Cited by 107Tuberous Sclerosis Complex ResearchPI3K/AKT/mTOR signaling in cancerGenetics and Neurodevelopmental Disorders

TSC1/TSC2 signaling in the CNS

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Han, Juliette M., Sahin, Mustafa·2011·FEBS Letters

Abstract

Over the past several years, the study of a hereditary tumor syndrome, tuberous sclerosis complex (TSC), has shed light on the regulation of cellular proliferation and growth. TSC is an autosomal dominant disorder that is due to inactivating mutations in TSC1 or TSC2 and characterized by benign tumors (hamartomas) involving multiple organ systems. The TSC1/2 complex has been found to play a crucial role in an evolutionarily-conserved signaling pathway that regulates cell growth: the mTORC1 pathway. This pathway promotes anabolic processes and inhibits catabolic processes in response to extracellular and intracellular factors. Findings in cancer biology have reinforced the critical role for TSC1/2 in cell growth and proliferation. In contrast to cancer cells, in the CNS, the TSC1/2 complex not only regulates cell growth/proliferation, but also orchestrates an intricate and finely tuned system that has distinctive roles under different conditions, depending on cell type, stage of development, and subcellular localization. Overall, TSC1/2 signaling in the CNS, via its multi-faceted roles, contributes to proper neural connectivity. Here, we will review the TSC signaling in the CNS.

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Crossref · 10.1016/j.febslet.2011.02.001

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  • PtdIns(3,4,5)P3 binds and activates PDK1, which contributes to activation of Akt.

    “This then binds and activates phosphoinositide-dependent protein kinase (PDK1), which in turn contributes to activation of the serine/threonine protein kinase Akt proteins.”
  • Activated Akt phosphorylates TSC2, reducing its GAP activity for Rheb.

    “Activated Akt phosphorylates TSC2, reducing its GTPase activating protein (GAP) activity for the Ras family GTPase, Rheb.”
  • BDNF binding to TrkB activates PI(3)K, which phosphorylates PtdIns(4,5)P2 to generate PtdIns(3,4,5)P3.

    “BDNF binding to TrkB activates the phosphatidylinositol-3-OH kinase (PI(3)K), which phosphorylates phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) at the 3′ position to generate phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3).”
  • Phosphorylation of TSC2 leads to Rheb activation, which triggers mTOR activation, contributing to protein synthesis.

    “Thus, phosphorylation of TSC2 leads to Rheb activation, which in turn triggers activation of the protein kinase mTOR, contributing to the activation of protein synthesis (Fig. 4)67.”
  • TSC is caused by mutations in TSC1 or TSC2, which encode tumour suppressor proteins forming the TSC1-TSC2 complex that regulates protein synthesis in many mammalian cell types including neurons.

    “This disorder is caused by mutations in TSC1 or TSC2 that encode tumour suppressor proteins which form the complex TSC1–TSC2 that regulate protein synthesis in a wide range of mammalian cell types, including neurons67.”

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Authors
Han, J. M., & Sahin, M.
Affiliations
Boston Children's Hospital (US)
Venue
FEBS Letters
Publisher
Wiley
Published
2011-02-15
Volume
585
Issue
7
Pages
973-980
ISSN
0014-5793 (ISSN-L)
OpenAlex
W2074197666
Cited by
105
References
123
Citations by year
2026: 2 · 2025: 3 · 2024: 3 · 2023: 10 · 2022: 6 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 2 · 2017: 10 · 2016: 4 · 2015: 9 · 2014: 13 · 2013: 14 · 2012: 10
FWCI
1.37
Type
journal article
Language
en
Open access
Locations
  • FEBS Letters (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (R01NS058956)
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 › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
tuberous sclerosis complex, TSC1, TSC2, mTORC1 signaling, central nervous system, neural cell proliferation, neural growth, neuronal connectivity, hamartoma, cell growth regulation
MeSH terms
Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Animals, Central Nervous System, Disease Models, Animal, Humans, Neurons, Tuberous Sclerosis, Signal Transduction, Tumor Suppressor Proteins

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