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Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling
Xinsheng Gao1, Yong Zhang, Peter Arrazola
1Department of Physiology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9040, USA.
Abstract:
Target of Rapamycin (TOR) mediates a signalling pathway that couples amino acid availability to S6 kinase (S6K) activation, translational initiation and cell growth. Here, we show that tuberous sclerosis 1 (Tsc1) and Tsc2, tumour suppressors that are responsible for the tuberous sclerosis syndrome, antagonize this amino acid-TOR signalling pathway. We show that Tsc1 and Tsc2 can physically associate with TOR and function upstream of TOR genetically. In Drosophila melanogaster and mammalian cells, loss of Tsc1 and Tsc2 results in a TOR-dependent increase of S6K activity. Furthermore, although S6K is normally inactivated in animal cells in response to amino acid starvation, loss of Tsc1-Tsc2 renders cells resistant to amino acid starvation. We propose that the Tsc1-Tsc2 complex antagonizes the TOR-mediated response to amino acid availability. Our studies identify Tsc1 and Tsc2 as regulators of the amino acid-TOR pathway and provide a new paradigm for how proteins involved in nutrient sensing function as tumour suppressors.
Insights
Tuberous sclerosis 1 (Tsc1) and Tsc2 proteins antagonize the amino acid-Target of Rapamycin (TOR) pathway. Loss of Tsc1 and Tsc2 leads to increased S6 kinase (S6K) activity and resistance to amino acid starvation.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- The Target of Rapamycin (TOR) pathway is crucial for nutrient sensing, regulating cell growth and translation.
- Amino acid availability signals through TOR to control S6 kinase (S6K) activation and protein synthesis.
- Tuberous sclerosis syndrome is linked to mutations in Tsc1 and Tsc2 tumor suppressor genes.
Purpose of the Study:
- To investigate the role of Tsc1 and Tsc2 in the amino acid-TOR signaling pathway.
- To determine how Tsc1 and Tsc2 interact with and regulate TOR.
- To understand the functional consequences of Tsc1/Tsc2 loss on nutrient-mediated signaling.
Main Methods:
- Co-immunoprecipitation to assess physical association between Tsc1/Tsc2 and TOR.
- Genetic analysis in Drosophila melanogaster and mammalian cells to study loss-of-function effects.
- Measurement of S6K activity under various nutrient conditions.
Main Results:
- Tsc1 and Tsc2 physically associate with TOR and function genetically upstream of TOR.
- Loss of Tsc1 and Tsc2 results in TOR-dependent hyperactivation of S6K.
- Cells lacking Tsc1 and Tsc2 exhibit resistance to amino acid starvation-induced S6K inactivation.
Conclusions:
- The Tsc1-Tsc2 complex acts as an antagonist to the amino acid-TOR signaling pathway.
- Tsc1 and Tsc2 are key regulators of nutrient sensing and cell growth.
- These findings provide a new perspective on how nutrient-sensing proteins function as tumor suppressors.