TSC Protein Complex, mTOR Complex 1, and Downstream Effects. The tuberous sclerosis complex (TSC) proteins, which include TSC1, TSC2, and TBC1D7, are negatively regulated by phosphorylation (+P) by AKT, ERK, and RSK, which are all core kinases that are activated during growth signaling. This complex is activated under hypoxia and on phosphorylation by AMPK in response to energy stress and functions as a GTPase-activating protein to negatively regulate RHEB, a Ras family member GTPase. RHEB-GTP activates mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), which is also regulated by intracellular amino acid levels and has multiple direct kinase targets and even more secondary targets of phosphorylation. In some cases, the mechanism of regulation is not completely understood (as indicated by a dashed line). In aggregate, these transcription factors, translation factors, and enzymes lead to biosynthesis of ribosomes and other components that are needed for efficient translation, including ATP and amino acids, as well as lipid precursors, NADPH, nucleotides, RNA, and DNA, to enable an increase in cell size and growth. Arrows indicate stimulatory events, which at times are mediated by phosphorylation; blocked lines indicate inhibitory effects. Biallelic (complete) loss of TSC1 or TSC2 leads to the loss of negative regulatory effects of the TSC protein complex and constitutive activation of mTORC1. CAD denotes carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase; EIF4E eukaryotic translation initiation factor 4E; 4EBP1 eukaryotic translation initiation factor 4E binding protein 1; G6PD glucose-6-phosphate dehydrogenase; HIF1A hypoxia-inducible factor 1α; PPP pentose phosphate pathway; SREBP1 sterol regulatory element-binding protein 1; and S6K1/2 ribosomal protein S6 kinase 1 and 2.
