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Cited by 387Tuberous Sclerosis Complex ResearchPI3K/AKT/mTOR signaling in cancerHippo pathway signaling and YAP/TAZ

Rhebbing up mTOR: New Insights on TSC1 and TSC2, and the Pathogenesis of Tuberous Sclerosis

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Kwiatkowski, David J.·2003·Cancer Biology & Therapy
DOI 10.4161/cbt.2.5.446
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Abstract

Tuberous sclerosis is an autosomal dominant human genetic disorder in which distinctive tumors called hamartomas develop. Germline mutations in either TSC1 or TSC2 cause this syndrome, and hamartomas typically display second hit events with loss of the remaining normal allele. Studies initiated in Drosophila have identified a role for the Tsc1 and Tsc2 genes in the regulation of cell and organ size, and genetic interaction studies have placed them in the PI3K-Akt-mTOR-S6K pathway. Biochemical studies have shown that activated Akt phosphorylates TSC2 in the TSC1/TSC2 protein complex, inactivating it; while TSC1/TSC2 has GAP activity for the Rheb GTPase (a member of the ras family), and activated Rheb-GTP activates mTOR. Thus, in cells lacking TSC1 or TSC2 there are increased levels of Rheb-GTP which leads to activation of mTOR, leading to cell size increase and growth. These developments provide enhanced understanding of this signaling pathway and fundamental insights into the pathogenesis of tuberous sclerosis, and open the possibility of treatment for hamartomas by several pharmacologic approaches.

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  • Whereas specific metabolites signal to mTORC1 through the Rag GTPase axis, stress conditions such as hypoxia, DNA damage stress, ER stress, and growth factor and survival signaling are filtered through to the Rheb GTPase through TSCC by post-translational modification.

    “Whereas it appears that specific metabolites signal to mTORC1 through the Rag GTPase axis, stress conditions such as hypoxia, DNA damage stress, ER stress, and growth factor and survival signaling, are filtered through to the Rheb GTPase through TSCC by post-translational modification (Kwiatkowski, 2003; Huang and Manning, 2008; Tomasoni and Mondino, 2011; Demetriades et al., 2016).”

    From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Kwiatkowski, 2003

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Authors
Kwiatkowski, D. J.
Affiliations
Brigham and Women's Hospital (US)
Corresponding author
Kwiatkowski, David J.
ORCID
Kwiatkowski, David J.
Venue
Cancer Biology & Therapy
Publisher
Informa UK Limited
Published
2003-05-04
Volume
2
Issue
5
Pages
471-476
ISSN
  • 1538-4047 (ISSN-L)
  • 1555-8576
DOI
10.4161/cbt.2.5.446
OpenAlex
W1995745999
Cited by
387
References
0
Citations by year
2026: 4 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 8 · 2020: 17 · 2019: 5 · 2018: 15 · 2017: 12 · 2016: 14 · 2015: 19 · 2014: 18 · 2013: 32 · 2012: 28
FWCI
2.28
Type
journal article
Language
en
Open access
Locations
  • Cancer Biology & Therapy (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (NS31535, NS24279)
  • National Institute of Neurological Disorders and Stroke (NS-31535, P01NS024279, NS 24279)
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
tuberous sclerosis complex, TSC1, TSC2, mTOR, hamartoma, cell size control, Akt phosphorylation, second hit, Drosophila, carcinogenesis, pharmacotherapy
MeSH terms
Ras Homolog Enriched in Brain Protein, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Humans, Neuropeptides, Protein Kinases, Proteins, Repressor Proteins, Tuberous Sclerosis, Signal Transduction, Phosphatidylinositol 3-Kinases, Ribosomal Protein S6 Kinases, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, Drosophila Proteins, TOR Serine-Threonine Kinases

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