ArticleThe Journal of biological chemistry2014
Insulin receptor substrate 2-mediated phosphatidylinositol 3-kinase signaling selectively inhibits glycogen synthase kinase 3β to regulate aerobic glycolysis.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 55 citations in OpenAlex.
- Insulin receptor substrate 2 (IRS2) confers resistance to PI3K pathway inhibition in PIK3CA mutant breast cancer.The Journal of biological chemistry · 2026Article
- Therapeutic delivery of albumin-binding siRNA targeting IRS2 to diverse cell types reduces mammary tumor growth.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Interaction of IRS2 with PLK1 protects cells from mitotic stress.Cell death & disease · 2026Article
- Spatially resolved transcriptomics identifies epithelial-specific oncogenic signaling networks in ameloblastoma.Journal of dental sciences · 2026Article
- Unique transcriptomic responses of rat and human alveolar macrophages in an in vitro model of overload with TiOParticle and fibre toxicology · 2025Article
- Ginsenoside CK modulates glucose metabolism via PPARγ to ameliorate SCOP-induced cognitive dysfunction.Metabolic brain disease · 2025Article
- Deciphering the role of classical oestrogen receptor in insulin resistance and type 2 diabetes mellitus: From molecular mechanism to clinical evidence.BioImpacts : BI · 2025Review
- Eye on the horizon: The metabolic landscape of the RPE in aging and disease.Progress in retinal and eye research · 2025Review
- 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
- In-depth analysis of lupeol: delving into the diverse pharmacological profile.Frontiers in pharmacology · 2024Review
- Circular RNA in Non-small Cell Lung Carcinoma: Identification of Targets and New Treatment Modalities.Cancer genomics & proteomics · 2023Review
- Pharmaco-proteogenomic characterization of liver cancer organoids for precision oncology.Science translational medicine · 2023Article
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- The insulin and IGF signaling pathway sustains breast cancer stem cells by IRS2/PI3K-mediated regulation of MYC.Cell reports · 2022Article
- IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells.Science signaling · 2022Article
- MPA alters metabolic phenotype of endometrial cancer-associated fibroblasts from obese women via IRS2 signaling.PloS one · 2022Article
- Sensory neurons derived from diabetic rats exhibit deficits in functional glycolysis and ATP that are ameliorated by IGF-1.Molecular metabolism · 2021Article
- Diversity of insulin and IGF signaling in breast cancer: Implications for therapy.Molecular and cellular endocrinology · 2021Review
- Molecular interactions of miR-338 during tumor progression and metastasis.Cellular & molecular biology letters · 2021Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Insulin receptor substrate 1 (IRS-1) and IRS-2 are cytoplasmic adaptor proteins that mediate the activation of signaling pathways in response to ligand stimulation of upstream cell surface receptors. Despite sharing a high level of homology and the ability to activate PI3K, only Irs-2 positively regulates aerobic glycolysis in mammary tumor cells. To determine the contribution of Irs-2-dependent PI3K signaling to this selective regulation, we generated an Irs-2 mutant deficient in the recruitment of PI3K. We identified four tyrosine residues (Tyr-649, Tyr-671, Tyr-734, and Tyr-814) that are essential for the association of PI3K with Irs-2 and demonstrate that combined mutation of these tyrosines inhibits glucose uptake and lactate production, two measures of aerobic glycolysis. Irs-2-dependent activation of PI3K regulates the phosphorylation of specific Akt substrates, most notably glycogen synthase kinase 3β (Gsk-3β). Inhibition of Gsk-3β by Irs-2-dependent PI3K signaling promotes glucose uptake and aerobic glycolysis. The regulation of unique subsets of Akt substrates by Irs-1 and Irs-2 may explain their non-redundant roles in mammary tumor biology. Taken together, our study reveals a novel mechanism by which Irs-2 signaling preferentially regulates tumor cell metabolism and adds to our understanding of how this adaptor protein contributes to breast cancer progression.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.