ArticleProceedings of the National Academy of Sciences of the United States of America2019
Regulation of GSK3 cellular location by FRAT modulates mTORC1-dependent cell growth and sensitivity to rapamycin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 25 citations in OpenAlex.
- FOXK1: a multifaceted regulator in metabolic reprogramming and disease progression.Biology direct · 2026Review
- Molecular Framework of the Onset and Progression of Skeletal Muscle Aging.International journal of molecular sciences · 2025Review
- mTORC1, the maestro of cell metabolism and growth.Genes & development · 2025Review
- GSK3β/NF-κB -dependent transcriptional regulation of homeostatic hepatocyteAmerican journal of physiology. Gastrointestinal and liver physiology · 2024Article
- Metabolic transitions regulate global protein fatty acylation.The Journal of biological chemistry · 2024Article
- Modeling structure-activity relationships with machine learning to identify GSK3-targeted small molecules as potential COVID-19 therapeutics.Frontiers in endocrinology · 2023Article
- Suppression of nuclear GSK3 signaling promotes serine/one-carbon metabolism and confers metabolic vulnerability in lung cancer cells.Science advances · 2022Article
- Mammalian eIF4E2-GSK3β maintains basal phosphorylation of p53 to resist senescence under hypoxia.Cell death & disease · 2022Article
- A Pleiotropic Role of Long Non-Coding RNAs in the Modulation of Wnt/β-Catenin and PI3K/Akt/mTOR Signaling Pathways in Esophageal Squamous Cell Carcinoma: Implication in Chemotherapeutic Drug Response.Current oncology (Toronto, Ont.) · 2022Review
- Regulation of Autophagy by the Glycogen Synthase Kinase-3 (GSK-3) Signaling Pathway.International journal of molecular sciences · 2022Review
- Click chemistry-enabled CRISPR screening reveals GSK3 as a regulator of PLD signaling.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Review
- GSK-3: a multifaceted player in acute leukemias.Leukemia · 2021Review
- Inhibition of PI3K/Akt signaling suppresses epithelial-to-mesenchymal transition in hepatocellular carcinoma through the Snail/GSK-3/beta-catenin pathway.Clinical and molecular hepatology · 2020Article
- miR-4634 augments the anti-tumor effects of RAD001 and associates well with clinical prognosis of non-small cell lung cancer.Scientific reports · 2020Article
- Rapamycin-Induced Autophagy Promotes the Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells in the Temporomandibular Joint in Response to IL-1BioMed research international · 2020Article
- Are Wnt/β-Catenin and PI3K/AKT/mTORC1 Distinct Pathways in Colorectal Cancer?Cellular and molecular gastroenterology and hepatology · 2020Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
The mTORC1 pathway regulates cell growth and proliferation by properly coupling critical processes such as gene expression, protein translation, and metabolism to the availability of growth factors and hormones, nutrients, cellular energetics, oxygen status, and cell stress. Although multiple cytoplasmic substrates of mTORC1 have been identified, how mTORC1 signals within the nucleus remains incompletely understood. Here, we report a mechanism by which mTORC1 modulates the phosphorylation of multiple nuclear events. We observed a significant nuclear enrichment of GSK3 when mTORC1 was suppressed, which promotes phosphorylation of several proteins such as GTF2F1 and FOXK1. Importantly, nuclear localization of GSK3 is sufficient to suppress cell proliferation. Additionally, expression of a nuclear exporter of GSK3, FRAT, restricts the nuclear localization of GSK3, represses nuclear protein phosphorylation, and prevents rapamycin-induced cytostasis. Finally, we observe a correlation between rapamycin resistance and FRAT expression in multiple-cancer cell lines. Resistance to Food and Drug Administration (FDA)-approved rapamycin analogs (rapalogs) is observed in many tumor settings, but the underling mechanisms remain incompletely understood. Given that FRAT expression levels are frequently elevated in various cancers, our observations provide a potential biomarker and strategy for overcoming rapamycin resistance.
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Registered trials
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.