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Nutrient sensing in the mTOR/S6K1 signalling pathway.
Biochemical Society Transactions
|March 21, 2007
Summary
Amino acids activate the mTOR/S6K1 pathway via hVps34, not TSC1/TSC2. This discovery challenges previous models of nutrient signaling and insulin resistance.
Area of Science:
- Cellular Biology
- Molecular Signaling
- Metabolism
Background:
- Nutrient overload causes insulin resistance by activating S6K1, suppressing PI3K signaling.
- The precise mechanism of amino acid (AA) entry into the mTOR/S6K1 pathway remains unclear.
Purpose of the Study:
- To elucidate the mechanism by which amino acids activate the mammalian target of rapamycin (mTOR)/S6K1 signaling pathway.
- To investigate the role of class 3 PI3K (hVps34) in mediating amino acid-induced mTOR/S6K1 activation.
Main Methods:
- Ectopic expression of hVps34 and its effects on S6K1 activation in the presence of amino acids.
- Utilizing small interfering RNAs (siRNAs) against hVps34 to assess its necessity for S6K1 activation.
- Measuring hVps34 activity via phosphatidylinositol 3-phosphate (PI3P) production upon amino acid stimulation.
- Employing cDNA constructs with FYVE domains to inhibit PI3P-mediated protein recruitment.
Main Results:
- Ectopic hVps34 expression activates S6K1 specifically in the presence of amino acids, an effect blocked by hVps34 siRNAs.
- Amino acid stimulation increases hVps34 activity, leading to PI3P production and recruitment of FYVE/PX domain-containing proteins to endosomal membranes.
- Overexpression of a FYVE-domain-containing cDNA attenuates S6K1 activation, confirming PI3P's role in the signaling cascade.
Conclusions:
- Amino acid input into the mTOR/S6K1 pathway is mediated by hVps34, not the TSC1/TSC2-Rheb axis.
- hVps34 acts as a crucial signaling node, with PI3P production serving as a platform for downstream effectors.
- This finding redefines the understanding of nutrient sensing and its link to metabolic regulation.
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