REDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling
Open accessAbstract
The protein kinase mTOR (mechanistic target of rapamycin) in complex 1 (mTORC1) promotes cell growth and proliferation in response to anabolic stimuli, including growth factors and nutrients. Growth factors activate mTORC1 by stimulating the kinase Akt, which phosphorylates and inhibits the tuberous sclerosis complex [TSC; which is composed of TSC1, TSC2, and TBC1D7 (Tre2-Bub2-Cdc16 domain family member 7)], thereby stimulating the mTORC1 activator Rheb (Ras homolog enriched in brain). We identified the mechanism through which REDD1 (regulated in DNA damage and development 1) represses the mTORC1 signaling pathway. We found that REDD1 promoted the protein phosphatase 2A (PP2A)-dependent dephosphorylation of Akt on Thr(308) but not on Ser(473). Consistent with previous studies showing that phosphorylation of Akt on Thr(308), but not on Ser(473), is necessary for phosphorylation of TSC2, we observed a REDD1-dependent reduction in the phosphorylation of TSC2 and subsequently in the activation state of Rheb. REDD1 and PP2A coimmunoprecipitated with Akt from wild-type but not REDD1 knockout mouse embryonic fibroblasts, suggesting that REDD1 may act as a targeting protein for the catalytic subunit of PP2A. Furthermore, binding to both Akt and PP2A was essential for REDD1 to repress signaling to mTORC1. Overall, the results demonstrate that REDD1 acts not only as a repressor of mTORC1 but also as a constant modulator of the phosphorylation of Akt in response to growth factors and nutrients.
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PP2A participates in dephosphorylation of a large number of substrates in addition to tau and APP, such as p53, MEK, ERK, and Akt.
“Furthermore, PP2A participates in dephosphorylation of a large number of substrates in addition to tau and APP, such as p53, mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and Akt (Dennis et al., 2014; Junttila et al., 2007; Ugi et al., 2002).”
From CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease (2018) · cites this paper as Dennis et al., 2014
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“REDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling.”
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- Authors
- Dennis, M. D., Coleman, C. S., Berg, A., Jefferson, L. S., & Kimball, S. R.
- Affiliations
- Pennsylvania State University (US)
- Corresponding author
- Kimball, Scot R.
- Venue
- Science Signaling
- Published
- 2014-07-22
- Volume
- 7
- Issue
- 335
- Pages
- ra68-ra68
- ISSN
- 1937-9145 (ISSN-L)
- 1945-0877
- PMC
- PMC4145530
- OpenAlex
- W1973310114
- Cited by
- 159
- References
- 52
- Citations by year
- 2026: 14 · 2025: 11 · 2024: 8 · 2023: 9 · 2022: 16 · 2021: 12 · 2020: 12 · 2019: 11 · 2018: 18 · 2017: 13 · 2016: 16 · 2015: 11 · 2014: 8
- FWCI
- 6.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Signaling (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000127)
- National Eye Institute (EY-023612, R00EY023612, K99EY023612)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-15658, R01DK094141, R56DK094141, DK-094141, R01DK013499, R01DK015658, DK-13499.)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Keywords
- REDD1, protein phosphatase 2A, Akt dephosphorylation, mTORC1 signaling, TSC2 phosphorylation, Akt Ser473 phosphorylation, tuberous sclerosis complex, growth factor signaling, nutrient signaling, cell growth and proliferation
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Fibroblasts, Humans, Phosphorylation, Transcription Factors, Signal Transduction, Mice, Knockout, Multiprotein Complexes, Proto-Oncogene Proteins c-akt, Mice, Protein Phosphatase 2, HEK293 Cells, TOR Serine-Threonine Kinases
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