4, 5 mTORC1 is comprised of raptor, mTOR, and mLST8, and the strength of association of raptor with mTOR is regulated by nutrient and growth signals. 3 TSC2 exerts GTPase activity to negatively regulate GTP-binding protein Rheb, which activates TORC1, thus downregulating TORC1 signaling.
As a main upstream kinase of the TORC1, AMPK is activated in response to glucose starvation and low intracellular ATP levels, which, in turn, phosphorylates and activates the TSC2 protein. It forms two complexes in cells, TORC1 and TORC2 (PDK2), with distinctive physiological functions. 1, 2 TOR is a serine/threonine kinase highly conserved from yeast to humans. The TOR pathway is an evolutionarily conserved pathway that plays critical roles in the regulation of cell proliferation, survival, and energy metabolism. In total 289 metabolites involved in selective pathways were identified 39 biochemical metabolites were found to be significantly altered, many of which are known to be associated with the cellular stress response. Extensive gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS/MS) analysis were used to obtain a rapamycin-dependent global metabolome profile from control or TAp73 −/− cells. To investigate the metabolic changes that occur upon inhibition of the mTOR pathway and the role of p73 in this response primary mouse embryonic fibroblast from control and TAp73 −/− were treated with the macrocyclic lactone rapamycin. p53, and its less investigated family member p73, have been shown to interact closely with mTOR pathways through the transcriptional regulation of different target genes. The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth, and deregulation of this pathway is associated with tumorigenesis.