Affinage

IRS2

Insulin receptor substrate 2 · UniProt Q9Y4H2

Length
1338 aa
Mass
137.3 kDa
Annotated
2026-04-28
100 papers in source corpus 46 papers cited in narrative 46 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRS2 is a cytoplasmic adaptor protein that transduces signals from insulin, IGF-1, cytokine, and receptor tyrosine kinase receptors to the PI3K–Akt axis, thereby governing glucose homeostasis, cell survival, proliferation, and differentiation across multiple tissues. Upon receptor activation, IRS2 is tyrosine-phosphorylated and recruits the p85 subunit of PI3K, activating Akt and downstream effectors including FoxO1, GSK3β, and mTOR; its activity is positively regulated by CREB-, TFE3-, HIF-2α-, PGC1A-, YAP/TAZ-, and SP1-driven transcription, cAMP/GLP-1 signaling, and Nedd4-mediated monoubiquitination that promotes membrane recruitment, while it is negatively regulated by serine phosphorylation (mTOR at Ser675, ERK1/2 at Ser907) triggering degradation and by SOCS1/3–elongin BC-mediated ubiquitin-proteasomal destruction (PMID:7675087, PMID:7559579, PMID:9368067, PMID:12228220, PMID:21098738, PMID:25879670, PMID:12842910, PMID:16327801, PMID:24037094, PMID:29400692). IRS2 is the dominant adaptor for pancreatic β-cell survival and Pdx1 maintenance, hepatic suppression of gluconeogenesis via the Akt–FoxO1 pathway, VTA dopamine neuron morphology, hippocampal LTP, myelination timing, macrophage M2a polarization, and female fertility (PMID:10471495, PMID:11994408, PMID:15711641, PMID:16374520, PMID:17143271, PMID:21955917, PMID:18717815, PMID:30451856, PMID:11014193). In cancer contexts, IRS2 stabilizes MYC by inhibiting GSK3β-mediated Thr58 phosphorylation in breast cancer stem cells, mediates ALK-driven Akt–FoxO3 survival signaling in neuroblastoma, and functions as a YAP/TAZ effector promoting hepatocellular carcinoma (PMID:36476848, PMID:30459283, PMID:29400692).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1995 High

    Identification of IRS-2 as a second insulin receptor substrate with PH and PTB domains established that insulin/IGF-1/cytokine signaling operates through a family of adaptor proteins rather than solely through IRS-1.

    Evidence Protein purification and cloning from myeloid progenitor cells; reciprocal IP and PI3K assays in IRS-1-deficient mice

    PMID:7559579 PMID:7675087

    Open questions at the time
    • Three-dimensional structure of full-length IRS-2 undetermined
    • Relative stoichiometry of IRS-1 vs IRS-2 at the insulin receptor not quantified
  2. 1997 High

    Demonstration that serine/threonine phosphorylation of IRS-2 blocks its binding to the insulin receptor juxtamembrane domain revealed the molecular basis of TNFα- and chronic-insulin-induced insulin resistance at the IRS-2 level.

    Evidence In vitro binding assays with His6-tagged IR domains; TNFα treatment and alkaline phosphatase reversal in Fao cells

    PMID:9368067

    Open questions at the time
    • Specific serine residues mediating TNFα-induced inhibition not mapped in this study
    • Kinase(s) responsible for inhibitory serine phosphorylation not identified here
  3. 1997 High

    Showing that IRS-1 and IRS-2 are not functionally interchangeable for IGF-1-driven mitogenesis — IRS-2 restores PI3K but not cell cycle progression — defined substrate-specific signaling outputs.

    Evidence Retroviral reconstitution in IRS-1-deficient cells; SH2-domain pull-downs across cell types

    PMID:9013772 PMID:9032279

    Open questions at the time
    • Molecular determinant on IRS-1 that uniquely drives S-phase entry not identified
    • Differential phosphosite usage between IRS-1 and IRS-2 not fully mapped
  4. 1998 High

    Subcellular fractionation revealed that IRS-2 is predominantly cytosolic yet phosphorylated at intracellular membranes, with more transient PI3K signaling than IRS-1, establishing compartmentalization as a mechanism for signaling specificity.

    Evidence Subcellular fractionation and in vitro reconstitution in 3T3-L1 adipocytes; GST-SH2 pull-downs in brown adipocytes

    PMID:9565570 PMID:9605931

    Open questions at the time
    • Mechanism driving IRS-2 membrane translocation not determined
    • Whether compartmentalization differs across cell types not systematically tested
  5. 1999 High

    Genetic epistasis in Irs2-haploinsufficient and Igf1r-haploinsufficient mice proved IRS-2 is the dominant adaptor coordinating IGF-1R-mediated β-cell development and compensation for insulin resistance, distinguishing its role from IRS-1.

    Evidence Intercross of Irs1+/-, Irs2+/-, and Igf1r+/- mice with metabolic phenotyping

    PMID:10471495

    Open questions at the time
    • IRS-2-specific downstream transcriptional programs in β-cells not characterized
    • Whether IRS-2 is required cell-autonomously in β-cells not yet resolved at this stage
  6. 2000 High

    Discovery that IRS-2 knockout causes female infertility (anovulatory ovaries, reduced gonadotrophs) and that hepatic IRS-2 is transcriptionally downregulated by hyperinsulinemia broadened IRS-2 biology beyond metabolism to reproduction and established a 'mixed resistance' model in liver.

    Evidence Irs2 knockout reproductive phenotyping; mRNA analysis in lipodystrophic and ob/ob mouse livers

    PMID:10949029 PMID:11014193

    Open questions at the time
    • Mechanism of IRS-2 transcriptional repression by chronic insulin not identified
    • Cell-autonomous role in pituitary gonadotrophs vs. ovarian cells not dissected
  7. 2002 High

    Identification of SOCS1/3–elongin BC as the E3 ligase complex mediating IRS-2 ubiquitin-proteasomal degradation, and demonstration that IRS-2 sustains Pdx1 expression in β-cells (rescued by Pdx1 transgene), defined both a key negative regulator and a critical transcriptional target of IRS-2 signaling.

    Evidence SOCS box mutagenesis and ubiquitination assays; Irs2-/-/Pdx1-transgenic genetic rescue; IL-4/T cell functional assays in Irs2-/- mice

    PMID:11739727 PMID:11994408 PMID:12228220

    Open questions at the time
    • Specific lysine residues on IRS-2 targeted by SOCS-mediated ubiquitination not mapped
    • Whether SOCS-mediated degradation is the dominant pathway in β-cells not tested
  8. 2003 High

    ChIP-validated CREB binding to the IRS2 promoter established a cAMP→CREB→IRS2→Akt feed-forward circuit that explained how incretin signaling promotes β-cell survival.

    Evidence A-CREB dominant-negative transgenic mice; chromatin immunoprecipitation of IRS2 promoter; cAMP-IRS2-Akt signaling in islets

    PMID:12842910

    Open questions at the time
    • Other transcription factors co-operating with CREB at the IRS2 promoter not identified
    • Epigenetic regulation of IRS2 promoter not addressed
  9. 2005 High

    Isoform-specific hepatic knockdown and liver-specific double knockouts established that IRS-1 and IRS-2 have partially non-overlapping hepatic roles — IRS-2 linked to SREBP-1c/lipogenesis, IRS-1 to gluconeogenesis suppression — with combined loss abolishing Akt–FoxO1 signaling. TFE3 and GLP-1/exendin-4 were identified as positive transcriptional and hormonal regulators of IRS-2.

    Evidence Adenoviral shRNA knockdown in liver; liver-specific Irs2 KO on Irs1-/- background; TFE3 adenoviral expression; exendin-4 treatment in Irs2-/- mice and human islets

    PMID:15711641 PMID:16272563 PMID:16327801 PMID:16374520

    Open questions at the time
    • Whether TFE3 regulation of IRS-2 operates in extrahepatic tissues not tested
    • Mechanistic basis for IRS-2-specific lipogenic gene regulation not fully delineated
  10. 2006 High

    IRS-2 was shown to regulate diverse biological contexts: β-catenin-driven mammary tumorigenesis upon overexpression, VTA dopamine neuron size and morphine reward via Akt, glucose-dependent transcriptional induction in β-cells, and a reciprocal stability circuit with FoxO1.

    Evidence Mammary-specific IRS-2 transgenic mice and β-catenin Co-IP; viral IRS2/Akt manipulation in rat VTA with behavioral assays; glucose dose-response in isolated islets; Irs2-/- MEFs with rapamycin and FoxO1 stability assays

    PMID:16574657 PMID:16916938 PMID:17030631 PMID:17143271

    Open questions at the time
    • Structural basis for IRS-2/β-catenin interaction unknown
    • Whether FoxO1–IRS-2 reciprocal circuit operates in all IRS-2-expressing tissues not tested
  11. 2007 High

    Brain-specific Irs2 deletion extended lifespan by ~18% and reduced hypothalamic oxidative stress, establishing CNS IRS-2 signaling as a determinant of organismal aging.

    Evidence Brain-specific Irs2 conditional KO mice; lifespan measurement; metabolic cage studies; SOD2 analysis

    PMID:17641201

    Open questions at the time
    • Specific neuronal populations mediating lifespan effect not identified
    • Whether caloric restriction and IRS-2 reduction share a common mechanism not tested
  12. 2008 High

    SILAC-based phosphotyrosine interactome mapping of IRS-2 revealed site-specific interaction partners and combinatorial phosphorylation effects, while IRS-2 was shown to be required for proper myelination timing via IGF-1R signaling.

    Evidence SILAC quantitative MS with phosphopeptide baits; Irs2-/- mouse myelin protein analysis at P10

    PMID:18717815 PMID:19001411

    Open questions at the time
    • Which tyrosine sites are critical for myelination signaling not identified
    • Oligodendrocyte-autonomous requirement for IRS-2 not demonstrated
  13. 2010 High

    Mapping mTOR-dependent Ser675 phosphorylation as a degradation signal and ERK1/2-dependent Ser907 phosphorylation as a modulator of adjacent Tyr911 defined the molecular logic of negative feedback serine phosphorylation on IRS-2.

    Evidence Phosphosite-specific monoclonal antibodies; Ala mutants; siRNA knockdown of ERK1/2 and mTOR; protein half-life in HEK293 cells

    PMID:21098738

    Open questions at the time
    • Full catalog of inhibitory serine phosphorylation sites on IRS-2 not complete
    • In vivo significance of Ser675 and Ser907 not tested in animal models
  14. 2011 High

    IRS-2 was found to be tyrosine-phosphorylated during hippocampal LTP induction and required for NMDA receptor-dependent Fyn/Akt/MAPK activation, and separately, reducing brain IRS-2 in Huntington disease mice improved motor function via FoxO1-dependent autophagy, revealing bidirectional roles in neuronal plasticity and neurodegeneration.

    Evidence Hippocampal slice LTP recordings in Irs2-/- mice; genetic modulation of Irs2 in R6/2 HD mice with autophagosome quantification

    PMID:21926467 PMID:21955917

    Open questions at the time
    • Upstream kinase phosphorylating IRS-2 during LTP not identified
    • Whether IRS-2 reduction benefits other polyglutamine diseases not tested
  15. 2013 High

    IRS-2 was placed downstream of ALK as a signaling node in neuroblastoma and downstream of HIF-2α in liver, expanding the receptor and transcriptional inputs that converge on IRS-2.

    Evidence Integrated proximal proteomics and siRNA in neuroblastoma cells; liver-specific HIF-2α activation with IRS-2 KO rescue

    PMID:24037094 PMID:30459283

    Open questions at the time
    • Whether ALK directly phosphorylates IRS-2 or acts via an intermediary kinase not resolved
    • Mechanism by which HIF-2α induces IRS-2 (direct vs. indirect) not fully determined
  16. 2015 High

    Nedd4 was identified as an E3 ligase that monoubiquitinates IRS-2, promoting Epsin1-dependent plasma membrane recruitment and enhanced IGF-1R signaling — the first positive ubiquitination event on IRS-2. Separately, FSH was shown to induce IRS-2 via SP1 in granulosa cells linking IRS-2 to ovarian physiology.

    Evidence Co-IP, ubiquitination assays, Epsin1 binding, zebrafish validation; IRS-2 promoter ChIP for SP1, siRNA knockdown in granulosa cells

    PMID:25879670 PMID:26388164

    Open questions at the time
    • Specific lysine(s) on IRS-2 monoubiquitinated by Nedd4 not mapped
    • Whether Nedd4-mediated membrane recruitment occurs in β-cells or neurons not tested
  17. 2018 High

    YAP/TAZ-driven IRS2 transcription was shown to amplify Akt signaling and drive hepatocellular carcinoma, while hyperinsulinemia-mediated IRS-2 downregulation in macrophages impaired M2a polarization through FoxO1/HDAC3/NCoR1 stabilization, extending IRS-2 biology to Hippo pathway oncogenesis and innate immune regulation.

    Evidence Pten/Sav1 double KO mice with AAV-Cas9 IRS2 knockout; myeloid-specific Irs2 and IR KO mice; macrophage activation assays

    PMID:29400692 PMID:30451856

    Open questions at the time
    • Direct YAP/TAZ binding to IRS2 promoter not shown by ChIP
    • Whether M2a polarization defect contributes to human metabolic disease not established
  18. 2019 High

    PGC1A was identified as a fasting-induced transcriptional driver of IRS2 (while suppressing IRS1), establishing the IRS1:IRS2 ratio as a regulated variable that primes the liver for insulin-mediated gluconeogenic suppression upon refeeding.

    Evidence Gain- and loss-of-function in primary hepatocytes; ex vivo glucose production; in vivo PGC1A overexpression

    PMID:30770439

    Open questions at the time
    • Whether PGC1A regulation of IRS2 extends to muscle or brain not tested
    • Co-activator complex used by PGC1A at the IRS2 locus not identified
  19. 2022 High

    IRS2-PI3K signaling was shown to stabilize MYC in breast cancer stem cells by inhibiting GSK3β-mediated Thr58 phosphorylation and proteasomal degradation, as proven by T58A-Myc rescue in Irs2-null cells, establishing a direct IRS2–GSK3β–MYC oncogenic axis.

    Evidence IRS2 KO in breast cancer cells; GSK3β activity; MYC Thr58 phosphorylation; T58A-Myc mutant rescue; stem cell functional assays

    PMID:36476848

    Open questions at the time
    • Whether this axis operates in non-breast cancers not tested
    • Contribution of IRS-1 to MYC stabilization not evaluated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of IRS-2, the complete catalog of regulatory serine/threonine phosphorylation sites and their kinases, the tissue-specific mechanisms controlling the IRS-1:IRS-2 ratio, and the structural basis for differential SH2-domain recruitment relative to IRS-1.
  • No high-resolution structure of IRS-2
  • Complete serine phosphorylation code not mapped
  • Tissue-specific transcriptional regulation not comprehensively defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 5 R-HSA-1430728 Metabolism 4 R-HSA-1266738 Developmental Biology 3 R-HSA-112316 Neuronal System 2 R-HSA-168256 Immune System 2
Partners
ALKCTNNB1GRB2GRK2NEDD4PIK3R1SOCS1SOCS3

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 IRS-2 (originally called 4PS) was identified as a second IRS-signaling protein that acts as an interface between signaling proteins with SH2 domains and the receptors for insulin, IGF-1, and several interleukins (IL-4, IL-9, IL-13). It contains a conserved N-terminal pleckstrin-homology domain and phosphotyrosine-binding domain. Protein purification and cloning from myeloid progenitor cells; sequence alignment with IRS-1 Nature High 7675087
1995 IRS-2 (4PS) is the primary alternative substrate of the insulin receptor in IRS-1-deficient mice. Following insulin stimulation, IRS-2 is phosphorylated, binds the p85 subunit of PI 3-kinase activating it, and associates with Grb2 in liver and muscle. Immunoprecipitation, immunoblotting, and PI 3-kinase assays using specific antibodies in IRS-1-deficient mice; immunodepletion experiments The Journal of biological chemistry High 7559579
1997 Serine/threonine phosphorylation of IRS-2 (induced by TNFα, sphingomyelinase, or chronic insulin) impairs its interaction with the juxtamembrane domain of the insulin receptor (amino acids 943-984), thereby inhibiting insulin-induced tyrosine phosphorylation of IRS-2 and propagation of the insulin signal. In vitro binding assays using His6-fusion peptides of IR domains; treatment of Fao cells with TNFα and alkaline phosphatase reversal experiments The Journal of biological chemistry High 9368067
1997 IRS-1 and IRS-2 undergo differential tyrosine phosphorylation and downstream signaling during insulin or IL-4 stimulation. IRS-2 predominates in hematopoietic cells; IRS-1 predominates in adipocytes. Distinct phosphorylation patterns during receptor interaction determine signaling specificity. Interaction with recombinant SH2 domain fusion proteins; differential expression analysis in cell lines Molecular endocrinology Medium 9013772
1997 IRS-1 and IRS-2 are not functionally interchangeable for IGF-1-stimulated mitogenesis despite both activating PI 3-kinase. IRS-1 (but not IRS-2) is required for cell cycle progression (S-phase entry), while IRS-2 overexpression can restore PI 3-kinase activation and immediate-early gene expression to the same degree as IRS-1. Retroviral gene transduction into IRS-1-deficient cells; mitogenesis, PI 3-kinase, and immediate-early gene assays Molecular and cellular biology High 9032279
1998 IRS-2 is differentially compartmentalized relative to IRS-1 in adipocytes: IRS-2 is concentrated 2-fold more in cytosol than in intracellular membranes (IM), whereas IRS-1 is enriched in IM. Insulin-stimulated tyrosine phosphorylation of IRS-2 occurs mainly in IM despite its cytosolic localization. After insulin stimulation, both IRS-1 and IRS-2 translocate from IM to cytosol. IRS-2-mediated PI 3-kinase signaling is more transient than IRS-1-mediated signaling. Subcellular fractionation, immunoblotting, in vitro reconstitution assay in 3T3-L1 adipocytes The Journal of biological chemistry High 9565570
1998 In fetal brown adipocytes, both IRS-1 and IRS-2 associate with p85α and activate PI 3-kinase in response to insulin/IGF-1, but only IRS-1 (not IRS-2) associates with Grb2 and links to the Ras-MAPK pathway, as shown by pull-down with GST-Grb2-SH2 and competition with a phosphopeptide containing pTyr895. GST-SH2 domain pull-down experiments, immunoprecipitation, phosphopeptide competition assays in fetal brown adipocytes Molecular endocrinology High 9605931
1999 Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signaling in vivo. Irs-2 has the major role in beta-cell development and compensation for peripheral insulin resistance; intercross with Igf1r heterozygotes revealed that Igf-1 receptors promote beta-cell development through the Irs-2 signaling pathway. Genetic intercross of Irs1+/- and Irs2+/- mice; intercross with Igf1r+/- mice; metabolic phenotyping Nature genetics High 10471495
2000 Chronic hyperinsulinemia downregulates IRS-2 mRNA in liver, producing insulin resistance in gluconeogenesis. Despite IRS-2 deficiency, insulin continues to stimulate SREBP-1c production, establishing a 'mixed' insulin resistance/sensitivity that aggravates hyperinsulinemia. Analysis of lipodystrophic and ob/ob mouse livers; mRNA expression and signaling pathway analysis Molecular cell High 10949029
2000 Deletion of IRS-2 causes female infertility due to small, anovulatory ovaries and reduced pituitary gonadotrophs, demonstrating IRS-2 integrates reproductive and energy homeostasis signals. Irs2 knockout mouse phenotypic analysis including hormonal measurements, pituitary size, and ovarian histology Nature High 11014193
2001 IRS-2 mediates IGF-I-stimulated breast cancer cell migration in metastatic variants; antisense reduction of IRS-2 diminishes IGF-mediated motility and anchorage-independent growth, defining IRS-2 as a positive regulator of breast cancer cell motility. Antisense IRS-2 transfection, IGF-I stimulation, migration and anchorage-independent growth assays Oncogene Medium 11704861
2001 IRS-1 and IRS-2 together are essential for adipocyte differentiation. Double-knockout of IRS-1 and IRS-2 completely abolishes adipocyte differentiation, PI 3-kinase activity during differentiation, and expression of C/EBPα and PPARγ. Mouse embryonic fibroblasts with four genotypes (WT, IRS-1-/-, IRS-2-/-, double KO); adipocyte differentiation assays, PI 3-kinase activity, gene expression Molecular and cellular biology High 11259600
2002 SOCS1 and SOCS3 bind IRS-1 and IRS-2 and promote their ubiquitin-mediated degradation via the elongin BC ubiquitin-ligase complex. Mutations in the SOCS box of SOCS1 abrogate interaction with elongin BC without affecting IRS binding, and eliminate ubiquitination/degradation of IRS proteins. Co-immunoprecipitation of endogenous and recombinant proteins; ubiquitination assays; SOCS box mutants; adenoviral expression in mouse liver The Journal of biological chemistry High 12228220
2002 Pdx1 expression is reduced in islets from Irs2-/- mice before diabetes onset. Transgenic overexpression of Pdx1 restores beta-cell mass and function in Irs2-/- mice, preventing diabetes, demonstrating IRS-2 signaling is required for maintaining Pdx1 expression in beta-cells. Irs2-/- mouse islet analysis; Pdx1 transgenic rescue; genetic epistasis with Pdx1 haploinsufficiency The Journal of clinical investigation High 11994408
2002 IRS-2 and Stat6 cooperate in IL-4-induced T cell proliferation and Th2 differentiation. IRS-2 deficiency compromises IL-4-induced proliferation (through co-regulation of p27kip1) and Th2 cytokine secretion, but both Stat6 and IRS-2 are dispensable for IL-4-induced survival. T cells from Stat6-/-, Irs2-/-, and double-deficient mice; proliferation, cytokine secretion, and apoptosis assays Molecular and cellular biology High 11739727
2003 cAMP promotes pancreatic beta-cell survival via CREB-mediated transcriptional induction of IRS2. CREB directly targets the IRS2 promoter in vivo; IRS2 induction by cAMP enhances Akt activation in response to insulin/IGF-1. A-CREB dominant-negative transgenic mice; chromatin immunoprecipitation; cAMP/IRS2/Akt signaling assays in islets Genes & development High 12842910
2005 Hepatic IRS-1 is linked preferentially to glucose homeostasis (gluconeogenesis suppression) while IRS-2 is linked to lipid metabolism (SREBP-1c/fatty acid synthase regulation) in liver. Combined knockdown causes defective Akt activation and Foxo1 phosphorylation with systemic insulin resistance. Adenovirus-mediated shRNA knockdown of IRS-1, IRS-2, or both in mouse liver; gene expression, metabolic, and signaling analyses The Journal of clinical investigation High 15711641
2005 TFE3 (a bHLH transcription factor) directly transactivates IRS-2 expression via E-box elements in the IRS-2 promoter, leading to enhanced Akt signaling and reduced plasma glucose. Expression cloning; adenoviral TFE3 expression in hepatocytes and in vivo; IRS-2 promoter analysis Nature medicine High 16327801
2005 Exendin-4 (GLP-1 receptor agonist) increases cAMP in beta cells, which promotes IRS-2 expression and Akt phosphorylation. Long-term beta-cell mass expansion by Ex4 requires IRS-2 signaling, as Ex4 fails to arrest beta-cell loss in Irs2-/- mice. cAMP measurement, IRS-2 expression, Akt phosphorylation in human islets and Min6 cells; Ex4 treatment of Irs2-/- mice The Journal of biological chemistry High 16272563
2005 Deletion of both hepatic Irs1 and Irs2 abolishes Akt-FoxO1 pathway signaling in liver, causing hyperglycemia and upregulation of gluconeogenic genes (Pck1, G6pc, Ppargc1). Irs2 alone or Irs1 alone in liver is sufficient to maintain near-normal glucose homeostasis. Liver-specific Irs2 knockout (LKO) on Irs1-/- background; signaling pathway analysis, gene expression profiling The Journal of clinical investigation High 16374520
2006 IRS-2 is a substrate of the TrkA receptor and the TRK-T1 oncogene. IRS-2 tyrosine phosphorylation by TrkA/TRK-T1 leads to recruitment of p85-PI3K, SHP-2, and Grb2 and increased PI 3-kinase activity. Direct interaction between TRK and IRS-2 was demonstrated by yeast two-hybrid. Co-immunoprecipitation, PI 3-kinase activity assays, yeast two-hybrid Journal of cellular physiology Medium 11147812
2006 FoxO1 and IRS-2 form a reciprocal stability circuit: Irs2 signaling promotes FoxO1 nuclear exclusion and degradation; loss of Irs2 increases FoxO1 stability. Conversely, FoxO1 transcription drives IRS-2 expression. Rapamycin inhibits Irs2 degradation and causes persistent FoxO1 degradation. Mouse embryo fibroblasts from Irs1-/- and Irs2-/- mice; protein stability assays; rapamycin treatment; PI 3-kinase and Akt activation measurements Molecular endocrinology High 16916938
2006 IRS-2 expression in pancreatic beta-cells is specifically regulated by glucose at the transcriptional level in a dose-dependent, Ca2+-dependent manner. Glucose-induced IRS-2 upregulation correlates with increased IRS-2 tyrosine phosphorylation and Akt activation, promoting beta-cell survival. IRS-2 mRNA/protein expression kinetics in isolated rat islets; glucose dose-response; intracellular Ca2+ inhibition experiments; Akt phosphorylation assays The Journal of biological chemistry High 16574657
2006 IRS-2 overexpression in mammary gland causes progressive hyperplasia and tumorigenesis. IRSs bind β-catenin in vitro and in vivo, and IRS-2 overexpression causes constitutive phosphorylation and mammary tumors with squamous differentiation consistent with β-catenin pathway activation. Transgenic mice with mammary-specific IRS-1 or IRS-2 overexpression; Co-IP of β-catenin with IRS proteins in vitro and in vivo Molecular and cellular biology High 17030631
2006 The IRS2-Akt signaling pathway in VTA dopamine neurons is downregulated by chronic morphine, mediating the decrease in dopamine cell size and diminishing morphine reward (conditioned place preference). Viral-mediated manipulation of IRS2-Akt in VTA established causal roles. Viral-mediated gene transfer to rat VTA; conditioned place preference; dopamine cell morphometry; chronic morphine pellet administration Nature neuroscience High 17143271
2007 Brain-specific Irs2 knockout in mice extends lifespan up to 18%, reduces meal-induced hypothalamic oxidative stress (stable SOD2), and maintains greater glucose oxidation, identifying brain IRS2 as a regulator of longevity and nutrient homeostasis. Brain-specific Irs2 conditional knockout mice; lifespan measurement; metabolic cage studies; hypothalamic SOD2 measurement Science High 17641201
2008 Phosphotyrosine interactome mapping of IRS-2 identified phosphorylation-specific interaction partners for multiple tyrosine sites, including shared partners with IRS-1 and several differential interactors. IRS-2 shows different combinatorial phosphorylation effects and differential binding of SHP2 compared to IRS-1. SILAC-based quantitative interaction proteomics with phosphorylated vs. non-phosphorylated bait peptides Molecular & cellular proteomics High 19001411
2008 IRS-2 deficiency impairs appropriate timing of myelination in vivo; IRS-2-/- mice show reduced myelin protein expression at postnatal day 10. Compensatory IRS-1 upregulation and increased IGF-1R signaling occur in IRS-2-/- brains, demonstrating IGF-1R/IRS-2 signals are critical for myelination timing. IRS-2-/- mice; myelin protein expression by Western blot/immunostaining; cerebral myelin isolation; compensatory IRS-1 analysis Journal of neurochemistry High 18717815
2009 Deletion of Irs2 in APP transgenic mice reduces amyloid-β deposition, increases transthyretin (an Aβ-binding clearance protein), and rescues behavioral deficits, while increasing tau phosphorylation (reduced tau-phosphatase PP2A despite inhibited GSK-3). This reveals divergent effects of IRS2 on amyloid vs. tau pathology. Genetic cross of Tg2576 APP mice with Irs2-/- mice; amyloid plaque quantification; tau phosphorylation; transthyretin and PP2A/GSK-3 analysis; behavioral testing Biochemical and biophysical research communications High 19523444
2009 In IRS2-/- mice, hepatic PTP1B expression and its association with the insulin receptor are increased. Double knockout of IRS2 and PTP1B restores IRS1-mediated PI 3-kinase/Akt/Foxo1 signaling in liver, improving glucose tolerance. PTP1B determines insulin receptor phosphorylation state and interplay between IRS1 and IRS2. IRS2-/-/PTP1B-/- double-knockout mice; hepatic insulin signaling analysis; isolated hepatocyte experiments; resveratrol pharmacological inhibition Diabetes High 20028942
2010 IRS-2 is phosphorylated at Ser675 by mTOR and at Ser907 by ERK1/2 following insulin stimulation. Ser675 phosphorylation accelerates IRS-2 protein degradation (mTOR-mediated negative feedback); Ser907 phosphorylation does not impair Grb2 association but affects adjacent Tyr911 phosphorylation. Monoclonal phosphosite-specific antibodies; siRNA knockdown of ERK1/2 and mTOR; Ala mutant IRS-2 expression in HEK293 cells; protein half-life measurement American journal of physiology. Endocrinology and metabolism High 21098738
2011 IRS-2 deficiency impairs NMDA receptor-dependent LTP in hippocampus. During LTP induction, IRS2 is tyrosine-phosphorylated. In Irs2-/- mice, tetanus stimulation fails to activate Fyn, AKT, and MAPK, and NMDA receptor activation is defective, despite normal NR2A, NR2B, and PSD95 expression. Hippocampal slice electrophysiology (LTP recordings); Western blot for Fyn/AKT/MAPK phosphorylation; IRS2 phosphorylation during LTP in control mice Cerebral cortex High 21955917
2011 Increasing Irs2 levels in brains of R6/2 Huntington disease mice worsens neuronal oxidative stress and mitochondrial dysfunction; reducing Irs2 improves motor performance, extends lifespan, and increases nuclear FoxO1 and autophagy. Thus IRS2 signaling modulates HD progression through FoxO1-dependent autophagy. Genetic modulation of Irs2 in R6/2 mice; FoxO1 localization; autophagosome counting; oxidative stress and mitochondrial function assays The Journal of clinical investigation High 21926467
2012 Cardiac-specific deletion of IRS1 and IRS2 causes dilated cardiomyopathy with reduced Akt→FoxO1 signaling, cardiac apoptosis, and fibrosis. Hyperinsulinemia reduces IRS1/2 in cardiomyocytes via p38α MAPK activation, identifying p38α as a mediator of cardiac insulin resistance. Heart-specific IRS1/2 double-knockout mice; neonatal cardiomyocyte experiments with chronic insulin exposure; p38 inhibition Diabetes High 24159000
2013 IRS2 is phosphorylated during caffeine-induced LTP (CAF LTP) in hippocampal CA1 in a Ca2+-dependent manner. Akt phosphorylation during CAF LTP is defective in Irs2-/- mice, demonstrating TrkB-IRS2-PI3K signaling is required for this form of synaptic plasticity. Hippocampal slice recordings; IRS2 phosphorylation measurement; Irs2-/- mice; Ca2+ chelation experiments Addiction biology Medium 27457910
2013 IRS2 is a major substrate and signaling node downstream of oncogenic ALK in neuroblastoma. ALK TKI treatment reduces IRS2 recruitment to ALK and IRS2 tyrosine phosphorylation. IRS2 links ALK to the Akt-FoxO3 survival axis; siRNA depletion of IRS2 or ALK reduces Akt/FoxO3 phosphorylation and cell viability. Integrated proximal proteomics (ALK interactome, phosphotyrosine interactome, phosphoproteome); siRNA depletion; ALK TKI treatment Science signaling High 30459283
2013 HIF-2α directly or indirectly induces IRS-2 expression in liver, sensitizing hepatic insulin signaling. Liver IRS-2 is both necessary and sufficient to mediate HIF-2α and VEGF inhibitor effects on glucose tolerance and hepatic insulin signaling including gluconeogenic gene suppression. Liver-specific constitutive HIF-2α activation; IRS-2 knockout rescue experiments; VEGF inhibitor treatment in diabetic mice Nature medicine High 24037094
2014 Insulin stimulates GRK2 recruitment to β2AR via IRS2, inducing β2AR phosphorylation at GRK sites (Ser355/356) and receptor internalization. IRS2 deletion disrupts the IR-GRK2 complex, attenuates β2AR phosphorylation and internalization, and abrogates insulin's counter-regulation of βAR signaling in cardiomyocytes. Co-immunoprecipitation of IR-GRK2 complex; IRS2 KO cardiomyocytes; β2AR phosphorylation and internalization assays; cAMP-PKA activity measurements Cellular signalling High 25460042
2015 Nedd4 is an E3 ubiquitin ligase for IRS-2 that monoubiquitinates IRS-2, promoting its association with Epsin1 and recruitment to the plasma membrane. Membrane recruitment enhances IGF-1 receptor-induced IRS-2 tyrosine phosphorylation and downstream signaling and mitogenesis. Co-IP; ubiquitination assays; Nedd4 overexpression; Epsin1 binding assays; zebrafish embryo growth experiments; prostate cancer cell proliferation Nature communications High 25879670
2015 FSH specifically induces IRS-2 expression in granulosa cells via the cAMP pathway and SP1 transcription factor binding to IRS-2 promoter SP1 sites. FSH stimulates SP1 nuclear translocation and IRS-2 promoter binding. IRS-2 mediates FSH-stimulated PI3K activity, Akt phosphorylation, GLUT4 translocation and glucose uptake in granulosa cells. IRS-2 promoter analysis; siRNA knockdown; chromatin immunoprecipitation; SP1 nuclear translocation imaging; GLUT4 translocation assay Cellular signalling High 26388164
2016 JAK2V617F (oncogenic JAK2) directly binds IRS2 in MPN cells; IRS2 silencing decreases STAT5 phosphorylation, reduces viability and increases apoptosis in JAK2V617F cells but not JAK2WT cells, demonstrating IRS2 as a binding partner and survival node specific to mutant JAK2 signaling. Co-immunoprecipitation of JAK2/IRS2; siRNA silencing; viability and apoptosis assays in MPN cell lines and primary patient samples Oncotarget Medium 26755644
2018 YAP/TAZ transcriptional activity in liver upregulates IRS2 expression, amplifying AKT signaling. Knockout of IRS2 by AAV-Cas9 represses liver tumorigenesis in Pten-/-/Sav1-/- mice, placing IRS2 downstream of Hippo/YAP-TAZ signaling as a driver of hepatocellular carcinoma. Genetic mouse models (Pten/Sav1 double KO); AAV-Cas9 IRS2 knockout; IRS2 expression correlation with YAP/TAZ in human HCC The Journal of clinical investigation High 29400692
2018 Hyperinsulinemia downregulates macrophage IRS2 expression via the insulin receptor, impairing the IL-4/IRS2/Akt pathway and M2a-subtype macrophage activation. This impairment stabilizes the FoxO1/HDAC3/NCoR1 corepressor complex and leads to systemic insulin resistance under high-fat diet. Myeloid cell-specific Irs2 and IR knockout mice; macrophage activation assays; FoxO1/HDAC3/NCoR1 complex analysis Nature communications High 30451856
2019 PGC1A drives IRS2 expression downstream of glucagon/cAMP/CREB signaling in hepatocytes while simultaneously reducing IRS1 expression, controlling the IRS1:IRS2 ratio during fasting. PGC1A-induced IRS2 is essential for insulin-mediated suppression of gluconeogenesis. Gain- and loss-of-function models in primary hepatocytes; protein and gene expression; ex vivo glucose production; in vivo PGC1A overexpression Proceedings of the National Academy of Sciences of the United States of America High 30770439
2021 IRS-2 is recruited into mutant huntingtin (mHTT) aggregates in pancreatic beta-cells, reducing PI3K/AKT/FoxO1 pathway activation and impairing glucose-stimulated insulin secretion and cell proliferation. Insulin treatment inhibits mHTT aggregation and restores PI3K/AKT/FoxO1 signaling. NIT-1 cells expressing N-terminal mHTT (160Q); co-localization of IRS-2 with mHTT aggregates; PI3K/AKT/FoxO1 signaling assays; insulin rescue experiments Journal of molecular neuroscience Medium 34331233
2022 IRS2-PI3K signaling stabilizes MYC in breast cancer stem cells by inhibiting GSK3β, suppressing MYC phosphorylation at Thr58, and reducing proteasomal degradation of MYC. A T58A-Myc mutant rescues CSC function in Irs2-/- cells. IRS2 knockout in breast cancer cells; GSK3β activity assays; MYC phosphorylation at Thr58; T58A-Myc mutant rescue; stem cell functional assays Cell reports High 36476848

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 776 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 700 12228220
2000 Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Molecular cell 626 10949029
2003 cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes & development 473 12842910
1999 Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nature genetics 452 10471495
2007 Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science (New York, N.Y.) 436 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
2000 IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 353 11014193
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
1995 4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice. The Journal of biological chemistry 189 7559579
2006 IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates. Nature neuroscience 183 17143271
1997 Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells. Molecular and cellular biology 183 9032279
2001 Essential role of insulin receptor substrate 1 (IRS-1) and IRS-2 in adipocyte differentiation. Molecular and cellular biology 178 11259600
2005 Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. The Journal of clinical investigation 176 16374520
2005 Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function. The Journal of biological chemistry 175 16272563
2002 Pdx1 restores beta cell function in Irs2 knockout mice. The Journal of clinical investigation 154 11994408
1998 Dynamics of insulin signaling in 3T3-L1 adipocytes. Differential compartmentalization and trafficking of insulin receptor substrate (IRS)-1 and IRS-2. The Journal of biological chemistry 151 9565570
2018 Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer. The Journal of clinical investigation 148 29400692
2013 Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38α MAPK during insulin resistance. Diabetes 142 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.) 126 9013772
2008 The phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2. Molecular & cellular proteomics : MCP 122 19001411
2005 TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes. Nature medicine 119 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 117 19803520
2009 Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice. Biochemical and biophysical research communications 111 19523444
2001 Regulation of breast cancer cell motility by insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines. Oncogene 111 11704861
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 95 30770439
2016 Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis. The Journal of endocrinology 93 26941037
2011 IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease. The Journal of clinical investigation 93 21926467
2004 Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 93 15247132
2013 A liver Hif-2α-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition. Nature medicine 91 24037094
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) 82 29717275
2013 miR-135a targets IRS2 and regulates insulin signaling and glucose uptake in the diabetic gastrocnemius skeletal muscle. Biochimica et biophysica acta 72 23579070
2011 Berberine reducing insulin resistance by up-regulating IRS-2 mRNA expression in nonalcoholic fatty liver disease (NAFLD) rat liver. European journal of pharmacology 69 21839075
2018 Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity. Nature communications 68 30451856
2015 Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity. Nature communications 68 25879670
2011 IRS-2 Deficiency impairs NMDA receptor-dependent long-term potentiation. Cerebral cortex (New York, N.Y. : 1991) 68 21955917
2006 Specific regulation of IRS-2 expression by glucose in rat primary pancreatic islet beta-cells. The Journal of biological chemistry 65 16574657
2002 Stat6 and IRS-2 cooperate in interleukin 4 (IL-4)-induced proliferation and differentiation but are dispensable for IL-4-dependent rescue from apoptosis. Molecular and cellular biology 64 11739727
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 59 31009952
2004 Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice. Diabetes 58 14693698
2008 IRS-2 branch of IGF-1 receptor signaling is essential for appropriate timing of myelination. Journal of neurochemistry 53 18717815
2004 Both insulin signaling defects in the liver and obesity contribute to insulin resistance and cause diabetes in Irs2(-/-) mice. The Journal of biological chemistry 52 15028732
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
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 49 38248343
1998 Insulin receptor substrate (IRS) proteins IRS-1 and IRS-2 differential signaling in the insulin/insulin-like growth factor-I pathways in fetal brown adipocytes. Molecular endocrinology (Baltimore, Md.) 49 9605931
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
2020 Multi-layered epigenetic regulation of IRS2 expression in the liver of obese individuals with type 2 diabetes. Diabetologia 47 32710190
2018 Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action. Cellular signalling 47 29550500
1999 Human insulin receptor substrate-2 (IRS-2) is a primary progesterone response gene. Molecular endocrinology (Baltimore, Md.) 47 10077005
2007 Exercise improves glucose homeostasis that has been impaired by a high-fat diet by potentiating pancreatic beta-cell function and mass through IRS2 in diabetic rats. Journal of applied physiology (Bethesda, Md. : 1985) 44 17761790
2008 Genetic variation in candidate obesity genes ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1 and risk for breast cancer in the Cancer Prevention Study II. Breast cancer research : BCR 42 18611262
2008 Molecular mechanisms of atherosclerosis in metabolic syndrome: role of reduced IRS2-dependent signaling. Arteriosclerosis, thrombosis, and vascular biology 41 18802016
2015 Ixodes ricinus salivary serpin IRS-2 affects Th17 differentiation via inhibition of the interleukin-6/STAT-3 signaling pathway. Infection and immunity 39 25712932
2014 Insulin receptor substrate-2 (Irs2) in endothelial cells plays a crucial role in insulin secretion. Diabetes 39 25277391
2011 FoxO feedback control of basal IRS-2 expression in pancreatic β-cells is distinct from that in hepatocytes. Diabetes 37 21933986
2003 Metabolic effects of the Gly1057Asp polymorphism in IRS-2 and interactions with obesity. Diabetes 37 12765968
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
2016 Caffeine-mediated BDNF release regulates long-term synaptic plasticity through activation of IRS2 signaling. Addiction biology 35 27457910
2015 FSH stimulates IRS-2 expression in human granulosa cells through cAMP/SP1, an inoperative FSH action in PCOS patients. Cellular signalling 35 26388164
1999 Differential role of insulin receptor substrate (IRS)-1 and IRS-2 in L6 skeletal muscle cells expressing the Arg1152 --> Gln insulin receptor. The Journal of biological chemistry 35 9915848
2018 Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma. Science signaling 34 30459283
2016 MicroRNA-181b suppresses TAG via target IRS2 and regulating multiple genes in the Hippo pathway. Experimental cell research 34 27616141
2010 Insulin-induced serine phosphorylation of IRS-2 via ERK1/2 and mTOR: studies on the function of Ser675 and Ser907. American journal of physiology. Endocrinology and metabolism 34 21098738
2013 Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis. Molecular metabolism 31 24567904
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 30 34848368
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
2022 The insulin and IGF signaling pathway sustains breast cancer stem cells by IRS2/PI3K-mediated regulation of MYC. Cell reports 29 36476848
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 29 34537327
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
1997 Differential association of phosphatidylinositol 3-kinase with insulin receptor substrate (IRS)-1 and IRS-2 in human thymocytes in response to IL-7. Journal of immunology (Baltimore, Md. : 1950) 28 9233603
2020 MiRNA-7 enhances erlotinib sensitivity of glioblastoma cells by blocking the IRS-1 and IRS-2 expression. The Journal of pharmacy and pharmacology 26 32026479
2019 Liraglutide ameliorates nonalcoholic fatty liver disease in diabetic mice via the IRS2/PI3K/Akt signaling pathway. Diabetes, metabolic syndrome and obesity : targets and therapy 26 31308717
2012 JNK3 maintains expression of the insulin receptor substrate 2 (IRS2) in insulin-secreting cells: functional consequences for insulin signaling. PloS one 26 22563476
2022 Estrogen Protects Cardiac Function and Energy Metabolism in Dilated Cardiomyopathy Induced by Loss of Cardiac IRS1 and IRS2. Circulation. Heart failure 25 35579013
2022 Arctigenin mitigates insulin resistance by modulating the IRS2/GLUT4 pathway via TLR4 in type 2 diabetes mellitus mice. International immunopharmacology 25 36481528
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
2020 RETRACTED: Long non-coding RNA LINC00525 promotes the non-small cell lung cancer progression by targeting miR-338-3p/IRS2 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 31991382
2018 Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity. Molecular metabolism 21 30553769
2021 Mutant Huntingtin Impairs Pancreatic β-cells by Recruiting IRS-2 and Disturbing the PI3K/AKT/FoxO1 Signaling Pathway in Huntington's Disease. Journal of molecular neuroscience : MN 20 34331233
2018 IRS2 depletion inhibits cell proliferation and decreases hormone secretion in mouse granulosa cells. The Journal of reproduction and development 20 29998910
2015 Combination of DPP-4 inhibitor and PPARγ agonist exerts protective effects on pancreatic β-cells in diabetic db/db mice through the augmentation of IRS-2 expression. Molecular and cellular endocrinology 20 26116826
2009 Association of the FTO gene with obesity and the metabolic syndrome is independent of the IRS-2 gene in the female population of Southern France. Diabetes & metabolism 20 19818665
2022 Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation. Frontiers in immunology 19 36177037
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