ArticleThe Journal of biological chemistry2016
The TORC1-activated Proteins, p70S6K and GRB10, Regulate IL-4 Signaling and M2 Macrophage Polarization by Modulating Phosphorylation of Insulin Receptor Substrate-2.
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 22 papers.
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Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- Expression Analysis of Mitochondrial Energy Metabolism-Related Genes Identifies IRS2 as a Key Modulator in M2 Synovial Macrophages of Osteoarthritis.Biomedicines · 2026Article
- Stage-Specific Reconstruction of Genome-Wide Genetic and Epigenetic Regulatory Networks Reveals Mechanistic Insights into Asthma Progression.International journal of molecular sciences · 2026Article
- Dissecting the Phospho-Regulatory Landscape of Protein Kinase N1 (PKN1) and Its Downstream Signaling: Functional Insights into the Activity-Dependent and Disease-Relevant Phosphosites.International journal of molecular sciences · 2026Article
- Ubiquitination regulates allergic asthma by affecting immune cells and immune responses.Biochemistry and biophysics reports · 2025Review
- Integrative Analyses of Bulk and Single-Cell RNA Seq Identified the Shared Genes in Acute Respiratory Distress Syndrome and Rheumatoid Arthritis.Molecular biotechnology · 2025Article
- Targeting BRD4 ameliorates experimental emphysema by disrupting super-enhancer in polarized alveolar macrophage.Respiratory research · 2025Article
- Serum 17Frontiers in immunology · 2025Article
- Defining the metabolic signatures associated with human macrophage polarisation.Biochemical Society transactions · 2023Article
- Article
- The Role of Insulin Receptor Substrate Proteins in Bronchopulmonary Dysplasia and Asthma: New Potential Perspectives.International journal of molecular sciences · 2022Review
- Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors.Cell reports · 2021Article
- Sex differences in M2 polarization, chemokine and IL-4 receptors in monocytes and macrophages from asthmatics.Cellular immunology · 2021Article
- Transcriptomic analysis reveals that mTOR pathway can be modulated in macrophage cells by the presence of cryptococcal cells.Genetics and molecular biology · 2021Article
- Notch signaling increases PPARγ protein stability and enhances lipid uptake through AKT in IL-4-stimulated THP-1 and primary human macrophages.FEBS open bio · 2020Article
- DNA methylation in nasal epithelium, atopy, and atopic asthma in children: a genome-wide study.The Lancet. Respiratory medicine · 2019Article
- Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks.International journal of molecular sciences · 2019Review
- Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway.International journal of molecular sciences · 2018Article
- Role of mTOR in Glucose and Lipid Metabolism.International journal of molecular sciences · 2018Review
- High miR-100 expression is associated with aggressive features and modulates TORC1 complex activation in lung carcinoids.Oncotarget · 2018Article
- Regulation of Metabolic Disease-Associated Inflammation by Nutrient Sensors.Mediators of inflammation · 2018Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Lung M2 macrophages are regulators of airway inflammation, associated with poor lung function in allergic asthma. Previously, we demonstrated that IL-4-induced M2 gene expression correlated with tyrosine phosphorylation of the insulin receptor substrate-2 (IRS-2) in macrophages. We hypothesized that negative regulation of IRS-2 activity after IL-4 stimulation is dependent upon serine phosphorylation of IRS-2. Herein, we describe an inverse relationship between tyrosine phosphorylation (Tyr(P)) and serine phosphorylation (Ser(P)) of IRS-2 after IL-4 stimulation. Inhibiting serine phosphatase activity increased Ser(P)-IRS-2 and decreased Tyr(P)-IRS-2 leading to reduced M2 gene expression (CD200R, CCL22, MMP12, and TGM2). We found that inhibition of p70S6K, downstream of TORC1, resulted in diminished Ser(P)-IRS-2 and prolonged Tyr(P)-IRS-2 as well. Inhibition of p70S6K increased expression of CD200R and CCL22 indicating that p70S6K negatively regulates some, but not all, human M2 genes. Knocking down GRB10, another negative regulatory protein downstream of TORC1, enhanced both Tyr(P)-IRS-2 and increased expression of all four M2 genes. Furthermore, GRB10 associated with IRS-2, NEDD4.2 (an E3-ubiquitin ligase), IL-4Rα, and γC after IL-4 stimulation. Both IL-4Rα and γC were ubiquitinated after 30 min of IL-4 treatment, suggesting that GRB10 may regulate degradation of the IL-4 receptor-signaling complex through interactions with NEDD4.2. Taken together, these data highlight two novel regulatory proteins that could be therapeutically manipulated to limit IL-4-induced IRS-2 signaling and polarization of M2 macrophages in allergic inflammation.
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