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Published on: September 6, 2024
Regulation of GSK3 cellular location by FRAT modulates mTORC1-dependent cell growth and sensitivity to rapamycin
Long He1,2,3, Dennis Liang Fei4, Michal J Nagiec4,2
1Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10021; loh2007@med.cornell.edu jblenis@med.cornell.edu.
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.
Insights
mTORC1 signaling in the nucleus involves GSK3, a kinase that suppresses cell proliferation. FRAT, a GSK3 nuclear exporter, blocks this effect and is linked to rapamycin resistance in cancer.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- The mechanistic target of rapamycin complex 1 (mTORC1) pathway is crucial for cell growth, regulating gene expression, translation, and metabolism.
- While cytoplasmic mTORC1 substrates are known, its nuclear signaling mechanisms remain largely unelucidated.
- Understanding nuclear mTORC1 signaling is vital for comprehending cell growth control and developing cancer therapies.
Purpose of the Study:
- To elucidate the mechanism by which mTORC1 influences nuclear events and cell proliferation.
- To investigate the role of glycogen synthase kinase 3 (GSK3) in mTORC1-mediated nuclear signaling.
- To explore the potential of FRAT as a regulator of GSK3 nuclear localization and a predictor of rapamycin resistance.
Main Methods:
- Investigated mTORC1 signaling and its effect on nuclear protein phosphorylation using cell culture models.
- Assessed the nuclear localization of GSK3 upon mTORC1 suppression.
- Examined the impact of FRAT expression on GSK3 nuclear import, protein phosphorylation, and cell proliferation.
- Correlated FRAT expression with rapamycin resistance in various cancer cell lines.
Main Results:
- mTORC1 suppression led to significant nuclear enrichment of GSK3.
- Nuclear GSK3 promoted the phosphorylation of nuclear proteins, including GTF2F1 and FOXK1, and suppressed cell proliferation.
- FRAT, a nuclear exporter of GSK3, inhibited GSK3 nuclear localization, repressed nuclear protein phosphorylation, and prevented rapamycin-induced growth arrest.
- Elevated FRAT expression correlated with rapamycin resistance in multiple cancer cell lines.
Conclusions:
- mTORC1 regulates nuclear events through GSK3, impacting cell proliferation.
- FRAT acts as a key regulator of GSK3 nuclear localization and function.
- FRAT expression may serve as a biomarker for predicting rapamycin resistance and offers a potential therapeutic strategy for overcoming it in cancer treatment.
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