Positive and Negative Regulation of TSC2 Activity and Its Effects on Downstream Effectors of the mTOR Pathway
Abstract
Tuberous sclerosis is an autosomal-dominant disorder caused by the mutation of one of the two tumor suppressor genes: TSC1 or TSC2, encoding protein products, hamartin, and tuberin, respectively. Both proteins form intracellular complexes exerting inhibitory activity on mammalian target of rapamycin (mTOR) kinase. It has been demonstrated that signal transduction from tuberin to mTOR is mediated by a G protein, Ras homologue enriched in brain (Rheb). In normal cells, tuberin having GTPase-activating protein properties toward Rheb controls signals of nutrient depletion, hypoxia, or stress, not allowing activation of mTOR and subsequent protein translation and cell proliferation. However, when environmental conditions change, tuberin is phosphorylated and it forms a complex with hamartin is degraded, and downstream targets of mTOR, S6K, and eEF2K, can be activated. In this review, we summarize very recent information contributing to our knowledge of TSC2 regulation by four cellular signaling pathways: PI3K/Akt, Ras/MAPK, LKB1/AMPK, and REDD1.
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Redd1 is a new stress-induced protein and a negative regulator of mTOR through the TSC1/TSC2 complex.
“Redd1 is a new stress-induced protein and is known as a negative regulator of mTOR through TSC1/TSC2 complex [106–115].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [113]
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Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia
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PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease
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- Authors
- Jozwiak, J., Jozwiak, S., Grzela, T., & Lazarczyk, M.
- Affiliations
- Medical University of Warsaw (PL)
- ORCID
- Grzela, Tomasz
- Venue
- NeuroMolecular Medicine
- Published
- 2005
- Volume
- 7
- Issue
- 4
- Pages
- 287-296
- ISSN
- 1535-1084 (ISSN-L)
- OpenAlex
- W1990797251
- Cited by
- 63
- References
- 3
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 3 · 2022: 3 · 2020: 1 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 3 · 2014: 4 · 2013: 7 · 2012: 3
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- NeuroMolecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundacja na rzecz Nauki Polskiej
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- tuberin, TSC2, hamartin, mTOR signaling, Rheb, GTPase-activating protein, PI3K/Akt signaling, RAS/MAPK pathway, LKB1/AMPK signaling, REDD1, S6K, eEF2K, tuberous sclerosis complex, tumor suppressor regulation
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, AMP-Activated Protein Kinase Kinases, Animals, Humans, Protein Kinases, Transcription Factors, Protein Biosynthesis, Signal Transduction, Protein Serine-Threonine Kinases, ras Proteins, Phosphatidylinositol 3-Kinases, MAP Kinase Signaling System, Tumor Suppressor Proteins, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases
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