ArticleProceedings of the National Academy of Sciences of the United States of America2024
The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
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- Akkermansia: A Potential Target for Natural Botanicals in Treatment of Nonalcoholic Fatty Liver Diseases.Chinese journal of integrative medicine · 2026Review
- Role of neddylation in diabetes metabolism: potential therapeutic target.Journal of diabetes and metabolic disorders · 2026Review
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- Redox Imbalance in Gestational Diabetes Mellitus: Mechanistic Insights, Emerging Biomarkers, and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- The Impact of Maternal Obesity and Diabetes on the Development of Congenital Heart Defects (CHDs) in Offspring: A Narrative Review.Metabolites · 2026Review
- The Skeletal Muscle as an Endocrine Firewall: Mitigating Metabolic Endotoxemia and Insulin Resistance in Polycystic Ovary Syndrome.Current obesity reports · 2026Review
- The spleen-brain axis in Alzheimer's disease and related dementias: Integrating immune and metabolic regulation.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Hydroalcoholic Extracts ofMolecules (Basel, Switzerland) · 2026Article
- 1-Deoxynojirimycin Combined with Theaflavins Targets PTGS2/MMP9 to Exert a Synergistic Hypoglycemic Effect.Nutrients · 2025Article
- Intestinal CD4Molecular medicine reports · 2025Article
- Spatial- and Phospho-Proteomic Profiling Reveals Pancreatic and Hepatic Dysfunction in a Rat Model of Lethal Insulin Overdose.International journal of molecular sciences · 2025Article
- Taurine in Type 2 Diabetes: Plasma Concentrations, Metabolic Pathways, and Potential as a Therapeutic Adjuvant.Current nutrition reports · 2025Review
- The pathophysiological link between type 1 diabetes and MASLD: insights into insulin resistance and liver dysfunction.Journal of endocrinological investigation · 2025Review
- Effectiveness of Insulin-Induced umbilical cord stem cells on Seladin-1/APP/GFAP expression in rat hippocampal CA1/CA3 regions following chronic hypoxia.Journal of molecular histology · 2025Article
- The insulin signalling network.Nature metabolism · 2025Review
- New discoveries in therapeutic targets and drug development pathways for type 2 diabetes mellitus under the guidance of precision medicine.European journal of medical research · 2025Review
- Impact of 4-Environment & health (Washington, D.C.) · 2025Article
- Kumquat Fruit Administration Counteracts Dysmetabolism-Related Neurodegeneration and the Associated Brain Insulin Resistance in the High-Fat Diet-Fed Mice.International journal of molecular sciences · 2025Article
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7 authors.
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Abstract
Serine phosphorylations on insulin receptor substrate 1 (IRS-1) by diverse kinases aoccur widely during obesity-, stress-, and inflammation-induced conditions in models of insulin resistance and type 2 diabetes. In this study, we define a region within the human IRS-1, which is directly C-terminal to the PTB domain encompassing numerous serine phosphorylation sites including Ser307 (mouse Ser302) and Ser312 (mouse 307) creating a phosphorylation insulin resistance (PIR) domain. We demonstrate that the IRS-1 PTB-PIR with its unphosphorylated serine residues interacts with the insulin receptor (IR) but loses the IR-binding when they are phosphorylated. Surface plasmon resonance studies further confirm that the PTB-PIR binds stronger to IR than just the PTB domain, and that phosphorylations at Ser307, Ser312, Ser315, and Ser323 within the PIR domain result in abrogating the binding. Insulin-responsive cells containing the mutant IRS-1 with all these four serines changed into glutamates to mimic phosphorylations show decreased levels of phosphorylations in IR, IRS-1, and AKT compared to the wild-type IRS-1. Hydrogen-deuterium exchange mass spectrometry experiments indicating the PIR domain interacting with the N-terminal lobe and the hinge regions of the IR kinase domain further suggest the possibility that the IRS-1 PIR domain protects the IR from the PTP1B-mediated dephosphorylation.
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