liver. PloS one 40 29364977
2017 MiR-30e inhibits tumor growth and chemoresistance via targeting IRS1 in Breast Cancer. Scientific reports 40 29162879
2023 Vitamin D supplementation alleviates insulin resistance in prediabetic rats by modifying IRS-1 and PPARγ/NF-κB expressions. Frontiers in endocrinology 39 37324274
2017 Long Noncoding RNA H19 Inhibits Cell Viability, Migration, and Invasion Via Downregulation of IRS-1 in Thyroid Cancer Cells. Technology in cancer research & treatment 38 29332545
2016 MiR-384 regulated IRS1 expression and suppressed cell proliferation of human hepatocellular carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 38 27542674
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 38 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
2001 IRS-1 and IRS-2 are recruited by TrkA receptor and oncogenic TRK-T1. Journal of cellular physiology 36 11147812
2018 Upregulation of IRS1 Enhances IGF1 Response in Y537S and D538G ESR1 Mutant Breast Cancer Cells. Endocrinology 35 29029116
2011 Raptor and Rheb negatively regulate skeletal myogenesis through suppression of insulin receptor substrate 1 (IRS1). The Journal of biological chemistry 32 21852229
2020 Berberine promotes peri-implant osteogenesis in diabetic rats by ROS-mediated IRS-1 pathway. BioFactors (Oxford, England) 29 33233028
2003 BCR-ABL binds to IRS-1 and IRS-1 phosphorylation is inhibited by imatinib in K562 cells. FEBS letters 29 12560071
2007 Insulin receptor substrate (IRS)-1 regulates murine embryonic stem (mES) cells self-renewal. Journal of cellular physiology 28 17620314
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 27 38625937
2023 Esculin ameliorates obesity-induced insulin resistance by improving adipose tissue remodeling and activating the IRS1/PI3K/AKT/GLUT4 pathway. Journal of ethnopharmacology 27 37778516
2020 MiRNA-7 enhances erlotinib sensitivity of glioblastoma cells by blocking the IRS-1 and IRS-2 expression. The Journal of pharmacy and pharmacology 27 32026479
2022 Estrogen Protects Cardiac Function and Energy Metabolism in Dilated Cardiomyopathy Induced by Loss of Cardiac IRS1 and IRS2. Circulation. Heart failure 26 35579013
2016 IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 26 26773517
2015 MicroRNA-128 suppresses cell growth and metastasis in colorectal carcinoma by targeting IRS1. Oncology reports 26 26352220
2020 miR-203 inhibits cell proliferation and ERK pathway in prostate cancer by targeting IRS-1. BMC cancer 25 33109107
2021 FoxP3-miR-150-5p/3p suppresses ovarian tumorigenesis via an IGF1R/IRS1 pathway feedback loop. Cell death & disease 24 33723215
2018 Hepatic IRS1 and ß-catenin expression is associated with histological progression and overt diabetes emergence in NAFLD patients. Journal of gastroenterology 24 29749571
2012 Association of IRS-1 and IRS-2 genes polymorphisms with polycystic ovary syndrome: a meta-analysis. Endocrine journal 24 22523112
2022 Cathepsin K activity controls cachexia-induced muscle atrophy via the modulation of IRS1 ubiquitination. Journal of cachexia, sarcopenia and muscle 23 35098692
2020 NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells. Signal transduction and targeted therapy 23 32296029
2013 Nexilin, a cardiomyopathy-associated F-actin binding protein, binds and regulates IRS1 signaling in skeletal muscle cells. PloS one 23 23383252
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 23 20837540
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 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
2020 FGFR1 overexpression renders breast cancer cells resistant to metformin through activation of IRS1/ERK signaling. Biochimica et biophysica acta. Molecular cell research 21 33007330
2017 IGF1 regulates RUNX1 expression via IRS1/2: Implications for antler chondrocyte differentiation. Cell cycle (Georgetown, Tex.) 21 28055425
2016 IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation. Scientific reports 21 27378176
2007 Insulin receptor substrate 1 (IRS-1) plays a unique role in normal epidermal physiology. Journal of cellular physiology 20 17508357
2022 H19 inhibition increases HDAC6 and regulates IRS1 levels and insulin signaling in the skeletal muscle during diabetes. Molecular medicine (Cambridge, Mass.) 19 35842608
2021 chi-miR-487b-3p Inhibits Goat Myoblast Proliferation and Differentiation by Targeting IRS1 through the IRS1/PI3K/Akt Signaling Pathway. International journal of molecular sciences 19 35008541

Missed literature

Know a paper Affinage missed for IRS1? Flag it for the maintainers and the community.

No submissions yet.