Journal Article

Regulation of GSK3 cellular location by FRAT modulates mTORC1-dependent cell growth and sensitivity to rapamycin

Nagiec, Michal J., Blenis, John, Kim, Bo Yeon, Mutvei, Anders P., Fei, Dennis Liang, He, Long, Lamprakis, Andreas

2019

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Active Transport, Cell Nucleus / Adaptor Proteins, Signal Transducing - drug effects / Adaptor Proteins, Signal Transducing - metabolism / Animals / Biological Sciences / Biomarkers / Carrier Proteins - drug effects / Carrier Proteins - metabolism / Cell Biology / Cell Cycle - drug effects / Cell growth / Cell Line, Tumor / Cell Nucleus - metabolism / Cell proliferation / Cell Proliferation - drug effects / Cytoplasm - metabolism / Cytostasis / Drug Resistance, Neoplasm - physiology / Embryonic Stem Cells / Forkhead Transcription Factors - metabolism / Gene expression / Glycogen Synthase Kinase 3 - metabolism / Growth factors / Hormones / Humans / Kinases / Localization / Mechanistic Target of Rapamycin Complex 1 - drug effects / Mechanistic Target of Rapamycin Complex 1 - metabolism / Menopause / Mice / Neoplasm Proteins - drug effects / Neoplasm Proteins - metabolism / Nuclear Proteins - metabolism / Nutrients / Phosphorylation / Protein turnover / Proteins / Proto-Oncogene Proteins - drug effects / Proto-Oncogene Proteins - metabolism / Rapamycin / Regulatory agencies / Signal Transduction - drug effects / Sirolimus - pharmacology / Substrates / TOR Serine-Threonine Kinases - metabolism / Transcription Factors - metabolism / Tumor cell lines