ArticleThe Journal of biological chemistry2016
Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 39 citations in OpenAlex.
- Article
- An estrogen receptor α-derived peptide improves glucose homeostasis during obesity.Nature communications · 2024Article
- Phosphorylation Codes in IRS-1 and IRS-2 Are Associated with the Activation/Inhibition of Insulin Canonical Signaling Pathways.Current issues in molecular biology · 2024Review
- ROS and ERK Pathway Mechanistic Approach on Hepatic Insulin Resistance After Chronic Oral Exposure to Cadmium NOAEL Dose.Biological trace element research · 2023Article
- Chronic Exposure to Chlorpyrifos Damages Thyroid Activity and Imbalances Hepatic Thyroid Hormones Signaling and Glucose Metabolism: Dependency of T3-FOXO1 Axis by Hyperglycemia.International journal of molecular sciences · 2023Article
- RBM15 suppresses hepatic insulin sensitivity of offspring of gestational diabetes mellitus mice via m6A-mediated regulation of CLDN4.Molecular medicine (Cambridge, Mass.) · 2023Article
- Beyond controlling cell size: functional analyses of S6K in tumorigenesis.Cell death & disease · 2022Review
- A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease.eLife · 2022Article
- Serum- and glucocorticoid-induced kinase drives hepatic insulin resistance by directly inhibiting AMP-activated protein kinase.Cell reports · 2021Article
- Insulin action at a molecular level - 100 years of progress.Molecular metabolism · 2021Review
- Co-expression Network Revealed Roles of RNA mFrontiers in cell and developmental biology · 2021Article
- Mechanisms of Insulin Action and Insulin Resistance.Physiological reviews · 2018Review
- PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Identification of protein kinase inhibitors to reprogram breast cancer cells.Cell death & disease · 2018Article
- Inactivating hepatic follistatin alleviates hyperglycemia.Nature medicine · 2018Article
- Ablation of insulin receptor substrates 1 and 2 suppressesProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Innate Immune Signaling in Drosophila Blocks Insulin Signaling by Uncoupling PI(3,4,5)PCell reports · 2018Article
- Biochemical and cellular properties of insulin receptor signalling.Nature reviews. Molecular cell biology · 2018Review
- QiDiTangShen Granules Reduced Diabetic Kidney Injury by Regulating the Phosphorylation Balance of the Tyrosine and Serine Residues of Insulin Receptor Substrate 1.Evidence-based complementary and alternative medicine : eCAM · 2018Article
- Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells.Blood · 2016Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Constitutive activation of the mammalian target of rapamycin complex 1 and S6 kinase (mTORC1→ S6K) attenuates insulin-stimulated Akt activity in certain tumors in part through "feedback" phosphorylation of the upstream insulin receptor substrate 1 (IRS1). However, the significance of this mechanism for regulating insulin sensitivity in normal tissue remains unclear. We investigated the function of Ser-302 in mouse IRS1, the major site of its phosphorylation by S6K in vitro, through genetic knock-in of a serine-to-alanine mutation (A302). Although insulin rapidly stimulated feedback phosphorylation of Ser-302 in mouse liver and muscle, homozygous A302 mice (A/A) and their knock-in controls (S/S) exhibited similar glucose homeostasis and muscle insulin signaling. Furthermore, both A302 and control primary hepatocytes from which Irs2 was deleted showed marked inhibition of insulin-stimulated IRS1 tyrosine phosphorylation and PI3K binding after emetine treatment to raise intracellular amino acids and activate mTORC1 → S6K signaling. To specifically activate mTORC1 in mouse tissue, we deleted hepatic Tsc1 using Cre adenovirus. Although it moderately decreased IRS1/PI3K association and Akt phosphorylation in liver, Tsc1 deletion failed to cause glucose intolerance or promote hyperinsulinemia in mixed background A/A or S/S mice. Moreover, Tsc1 deletion failed to stimulate phospho-Ser-302 or other putative S6K sites within IRS1, whereas ribosomal S6 protein was constitutively phosphorylated. Following acute Tsc1 deletion from hepatocytes, Akt phosphorylation, but not IRS1/PI3K association, was rapidly restored by treatment with the mTORC1 inhibitor rapamycin. Thus, within the hepatic compartment, mTORC1 → S6K signaling regulates Akt largely through IRS-independent means with little effect upon physiologic insulin sensitivity.
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