Affinage

IRS2

Insulin receptor substrate 2 · UniProt Q9Y4H2

Length
1338 aa
Mass
137.3 kDa
Annotated
2026-06-10
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRS2 is a cytoplasmic scaffolding adaptor that couples insulin, IGF-1, and cytokine receptors to downstream PI3K/Akt signaling, controlling whole-body glucose and lipid metabolism, beta-cell mass, and neuronal function (PMID:7675087, PMID:10471495). Identified originally as the second IRS protein (4PS), it contains an N-terminal pleckstrin-homology and phosphotyrosine-binding domain and links activated receptors to SH2-domain effectors including PI3K (PMID:7675087); it docks on the juxtamembrane domain of the insulin receptor (residues 943–984), an interaction disrupted by inflammatory serine phosphorylation (PMID:9368067). Beyond the insulin receptor, IRS2 is tyrosine-phosphorylated by diverse kinases—the α6β4 integrin (via β4 Y1494) in carcinoma invasion (PMID:11438664), TrkB downstream of BDNF and JAK2 downstream of leptin in neural contexts (PMID:9374521, PMID:9389430), oncogenic ALK in neuroblastoma (PMID:30459283), and JAK2V617F in myeloproliferative cells (PMID:26755644)—channeling each into PI3K recruitment. Genetic epistasis establishes IRS2 as the dominant IRS isoform in liver and in beta-cell development and compensation, where IGF-1 receptor signaling acts through IRS2 (PMID:10471495, PMID:10642598); it preferentially activates p110α-PI3K→Akt→FoxO1 more efficiently than IRS1, forming a reciprocal stability circuit with FoxO1 (PMID:16916938). The IRS2→Akt→FoxO1 axis drives hepatic glucose/lipid control (PMID:15711641, PMID:16374520), beta-cell survival and proliferation via Pdx1 and mTOR→cyclin D2 (PMID:11994408, PMID:26740601), energy balance and longevity through hypothalamic LepRb neurons (PMID:17641201, PMID:22560222), hippocampal LTP (PMID:21955917), and dopamine-neuron morphology and reward (PMID:17143271). IRS2 abundance is tightly controlled: positively by Nedd4-mediated monoubiquitination promoting Epsin1-dependent membrane recruitment (PMID:25879670), by basal serine phosphorylation (PMID:12033942), and by PKA phosphorylation of Ser1137/1138 that recruits 14-3-3 to block degradation (PMID:23615913); and negatively by SOCS1/3-elongin BC-mediated proteasomal degradation (PMID:12228220), PKCβ/AngII serine phosphorylation (Ser303/Ser675) (PMID:23775122), MAP4K4 (PMID:19690174), and aldosterone-driven mTORC1/IKKβ pathways (PMID:19095745). Its transcription is induced by TFE3, HIF-2α, PGC1A/CREB, and YAP/TAZ and repressed by ATF3, providing nutrient- and stress-responsive control of IRS2 levels (PMID:16327801, PMID:24037094, PMID:30770439, PMID:29400692, PMID:18057093). Gain-of-function and mutational studies implicate IRS2 in mammary, breast, and liver tumorigenesis through β-catenin, MYC stabilization, and amplified Akt signaling (PMID:17030631, PMID:36476848, PMID:29669935, PMID:29400692).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 1995 High

    Established that a second IRS protein exists, defining IRS2 as a multi-receptor scaffold that links insulin, IGF-1, and cytokine receptors to SH2-domain effectors and explaining residual signaling in IRS1-deficient cells.

    Evidence Protein purification, cloning, and sequence-function analysis across cell types including IRS1-/- mice

    PMID:7675087

    Open questions at the time
    • Did not resolve receptor-specific phosphosite usage
    • No structural model of PH/PTB domain engagement
  2. 1997 High

    Defined the physical receptor-docking interface and showed it is regulated, mapping IRS2 binding to the insulin receptor juxtamembrane domain and demonstrating that inflammatory serine phosphorylation disrupts coupling.

    Evidence GST-fusion pulldown with IR peptides, co-IP in Fao hepatoma cells with TNFα/sphingomyelinase, phosphatase reversal

    PMID:9013772 PMID:9368067

    Open questions at the time
    • Specific serine sites mediating disruption not mapped here
    • Hematopoietic specificity mechanism not fully defined
  3. 1997 Medium

    Showed IRS2 mediates signaling for non-insulin receptors, with leptin/JAK2 and BDNF/TrkB driving IRS2-PI3K activation in muscle and neurons, broadening its receptor repertoire.

    Evidence IP-based PI3K activity assays and phosphotyrosine immunoblotting in C2C12 myotubes and primary cortical neurons with kinase inhibitors

    PMID:9374521 PMID:9389430

    Open questions at the time
    • Direct vs indirect kinase-IRS2 contact not resolved
    • Physiological relevance in vivo not tested at this stage
  4. 1999 High

    Placed IRS2 at the center of beta-cell biology, establishing through genetic epistasis that IRS2 is dominant for beta-cell development and peripheral compensation and that IGF-1R acts through IRS2.

    Evidence Intercrosses of Irs1, Irs2, and Igf1r null mice with metabolic and beta-cell phenotyping

    PMID:10471495

    Open questions at the time
    • Downstream effectors in beta cells not yet identified
    • Tissue-resolved contributions not separated
  5. 2000 High

    Resolved tissue division of labor among IRS isoforms, demonstrating IRS2 dominance in liver versus IRS1 in skeletal muscle.

    Evidence Combined heterozygous null mouse genetics with euglycemic clamp and signaling assays

    PMID:10642598

    Open questions at the time
    • Molecular basis of tissue specificity unexplained
    • Did not address transcriptional control of the ratio
  6. 2002 High

    Defined the dominant degradation and stability machinery controlling IRS2 abundance: SOCS1/3 recruit the elongin BC ubiquitin ligase for proteasomal turnover, while basal serine phosphorylation positively primes IR-mediated tyrosine phosphorylation.

    Evidence Co-IP, ubiquitination assays, SOCS-box point mutants, in vitro IR kinase assays with phosphatase/GSK3β treatments, adenoviral hepatic overexpression

    PMID:12033942 PMID:12228220

    Open questions at the time
    • Kinases setting basal positive sites not all defined
    • Relative quantitative contribution of each pathway in vivo unclear
  7. 2002 High

    Identified the transcriptional output that sustains beta-cell survival, placing Pdx1 downstream of IRS2 such that Pdx1 restoration rescues beta-cell mass and prevents diabetes.

    Evidence Pdx1 transgene rescue on Irs2-/- background with beta-cell mass and survival analysis

    PMID:11994408

    Open questions at the time
    • Mechanistic link from Akt/FoxO1 to Pdx1 not fully mapped
    • Did not address proliferation vs survival contributions
  8. 2004 High

    Positioned PTP1B upstream of IRS2 as a negative regulator acting at the receptor level, with Ptp1b deletion rescuing insulin sensitivity and beta-cell area in Irs2-/- mice.

    Evidence Irs2-/-::Ptp1b-/- double-knockout genetics with metabolic phenotyping

    PMID:14693698

    Open questions at the time
    • Whether PTP1B acts directly on IRS2 not established
    • Compensatory IRS1 contribution explored only later
  9. 2005 High

    Defined IRS2's non-redundant hepatic role in lipid versus glucose control and showed cAMP/GLP-1 signaling expands beta-cell mass through IRS2.

    Evidence Adenoviral hepatic shRNA knockdown with gene expression and metabolic readouts; cAMP/Akt analysis and Ex4 treatment of Irs2-/- mice

    PMID:15711641 PMID:16272563

    Open questions at the time
    • Mechanism partitioning IRS1 vs IRS2 to distinct gene programs unresolved
    • Direct cAMP-to-IRS2 transcriptional link not defined here
  10. 2006 High

    Established the IRS2-FoxO1 reciprocal stability circuit and IRS2's preferential coupling to p110α-PI3K, providing the core signaling logic for downstream metabolic and survival outputs.

    Evidence Wild-type, Irs1-/-, Irs2-/- MEFs with PI3K co-IP, Akt/FoxO1 phosphorylation, and rapamycin treatment

    PMID:16916938

    Open questions at the time
    • Structural basis of p110α preference not defined
    • In vivo relevance of rapamycin-sensitive degradation not tested here
  11. 2006 High

    Extended IRS2 function to the nervous system, showing VTA IRS2-Akt signaling controls dopamine-neuron size and morphine reward behavior.

    Evidence Viral dominant-negative and constitutively active IRS2 in rat VTA with morphology and conditioned place preference assays

    PMID:17143271

    Open questions at the time
    • Receptor driving VTA IRS2 phosphorylation not identified
    • Molecular link to neuronal size not detailed
  12. 2007 High

    Identified bidirectional transcriptional control of IRS2 by TFE3 (activating) and ATF3 (repressing), connecting IRS2 levels to metabolic improvement and stress-induced beta-cell apoptosis.

    Evidence Promoter luciferase and ChIP/Pol II occupancy assays with adenoviral and transgenic in vivo validation

    PMID:16327801 PMID:18057093

    Open questions at the time
    • Combinatorial promoter logic with other factors unresolved
    • Upstream signals controlling these TFs not fully defined
  13. 2007 Medium

    Linked IRS2 to oncogenic signaling beyond metabolism, showing IRS2 binds β-catenin and that mammary overexpression drives hyperplasia, tumorigenesis, and metastasis.

    Evidence Reciprocal co-IP of IRS2 with β-catenin and transgenic mammary tumor model with histopathology

    PMID:17030631

    Open questions at the time
    • Direct vs indirect β-catenin binding not structurally defined
    • Single-lab transgenic model not independently replicated in timeline
  14. 2008 Medium

    Expanded the negative-regulatory network, defining an aldosterone/glucocorticoid-receptor, ROS-dependent IKKβ/mTORC1 pathway that degrades IRS2 to impair insulin action.

    Evidence Pharmacological inhibitor dissection in 3T3-L1 adipocytes with sucrose-gradient fractionation

    PMID:19095745

    Open questions at the time
    • Direct kinase writing degradation-promoting marks not identified
    • Single-lab pharmacological inference
  15. 2009 Medium

    Identified MAP4K4 as the mediator of TNF-α-induced post-transcriptional loss of IRS2 protein in beta cells, distinguishing protein-level from mRNA-level control.

    Evidence siRNA knockdown in primary FACS-sorted beta cells with protein/mRNA discrimination and insulin secretion readouts

    PMID:19690174

    Open questions at the time
    • Direct MAP4K4 substrate sites on IRS2 not mapped
    • Single-lab finding
  16. 2009 High

    Refined the PTP1B-IRS2 epistasis to a hepatic mechanism, showing PTP1B loss restores IRS1-mediated PI3K/Akt/FoxO1 signaling in Irs2-/- liver and that resveratrol mimics this.

    Evidence Irs2-/-/Ptp1b-/- genetics, PTP1B-IR co-IP, and resveratrol pharmacology

    PMID:20028942

    Open questions at the time
    • Mechanism of increased PTP1B in Irs2-/- liver unclear
    • Resveratrol target specificity not fully resolved
  17. 2010 High

    Demonstrated IRS proteins are required for skeletal muscle growth and metabolic flux, with combined Irs1/Irs2 loss abolishing Akt→mTOR signaling and shifting fuel use.

    Evidence MCK-Cre double muscle-specific knockout with metabolic flux and signaling analysis

    PMID:21135130

    Open questions at the time
    • IRS2-specific contribution versus IRS1 not isolated
    • Did not address recovery or compensation
  18. 2011 High

    Established IRS2 as a required component of hippocampal LTP signaling and showed bidirectional roles in neurodegeneration, where lowering Irs2 protects in a Huntington's model via FoxO1-driven autophagy/antioxidant programs.

    Evidence Hippocampal slice electrophysiology with IRS2 phospho-detection; bidirectional Irs2 modulation in R6/2 HD mice

    PMID:21926467 PMID:21955917

    Open questions at the time
    • Receptor/kinase phosphorylating IRS2 during LTP not identified
    • Mechanism linking IRS2 to NMDA/Fyn activation unresolved
  19. 2011 Medium

    Identified isoform- and context-specific regulators of IRS2 abundance: JNK3 maintains IRS2 expression transcriptionally via FoxO3A in beta cells, and chronic leptin remodels IR/IRS2/SOCS3/JAK2 associations in hypothalamus.

    Evidence Isoform-specific siRNA in beta cell lines; co-IP in rat hypothalamus with chronic icv leptin and acute insulin

    PMID:21255014 PMID:22563476

    Open questions at the time
    • Direct vs indirect JNK3 effects not separated
    • Single-lab co-IP without reciprocal validation in vivo
  20. 2012 High

    Placed FoxO1 genetically downstream of IRS2 in energy balance, showing FoxO1 deletion in LepRb neurons normalizes the obesity and glucose phenotypes of neuronal Irs2 loss.

    Evidence Lepr-Cre × Irs2-flox conditional knockout with epistatic FoxO1 deletion and metabolic phenotyping

    PMID:22560222

    Open questions at the time
    • Arcuate transcriptional targets mediating the effect not fully defined
    • Neuron-subtype resolution limited
  21. 2013 High

    Mapped specific inhibitory serine sites on IRS2 (Ser303/Ser675) phosphorylated by AngII/PKCβ2 that block insulin-induced tyrosine phosphorylation and a stabilizing PKA/14-3-3 mechanism at Ser1137/1138, providing residue-level control of IRS2 activity and stability.

    Evidence Site-directed mutagenesis, phospho-specific antibodies, GST-14-3-3 pulldowns, mass spectrometry, cycloheximide chase in endothelial cells and HEK293/hepatocytes

    PMID:23615913 PMID:23775122

    Open questions at the time
    • Interplay between positive and negative serine sites unresolved
    • In vivo stoichiometry of these modifications unknown
  22. 2013 High

    Established cardiac and vascular roles for IRS proteins and additional regulators, showing heart-specific IRS1/IRS2 loss causes heart failure (with p38α as a writer of IRS loss) and HIF-2α as a hepatic IRS2 inducer necessary and sufficient for its metabolic effects.

    Evidence Heart-specific double KO with echocardiography and cardiomyocyte p38 analysis; liver-specific HIF-2α activation with Irs2-/- rescue

    PMID:24037094 PMID:24159000

    Open questions at the time
    • IRS2-specific cardiac function separate from IRS1 not isolated
    • Direct vs indirect HIF-2α induction not fully separated
  23. 2014 High

    Revealed non-canonical and vascular IRS2 functions: IRS2-dependent GRK2 recruitment to the insulin receptor suppresses β2AR/cAMP signaling in cardiomyocytes, and endothelial IRS2 governs islet blood flow required for glucose-induced insulin secretion.

    Evidence Co-IP and phosphorylation/internalization assays in IRS2-knockout cardiomyocytes; EC-specific Irs2 knockout with islet perfusion and enalapril rescue

    PMID:25277391 PMID:25460042

    Open questions at the time
    • Structural basis of IR-IRS2-GRK2 complex not resolved
    • Endothelial IRS2 effectors controlling perfusion not detailed
  24. 2015 High

    Defined positive ubiquitin-based regulation, showing Nedd4 monoubiquitinates IRS2 to recruit Epsin1 and drive plasma-membrane localization that enhances IGF-1R-induced tyrosine phosphorylation and growth, and extended IRS2 function to podocyte insulin signaling via PTEN.

    Evidence Ubiquitination and Epsin1 binding assays, membrane fractionation, zebrafish rescue; Irs2-/- podocytes with PTEN-knockdown rescue

    PMID:25879670 PMID:26384875

    Open questions at the time
    • Ubiquitin chain topology and reversal enzymes not defined
    • Whether PTEN regulation is direct unresolved
  25. 2016 High

    Defined the proliferative arm of beta-cell IRS2 signaling, showing glucose-induced replication requires IRS2→mTOR→cyclin D2 independent of the insulin receptor.

    Evidence IRS2 and IR knockout mice, mTOR/ERK inhibitors, and cyclin D2 adenoviral rescue validated in human islets

    PMID:26740601

    Open questions at the time
    • Upstream receptor driving glucose-induced IRS2 activation unidentified
    • Link from mTOR to cyclin D2 transcription not detailed
  26. 2018 High

    Consolidated IRS2's roles in cancer and immunometabolism: ALK and YAP/TAZ drive IRS2-dependent AKT signaling in neuroblastoma and liver cancer, IRS2 mutations enhance breast cancer invasion, and macrophage IRS2 controls IL-4-induced M2 polarization via a FoxO1/HDAC3/NCoR1 corepressor.

    Evidence MS-based interactome and siRNA in neuroblastoma; AAV-Cas9 IRS2 knockout in PTEN/SAV1 mice; PILC IRS2-mutant invasion assays; myeloid-specific Irs2/IR knockouts with corepressor co-IP

    PMID:29400692 PMID:29669935 PMID:30451856 PMID:30459283

    Open questions at the time
    • Mechanism of IRS2 mutant gain-of-function in invasion not defined
    • Direct vs indirect corepressor regulation by IRS2 unresolved
  27. 2019 High

    Defined fasting-state transcriptional reprogramming of the IRS1:IRS2 ratio, showing glucagon/cAMP→CREB→PGC1A induces IRS2 while suppressing IRS1, with IRS2 required for insulin suppression of gluconeogenesis.

    Evidence Primary hepatocyte gain/loss of PGC1A with CREB inhibition, glucose-production assays, and in vivo overexpression

    PMID:30770439

    Open questions at the time
    • Direct PGC1A coactivator targets on IRS2 promoter not mapped
    • Integration with other IRS2-inducing TFs unresolved
  28. 2022 High

    Defined a cancer-stem-cell mechanism whereby IRS2-PI3K inhibits GSK3β to block MYC Thr58 phosphorylation, stabilizing MYC to sustain breast CSC self-renewal.

    Evidence IRS2 knockout cells, GSK3β/MYC phospho-assays, proteasome inhibition, and T58A-MYC rescue in Irs2-/- cells with sphere assays

    PMID:36476848

    Open questions at the time
    • In vivo tumor relevance not established here
    • Single-lab mechanism

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many positive and negative IRS2 inputs—receptor docking, monoubiquitination/membrane recruitment, multisite serine phosphorylation, and competing transcriptional regulators—are quantitatively integrated to set IRS2 abundance and activity in a tissue- and stimulus-specific manner remains unresolved.
  • No integrated stoichiometric model of IRS2 PTM crosstalk
  • Structural basis for p110α-PI3K selectivity over IRS1 unknown
  • Mechanisms determining tissue-specific IRS isoform dominance incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3
Partners
ALKGRK2IGF1RINSRJAK2NEDD4PIK3R1SOCS3

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 IRS-2 (initially called 4PS) was identified as a second IRS-signaling protein with a conserved amino terminus containing a pleckstrin-homology domain and a phosphotyrosine-binding domain, acting as a scaffold linking insulin, IGF-1, IL-4, IL-9, IL-13, and other cytokine receptors to downstream SH2-domain-containing signaling proteins. Protein purification, molecular cloning, sequence alignment, and expression analysis in multiple cell types including IRS-1-/- mice Nature High 7675087
1997 IRS-2, like IRS-1, interacts with the juxtamembrane (JM) domain (amino acids 943–984) of the insulin receptor; elevated serine/threonine phosphorylation of IRS-2 induced by TNFα or chronic hyperinsulinemia impairs this interaction and reduces insulin-induced tyrosine phosphorylation of IRS-2. GST-fusion pulldown with bacterial His6-IR peptides, co-immunoprecipitation in Fao hepatoma cells treated with TNFα or sphingomyelinase, alkaline phosphatase reversal experiments The Journal of biological chemistry High 9368067
1997 IRS-2 is encoded by a single-exon gene on murine chromosome 8; in hematopoietic cells IRS-2 predominates over IRS-1 and undergoes distinct tyrosine phosphorylation patterns during insulin versus IL-4 stimulation, conferring signaling specificity through differential interaction with SH2 domains. Gene isolation, chromosomal mapping, Northern/Western blot tissue expression profiling, interaction with recombinant SH2 domains in 32D cells Molecular endocrinology Medium 9013772
1997 Leptin activates PI-3 kinase via IRS-2 (but not IRS-1) and JAK-2 in C2C12 myotubes; leptin-stimulated PI-3 kinase activity is detected only in IRS-2 immunoprecipitates and in JAK-2 immunoprecipitates, accompanied by tyrosine phosphorylation of both JAK-2 and IRS-2. PI-3 kinase activity assay in immunoprecipitates using non-cross-reacting IRS-1, IRS-2, JAK-1, and JAK-2 antibodies; tyrosine phosphorylation immunoblotting Diabetologia Medium 9389430
1997 BDNF stimulates tyrosine phosphorylation of IRS-1 and IRS-2 and their association with PI3-K in cultured cerebral cortical neurons; this signaling is dependent on TrkB kinase activity and is not mediated by direct TrkB–PI3-K association. Co-immunoprecipitation, Western blotting with phosphotyrosine antibodies, kinase inhibitor (K-252a) experiments in primary cortical neurons The Journal of biological chemistry Medium 9374521
1999 Genetic epistasis in mice shows that Irs-2 is the dominant IRS isoform for beta-cell development and compensation for peripheral insulin resistance, and that Igf-1 receptors promote beta-cell development and survival through the Irs-2 signaling pathway. Intercross of Irs1+/-, Irs2+/-, and Igf1r+/- null mice; glucose metabolism and beta-cell morphology phenotyping Nature genetics High 10471495
2000 Tissue-specific epistasis in mice with combined ir/irs-1/irs-2 heterozygous null mutations reveals that IRS-2 plays the dominant role in hepatic insulin signaling, while IRS-1 is predominant in skeletal muscle. Generation and metabolic phenotyping of ir(+/-), ir/irs-1(+/-), ir/irs-2(+/-), and triple heterozygous mice; euglycemic clamp, insulin signaling assays The Journal of clinical investigation High 10642598
2001 IRS-2 is phosphorylated on tyrosine by the alpha6beta4 integrin, which promotes IRS-2 association with PI3K; the beta4 subunit tyrosine Y1494 is specifically required for IRS-2 phosphorylation and PI3K activation, and is essential for alpha6beta4-dependent carcinoma invasion. Co-immunoprecipitation of IRS-2 with PI3K, site-directed mutagenesis of beta4 Y1494, cell invasion assays Molecular and cellular biology High 11438664
2002 SOCS1 and SOCS3 bind both IRS-1 and IRS-2 and promote their ubiquitination and proteasomal degradation via the elongin BC ubiquitin-ligase complex; mutations in the SOCS box of SOCS1 that abrogate elongin BC interaction eliminate IRS degradation without affecting SOCS1–IRS binding, demonstrating that the SOCS box recruits the ubiquitin ligase. Co-immunoprecipitation of endogenous and recombinant IRS proteins with SOCS proteins, ubiquitination assays, SOCS box point mutants, adenoviral hepatic overexpression in mice The Journal of biological chemistry High 12228220
2002 Basal serine/threonine phosphorylation of IRS-2 plays a positive role in subsequent insulin receptor-mediated tyrosine phosphorylation, whereas hyperphosphorylation by GSK3β decreases tyrosine phosphorylation; dephosphorylation of basal sites also increased IGF-1 receptor-mediated IRS-2 phosphorylation, showing divergent regulation compared to the insulin receptor. In vitro insulin receptor kinase assay on recombinant FLAG-IRS-2 after alkaline phosphatase dephosphorylation or GSK3β hyperphosphorylation; confirmed in endogenous IRS-2 from 3T3-L1 adipocytes Biochemistry High 12033942
2002 Pdx1 expression is reduced in islets of Irs2-/- mice before diabetes onset; transgenic restoration of Pdx1 rescues beta-cell mass and prevents diabetes in Irs2-/- mice, placing Pdx1 downstream of Irs2 signaling in beta-cell survival. Genetic rescue experiment: Pdx1 transgene on Irs2-/- background; beta-cell mass quantification, glucose tolerance, survival analysis The Journal of clinical investigation High 11994408
2004 PTP1B dephosphorylates and inactivates the insulin receptor, thereby limiting IRS-2-mediated signaling; deletion of Ptp1b in Irs2-/- mice restores peripheral insulin sensitivity and beta-cell area, demonstrating that PTP1B acts upstream of IRS-2 by controlling insulin receptor phosphorylation state. Double-knockout mouse genetics (Irs2-/-::Ptp1b-/-), metabolic phenotyping, insulin signaling biochemistry Diabetes High 14693698
2005 Hepatic IRS-2 knockdown via adenoviral shRNA upregulates lipogenic enzymes SREBP-1c and fatty acid synthase and causes hepatic lipid accumulation, while IRS-1 knockdown upregulates gluconeogenic enzymes; combined IRS-1/IRS-2 knockdown abolishes Akt→FoxO1 signaling and causes systemic insulin resistance. Adenoviral shRNA-mediated knockdown of IRS-1, IRS-2, or both in mouse liver; gene expression, metabolic phenotyping, Akt/FoxO1 phosphorylation The Journal of clinical investigation High 15711641
2005 Exendin-4 increases cAMP in beta cells, which upregulates Irs2 expression and stimulates Akt phosphorylation; Irs2 is required for Ex4-mediated long-term beta-cell growth and survival but not short-term insulin secretion effects, demonstrating that GLP-1 receptor agonists act through the Irs2 branch to expand beta-cell mass. cAMP measurement in human islets and Min6 cells, Akt phosphorylation, Ex4 treatment of Irs2-/- mice, beta-cell mass quantification The Journal of biological chemistry High 16272563
2005 Liver-specific deletion of Irs2 combined with whole-body Irs1 knockout abolishes hepatic Akt→FoxO1 signaling and causes hyperglycemia, while single-tissue knockouts cause insulin resistance without diabetes; Irs1 or Irs2 individually regulate hundreds of hepatic genes including Pck1, G6pc, and Igfbp1. Cre-lox conditional liver-specific Irs2 deletion on Irs1-/- background; insulin signaling, hepatic gene expression microarray, metabolic phenotyping The Journal of clinical investigation High 16374520
2006 Viral-mediated downregulation of the IRS2-Akt signaling pathway in the VTA mediates chronic morphine-induced decrease in dopamine neuron cell size and diminishes morphine reward as measured by conditioned place preference. Viral-mediated gene transfer of IRS2 dominant negative and constitutively active constructs into rat VTA; neuron size measurement, conditioned place preference behavioral assay Nature neuroscience High 17143271
2006 FoxO1 and IRS-2 form a reciprocal stability circuit: IRS-2 efficiently activates p110α-PI3K→Akt→FoxO1 phosphorylation/degradation, while prolonged insulin stimulation leads to rapamycin-sensitive IRS-2 degradation that allows FoxO1 to re-accumulate; IRS-2 activates p110α-PI3K more efficiently than IRS-1 does. Wild-type, Irs1-/-, and Irs2-/- mouse embryo fibroblasts; PI3K co-immunoprecipitation, Akt and FoxO1 phosphorylation, rapamycin treatment, immunofluorescence Molecular endocrinology High 16916938
2007 IRS-2 binds beta-catenin in vitro and in vivo; transgenic overexpression of IRS-2 in the mammary gland causes progressive hyperplasia, tumorigenesis, and metastasis with extensive squamous differentiation consistent with beta-catenin pathway activation. Co-immunoprecipitation of IRS-2 with beta-catenin in vitro and in vivo, transgenic mouse mammary tumor model with histopathology Molecular and cellular biology Medium 17030631
2007 TFE3, a bHLH transcription factor, directly transactivates the IRS2 promoter via an E-box element; adenoviral TFE3 expression in hepatocytes strongly increases IRS-2 and Akt expression and downstream insulin signaling, reducing blood glucose in multiple diabetic mouse models. Promoter luciferase reporter assays, adenoviral TFE3 overexpression in hepatocytes and in vivo, Western blotting for IRS-2/Akt phosphorylation Nature medicine High 16327801
2007 ATF3, a stress-inducible transcription factor, binds to the IRS2 promoter in vivo and represses IRS2 gene transcription, contributing to beta-cell apoptosis; IRS2 overexpression rescues beta-cells from ATF3-induced apoptosis. Chromatin immunoprecipitation (ChIP) assay, Pol II occupancy assay, gain/loss-of-function ATF3 with IRS2 expression measurement, ATF3 transgenic and IRS2 transgenic mice with RIP-driven transgenes Diabetes High 18057093
2007 Brain-specific Irs2 knockout mice develop obesity and glucose intolerance, but display greater physical activity and stable hypothalamic SOD2 concentrations during meals, extending lifespan by up to 18%, establishing that Irs2 signaling in the brain coordinates energy balance, oxidative stress responses, and longevity. Brain-specific Cre-lox Irs2 knockout mice; metabolic phenotyping, activity monitoring, SOD2 immunostaining, lifespan analysis Science High 17641201
2008 Aldosterone promotes degradation of IRS-2 (and IRS-1) through a glucocorticoid receptor-mediated, reactive oxygen species-dependent pathway involving activation of IKKβ and mTORC1; this degradation reduces insulin-induced Akt phosphorylation and glucose uptake in 3T3-L1 adipocytes. Time- and dose-response IRS protein immunoblotting in 3T3-L1 adipocytes; pharmacological inhibitors of mineralocorticoid receptor, glucocorticoid receptor, NAC (antioxidant), rapamycin, BMS345541, and proteasome inhibitor lactacystin; sucrose-gradient fractionation Endocrinology Medium 19095745
2009 Deletion of PTP1B in IRS2-/- mice restores hepatic IRS1-mediated PI3K/Akt/FoxO1 signaling; in IRS2-/- livers, PTP1B expression and its association with the insulin receptor are increased, and resveratrol treatment reduces PTP1B activity and restores IRS1-mediated signaling. Double-knockout mouse genetics (IRS2-/-/PTP1B-/-), co-immunoprecipitation of PTP1B with IR, hepatic insulin signaling biochemistry, resveratrol pharmacological intervention Diabetes High 20028942
2010 Muscle-specific combined deletion of Irs1 and Irs2 severely reduces skeletal muscle growth, abolishes Akt→mTOR signaling, increases Foxo-dependent atrogene expression and amino acid release, shifts glucose utilization from oxidation to lactate, and elevates AMPK→ACC phosphorylation and fatty acid oxidation. MCK-Cre driven double muscle-specific Irs1/Irs2 knockout; muscle mass quantification, insulin signaling biochemistry, glucose uptake, metabolic flux, AMPK/ACC phosphorylation Molecular and cellular biology High 21135130
2011 IRS-2 is phosphorylated during induction of LTP in hippocampus; IRS-2-deficient mice fail to activate postsynaptic NMDA receptors or Fyn, AKT, and MAPK in response to tetanic stimulation, demonstrating IRS-2 as a required component of LTP signaling machinery. Hippocampal slice electrophysiology (LTP recording), Western blotting for IRS-2 phosphorylation during LTP, biochemical analysis of Fyn/AKT/MAPK in Irs2-/- slices Cerebral cortex High 21955917
2011 Increasing Irs2 levels in R6/2 HD mouse brains reduces life span and increases neuronal oxidative stress and mitochondrial dysfunction; conversely, reducing Irs2 levels improves motor performance and extends lifespan, associated with increased nuclear FoxO1 and upregulation of FoxO1-dependent autophagy and antioxidant genes. Genetic modulation of Irs2 levels in R6/2 HD model mice; behavioral testing, mitochondrial function assays, autophagosome counting, oxidative stress markers, FoxO1 nuclear localization The Journal of clinical investigation High 21926467
2012 Irs2 signaling in leptin receptor-expressing (LepRb) neurons suppresses FoxO1 to control energy balance; deletion of FoxO1 in LepRb neurons normalizes obesity, glucose homeostasis, and arcuate gene expression caused by Irs2 ablation in those neurons, placing FoxO1 downstream of IRS2 in energy balance regulation. Lepr-Cre × Irs2-flox conditional knockout; FoxO1 conditional deletion epistasis experiment; metabolic phenotyping, insulin-stimulated FoxO1 nuclear exclusion assay Cell metabolism High 22560222
2013 Angiotensin II and PKCβ2 phosphorylate specific serine residues on IRS-2 (Ser303, Ser343, Ser675) in endothelial cells, inhibiting insulin-induced tyrosine phosphorylation (Tyr653, Tyr671, Tyr911) and downstream Akt/eNOS activation; AngII specifically targets Ser303 to inhibit p-Tyr911 and p-Akt/eNOS. Site-directed mutagenesis of IRS-2 serine residues (S303A, S675A), PKCβ2 overexpression and dominant-negative, losartan receptor antagonist, phospho-specific antibodies; confirmed in vessels of insulin-resistant Zucker fatty rats Molecular and cellular biology High 23775122
2013 Heart-specific double knockout of IRS1 and IRS2 causes reduced ventricular mass, cardiac apoptosis, fibrosis, and heart failure with diminished Akt→FoxO1 signaling and impaired cardiac metabolic gene expression; chronic insulin exposure reduces cardiac IRS1/IRS2 via p38α MAPK activation. Heart-specific Cre-lox IRS1/IRS2 double KO; echocardiography, cardiac apoptosis/fibrosis assays, p38 activation in neonatal rat ventricular cardiomyocytes with chronic insulin Diabetes High 24159000
2013 Phosphorylation of IRS-2 at Ser1137/1138 by PKA (induced by cAMP/forskolin) promotes binding of 14-3-3 proteins and protects IRS-2 from proteasomal degradation, increasing IRS-2 protein stability. GST-14-3-3 pulldown assays with deletion constructs, mass spectrometry phosphorylation site identification, Ser1137/1138 alanine mutants, cycloheximide chase stability assay, 14-3-3 antagonist treatment in HEK293 cells and primary hepatocytes The Journal of biological chemistry High 23615913
2014 IRS-2 in endothelial cells is required for normal islet blood flow and glucose-induced insulin secretion; endothelial cell-specific Irs2 knockout impairs islet perfusion, and restoration of blood flow with enalapril rescues insulin secretion. EC-specific Irs2 knockout (ETIrs2KO) mice; islet perfusion experiments, enalapril pharmacological rescue, glucose and arginine stimulation tests Diabetes High 25277391
2014 Insulin stimulates IRS2-dependent recruitment of GRK2 to the insulin receptor, which then phosphorylates β2AR at Ser355/356, promoting β2AR internalization and suppression of βAR-induced cAMP-PKA signaling and contractile response in cardiomyocytes; IRS2 deletion disrupts the IR–GRK2 complex. Co-immunoprecipitation of IRS2 with IR and GRK2; β2AR phosphorylation and internalization assays; IRS2 knockout cardiomyocytes; cAMP and contractility measurements Cellular signalling High 25460042
2015 Nedd4 E3 ubiquitin ligase monoubiquitinates IRS-2, promoting its association with the ubiquitin-binding protein Epsin1 and recruitment of IRS-2 to the plasma membrane; this enhances IGF-I receptor-induced IRS-2 tyrosine phosphorylation, IGF-I signaling, and cell proliferation, confirmed by in vivo zebrafish growth experiments. Co-immunoprecipitation, ubiquitination assays, Epsin1 binding assays, membrane fractionation, siRNA knockdown, zebrafish IRS-2 knockdown rescue with Nedd4 Nature communications High 25879670
2015 IRS2 deficiency in podocytes causes insulin resistance through upregulation of PTEN; suppressing PTEN in Irs2-/- podocytes rescues AKT signaling, GLUT4-mediated glucose uptake, F-actin remodeling, and cell motility, placing PTEN downstream of IRS2 in podocyte insulin signaling. Conditionally immortalized Irs2-/- podocytes; AKT phosphorylation, GLUT4 glucose uptake assay, F-actin staining, Transwell motility assay, siRNA PTEN knockdown rescue Biochimica et biophysica acta High 26384875
2016 Glucose-induced beta-cell proliferation requires IRS2 and mTOR but not the insulin receptor; IRS2 or mTOR loss reduces cyclin D2 expression, and restoring cyclin D2 rescues the proliferation defect, placing IRS2→mTOR→cyclin D2 as the pathway for glucose-driven beta-cell replication. IRS2 knockout mice with in vivo hyperglycemia model and ex vivo islet culture; insulin receptor knockout; mTOR/ERK inhibitors; cyclin D2 adenoviral rescue; confirmed in human islets Diabetes High 26740601
2018 YAP/TAZ activation in the liver upregulates IRS2 expression, amplifying AKT signaling; YAP/TAZ ablation or Hippo pathway activation rescues NAFLD and liver cancer in PTEN/SAV1 double-knockout mice, and AAV-Cas9 knockout of IRS2 successfully represses liver tumorigenesis in this model. PTEN/SAV1 double liver-specific knockout mice; YAP/TAZ/IRS2 expression analysis; AAV-Cas9 IRS2 knockout; AKT inhibitor MK-2206 treatment; correlation of YAP/TAZ and IRS2 in human HCC The Journal of clinical investigation High 29400692
2018 IRS2 is recruited to and tyrosine-phosphorylated by oncogenic ALK in neuroblastoma cells; ALK TKI treatment decreases IRS2 recruitment to ALK and IRS2 tyrosine phosphorylation; siRNA depletion of ALK or IRS2 reduces AKT and FoxO3 phosphorylation and decreases viability of ALK-driven neuroblastoma cells. Quantitative mass spectrometry-based proximal proteomics (IPP), co-immunoprecipitation, phosphotyrosine interactome, siRNA knockdown of IRS2, cell viability assays, ALK TKI treatment Science signaling High 30459283
2018 Downregulation of macrophage IRS2 expression by hyperinsulinemia via insulin receptor impairs IL-4-induced M2a-subtype macrophage activation; mechanistically, loss of IRS2 stabilizes the FoxO1/HDAC3/NCoR1 corepressor complex; myeloid-specific IR knockout preserves IRS2 and IL-4/IRS2/Akt signaling and reduces insulin resistance. Myeloid cell-specific Irs2-deficient mice and myeloid-specific IR-deficient mice; macrophage polarization assays, co-immunoprecipitation of FoxO1/HDAC3/NCoR1 complex, AKT phosphorylation, high-fat diet metabolic phenotyping Nature communications High 30451856
2018 IRS2 mutations identified in pleomorphic invasive lobular carcinoma enhance breast cancer cell invasion, defining IRS2 as functionally important in the aggressive nature of PILC through the IR/IGF1R/IRS2 signaling pathway. Targeted sequencing, functional invasion assays with PILC-derived IRS2 mutants in breast cancer cells JCI insight Medium 29669935
2019 PGC1A, induced by glucagon/cAMP signaling through CREB, drives IRS2 expression while simultaneously reducing IRS1 expression in hepatocytes, thereby shifting the IRS1:IRS2 ratio during fasting; PGC1A-induced IRS2 expression is required for suppression of hepatocyte gluconeogenesis by insulin. Primary hepatocyte gain- and loss-of-function of PGC1A; CREB inhibitor experiments; ex vivo glucose production assays; in vivo PGC1A hepatic overexpression Proceedings of the National Academy of Sciences High 30770439
2009 MAP4K4 is a key mediator of TNF-α-induced decrease of IRS-2 protein levels in primary beta cells (without change in mRNA); MAP4K4 siRNA knockdown protects against TNF-α-induced IRS-2 protein reduction and preserves glucose-stimulated insulin secretion and Akt phosphorylation. siRNA knockdown of MAP4K4 in human and rat primary FACS-sorted beta cells; IRS-2 protein and mRNA measurement; Akt/AS160 phosphorylation; glucose-stimulated insulin secretion The Journal of biological chemistry Medium 19690174
2011 JNK3 maintains IRS-2 protein expression in insulin-secreting cells and is required for Akt2 (but not Akt1) activation by insulin; JNK3 mediates its effects at the transcriptional level through maintenance of FoxO3A activity that controls IRS2 expression, while JNK1/2 have opposing pro-apoptotic effects. siRNA silencing of individual JNK isoforms in beta cell lines; IRS-2 protein/mRNA measurement, Akt1/Akt2 and GSK3β phosphorylation, FoxO3A activity assays PloS one Medium 22563476
2013 HIF-2α activation in liver directly and indirectly induces IRS-2 expression; liver-specific constitutive HIF-2α is sufficient to augment hepatic insulin signaling through IRS-2 induction, and liver Irs2 is both necessary and sufficient to mediate HIF-2α and VEGF inhibition effects on glucose tolerance. Liver-specific constitutive HIF-2α activation, IRS-2 expression analysis, Irs2-/- rescue experiments, VEGF inhibitor treatment in diabetic db/db mice Nature medicine High 24037094
2016 JAK2V617F binds IRS2 in JAK2-mutant HEL cells; IRS2 silencing in JAK2V617F cells decreases STAT5 phosphorylation, reduces cell viability, and increases apoptosis, effects enhanced when combined with ruxolitinib; this interaction is absent in JAK2WT cells. Co-immunoprecipitation of JAK2 with IRS2, siRNA IRS2 knockdown, cell viability and apoptosis assays, STAT5 phosphorylation; validated with pharmacological IRS1/2 inhibition in primary MPN patient samples Oncotarget Medium 26755644
2022 IRS2-PI3K signaling enhances MYC expression by inhibiting GSK3β activity and reducing MYC phosphorylation at Thr58, thereby preventing proteasomal degradation of MYC and sustaining active pS62-MYC to support breast cancer stem cell self-renewal; a T58A-MYC mutant rescues CSC function in Irs2-/- cells. IRS2 knockout cells, GSK3β activity assays, MYC T58 phosphorylation immunoblotting, proteasome inhibitor experiments, T58A-MYC rescue construct in Irs2-/- cells, CSC sphere assay Cell reports High 36476848
2011 Chronic central leptin infusion decreases the association between the insulin receptor β chain and IRS2 in the hypothalamus, increases SOCS3 association with the insulin receptor, and augments JAK2-IRS2 association, thereby blunting insulin's ability to activate the IRS2-mediated PI3K/Akt pathway. Co-immunoprecipitation of IRβ with IRS2 and SOCS3, co-IP of JAK2 with IRS2 in rat hypothalamus, chronic icv leptin infusion followed by acute icv insulin injection, Akt phosphorylation biochemistry Journal of neurochemistry Medium 21255014

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 788 22869320
1995 Role of IRS-2 in insulin and cytokine signalling. Nature 740 7675087
2002 SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. The Journal of biological chemistry 702 12228220
1999 Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nature genetics 454 10471495
2007 Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science (New York, N.Y.) 440 17641201
1997 A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. The Journal of biological chemistry 428 9368067
2000 Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. The Journal of clinical investigation 388 10642598
2007 Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance. The Journal of clinical investigation 284 17200721
2005 Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. The Journal of clinical investigation 215 15711641
2006 IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates. Nature neuroscience 183 17143271
2005 Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. The Journal of clinical investigation 179 16374520
2005 Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function. The Journal of biological chemistry 176 16272563
1997 Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Diabetologia 172 9389430
2002 Pdx1 restores beta cell function in Irs2 knockout mice. The Journal of clinical investigation 154 11994408
2018 Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer. The Journal of clinical investigation 152 29400692
2002 Increased insulin sensitivity and upregulation of insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2 in liver of Ames dwarf mice. The Journal of endocrinology 152 11927387
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
2001 Identification of insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the alpha6beta4 integrin-dependent activation of phosphoinositide 3-OH kinase and promotion of invasion. Molecular and cellular biology 146 11438664
2013 Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38α MAPK during insulin resistance. Diabetes 143 24159000
2007 Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2. Cell cycle (Georgetown, Tex.) 142 17374994
2006 Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2. Molecular and cellular biology 140 17030631
1997 The IRS-2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine action. Molecular endocrinology (Baltimore, Md.) 127 9013772
1997 Insulin receptor substrate (IRS)-1 and IRS-2 are tyrosine-phosphorylated and associated with phosphatidylinositol 3-kinase in response to brain-derived neurotrophic factor in cultured cerebral cortical neurons. The Journal of biological chemistry 124 9374521
2005 TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes. Nature medicine 120 16327801
2009 Epigallocatechin gallate (EGCG) and rutin suppress the glucotoxicity through activating IRS2 and AMPK signaling in rat pancreatic beta cells. Journal of agricultural and food chemistry 118 19803520
2009 Inhibition of PTP1B restores IRS1-mediated hepatic insulin signaling in IRS2-deficient mice. Diabetes 99 20028942
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
2008 Aldosterone inhibits insulin-induced glucose uptake by degradation of insulin receptor substrate (IRS) 1 and IRS2 via a reactive oxygen species-mediated pathway in 3T3-L1 adipocytes. Endocrinology 96 19095745
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 94 15247132
2011 IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease. The Journal of clinical investigation 93 21926467
2013 A liver Hif-2α-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition. Nature medicine 91 24037094
2016 Glucose Induces Mouse β-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor. Diabetes 89 26740601
2007 Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis. Cell cycle (Georgetown, Tex.) 86 17361103
2018 Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers. International journal of obesity (2005) 83 29717275
2002 Positive and negative regulatory role of insulin receptor substrate 1 and 2 (IRS-1 and IRS-2) serine/threonine phosphorylation. Biochemistry 77 12033942
2013 miR-135a targets IRS2 and regulates insulin signaling and glucose uptake in the diabetic gastrocnemius skeletal muscle. Biochimica et biophysica acta 72 23579070
2018 Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity. Nature communications 70 30451856
2015 Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity. Nature communications 69 25879670
2011 IRS-2 Deficiency impairs NMDA receptor-dependent long-term potentiation. Cerebral cortex (New York, N.Y. : 1991) 69 21955917
1996 Insulin receptor substrate 1 and 2 (IRS1 and IRS2): what a tangled web we weave. Trends in cell biology 67 15157524
2017 MiR-338-3p inhibits the growth and invasion of non-small cell lung cancer cells by targeting IRS2. American journal of cancer research 62 28123847
2019 Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study. Human molecular genetics 60 31009952
2004 Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice. Diabetes 58 14693698
2020 Long noncoding RNA lncARSR promotes nonalcoholic fatty liver disease and hepatocellular carcinoma by promoting YAP1 and activating the IRS2/AKT pathway. Journal of translational medicine 55 32169080
2007 The repression of IRS2 gene by ATF3, a stress-inducible gene, contributes to pancreatic beta-cell apoptosis. Diabetes 55 18057093
2024 Phosphorylation Codes in IRS-1 and IRS-2 Are Associated with the Activation/Inhibition of Insulin Canonical Signaling Pathways. Current issues in molecular biology 53 38248343
2008 IRS-2 branch of IGF-1 receptor signaling is essential for appropriate timing of myelination. Journal of neurochemistry 53 18717815
2011 Chromatin-modifying drugs induce miRNA-153 expression to suppress Irs-2 in glioblastoma cell lines. International journal of cancer 51 21213215
2006 The reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling. Molecular endocrinology (Baltimore, Md.) 51 16916938
2020 Multi-layered epigenetic regulation of IRS2 expression in the liver of obese individuals with type 2 diabetes. Diabetologia 50 32710190
2012 IRS2 signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action. Cell metabolism 50 22560222
2003 Complex haplotypes of IRS2 gene are associated with severe obesity and reveal heterogeneity in the effect of Gly1057Asp mutation. Human genetics 50 12687350
2018 Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action. Cellular signalling 48 29550500
2009 Silencing mitogen-activated protein 4 kinase 4 (MAP4K4) protects beta cells from tumor necrosis factor-alpha-induced decrease of IRS-2 and inhibition of glucose-stimulated insulin secretion. The Journal of biological chemistry 48 19690174
2013 IRS2 is a candidate driver oncogene on 13q34 in colorectal cancer. International journal of experimental pathology 46 23594372
2013 Serine phosphorylation sites on IRS2 activated by angiotensin II and protein kinase C to induce selective insulin resistance in endothelial cells. Molecular and cellular biology 46 23775122
2004 IRS-2 mediates the antiapoptotic effect of insulin in neonatal hepatocytes. Hepatology (Baltimore, Md.) 43 15565601
2008 Molecular mechanisms of atherosclerosis in metabolic syndrome: role of reduced IRS2-dependent signaling. Arteriosclerosis, thrombosis, and vascular biology 41 18802016
2014 Insulin receptor substrate-2 (Irs2) in endothelial cells plays a crucial role in insulin secretion. Diabetes 39 25277391
2009 Association between total immunoglobulin E and antibody responses to naturally acquired Ascaris lumbricoides infection and polymorphisms of immune system-related LIG4, TNFSF13B and IRS2 genes. Clinical and experimental immunology 38 19604268
2012 Insulin receptor substrate 2 (IRS2)-deficient mice show sensorineural hearing loss that is delayed by concomitant protein tyrosine phosphatase 1B (PTP1B) loss of function. Molecular medicine (Cambridge, Mass.) 36 22160220
2001 IRS-1 and IRS-2 are recruited by TrkA receptor and oncogenic TRK-T1. Journal of cellular physiology 36 11147812
2020 Endothelial TFEB (Transcription Factor EB) Improves Glucose Tolerance via Upregulation of IRS (Insulin Receptor Substrate) 1 and IRS2. Arteriosclerosis, thrombosis, and vascular biology 35 33297755
2018 Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma. Science signaling 35 30459283
2017 IRS-2 Partially Compensates for the Insulin Signal Defects in IRS-1-/- Mice Mediated by miR-33. Molecules and cells 34 28190325
2016 MicroRNA-181b suppresses TAG via target IRS2 and regulating multiple genes in the Hippo pathway. Experimental cell research 34 27616141
2011 Calcium/calmodulin-dependent kinase IV controls glucose-induced Irs2 expression in mouse beta cells via activation of cAMP response element-binding protein. Diabetologia 34 21301804
2022 The insulin and IGF signaling pathway sustains breast cancer stem cells by IRS2/PI3K-mediated regulation of MYC. Cell reports 32 36476848
2021 Silencing TXNIP ameliorates high uric acid-induced insulin resistance via the IRS2/AKT and Nrf2/HO-1 pathways in macrophages. Free radical biology & medicine 31 34848368
2016 MiR-126 Suppresses the Glucose-Stimulated Proliferation via IRS-2 in INS-1 β Cells. PloS one 31 26919700
2013 Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis. Molecular metabolism 31 24567904
2007 Exendin-4 and exercise promotes beta-cell function and mass through IRS2 induction in islets of diabetic rats. Life sciences 31 18237751
2021 Differential involvement of insulin receptor substrate (IRS)-1 and IRS-2 in brain insulin signaling is associated with the effects on amyloid pathology in a mouse model of Alzheimer's disease. Neurobiology of disease 30 34537327
2015 IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes. Biochimica et biophysica acta 30 26384875
2014 Insulin induces IRS2-dependent and GRK2-mediated β2AR internalization to attenuate βAR signaling in cardiomyocytes. Cellular signalling 30 25460042
2003 Pdx1 expression in Irs2-deficient mouse beta-cells is regulated in a strain-dependent manner. The Journal of biological chemistry 30 12869553
2020 High uric acid promotes dysfunction in pancreatic β cells by blocking IRS2/AKT signalling. Molecular and cellular endocrinology 28 33127482
2015 The upregulation of miRNA-146a inhibited biological behaviors of ESCC through inhibition of IRS2. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 28 26508028
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
2014 IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines. Molecular cancer therapeutics 27 25527633
2012 JNK3 maintains expression of the insulin receptor substrate 2 (IRS2) in insulin-secreting cells: functional consequences for insulin signaling. PloS one 27 22563476
2022 Estrogen Protects Cardiac Function and Energy Metabolism in Dilated Cardiomyopathy Induced by Loss of Cardiac IRS1 and IRS2. Circulation. Heart failure 26 35579013
2014 β-Cell proliferation after a partial pancreatectomy is independent of IRS-2 in mice. Endocrinology 26 24517226
2013 Phosphorylation of serine 1137/1138 of mouse insulin receptor substrate (IRS) 2 regulates cAMP-dependent binding to 14-3-3 proteins and IRS2 protein degradation. The Journal of biological chemistry 26 23615913
2011 Decreased IRS2 and TIMP3 expression in monocytes from offspring of type 2 diabetic patients is correlated with insulin resistance and increased intima-media thickness. Diabetes 26 21984580
2004 Restoration of insulin secretion in pancreatic islets of protein-deficient rats by reduced expression of insulin receptor substrate (IRS)-1 and IRS-2. The Journal of endocrinology 26 15072564
2022 Arctigenin mitigates insulin resistance by modulating the IRS2/GLUT4 pathway via TLR4 in type 2 diabetes mellitus mice. International immunopharmacology 25 36481528
2018 IRS2 mutations linked to invasion in pleomorphic invasive lobular carcinoma. JCI insight 25 29669935
2011 Chronic central leptin infusion modifies the response to acute central insulin injection by reducing the interaction of the insulin receptor with IRS2 and increasing its association with SOCS3. Journal of neurochemistry 25 21255014
2012 Association of IRS-1 and IRS-2 genes polymorphisms with polycystic ovary syndrome: a meta-analysis. Endocrine journal 24 22523112
2002 Reduced IRS-2 and GLUT4 expression in PPARgamma2-induced adipocytes derived from C/EBPbeta and C/EBPdelta-deficient mouse embryonic fibroblasts. Journal of cell science 24 12186946
2022 Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation. Frontiers in immunology 22 36177037
2011 IRS2 and PTP1B: Two opposite modulators of hepatic insulin signalling. Archives of physiology and biochemistry 22 21401320
2019 PDK-1 mediated Hippo-YAP-IRS2 signaling pathway and involved in the apoptosis of non-small cell lung cancer cells. Bioscience reports 21 30988063
2018 IRS2 depletion inhibits cell proliferation and decreases hormone secretion in mouse granulosa cells. The Journal of reproduction and development 21 29998910
2018 Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity. Molecular metabolism 21 30553769
2008 Irs2 inactivation suppresses tumor progression in Pten+/- mice. The American journal of pathology 20 19095950
2020 MiRNA-200a-3p suppresses the proliferation, migration and invasion of non-small cell lung cancer through targeting IRS2. European review for medical and pharmacological sciences 19 32016973
2016 IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive myeloproliferative neoplasms. Oncotarget 19 26755644
2015 miR-106a* inhibits the proliferation of renal carcinoma cells by targeting IRS-2. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 19 26018509

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