A. mTOR complex 1 (mTORC1) activation initiates a
downstream anabolic programme that enhances the production of proteins, lipids,
nucleotides and other macromolecules while inhibiting catabolic processes, such
as autophagy and lysosome biogenesis. B. By regulating the
expression or nuclear localization of transcription factors, mTORC1 and mTORC2
control the expression of genes that promote organelle biogenesis or alter
metabolic flux through biosynthetic pathways. Although these transcription
factors can be independently activated by specific, acute cellular stress
signals (for example, hypoxia inducible factor 1α (HIF1α) can be
directly activated by hypoxia and ATF4 can be directly activated by endoplasmic
reticulum stress), mTORC1 and mTORC2 toggle the activation of these factors in a
coordinated manner to support growth and proliferation. Thus, activation of
mTORC1 can simultaneously activate ATF4, the sterol regulatory element binding
proteins (SREBPs), HIF1α and yin–yang 1 (YY1)−peroxisome
proliferator-activated receptor-γ (PPARγ) coactivator 1α
(PGC1α) to drive diverse processes involved in cellular growth, all while
blocking lysosomal biogenesis through transcription factor EB (TFEB).
C. mTORC2 activates the AGC family kinases protein kinase C
(PKC), Akt and serum- and glucocorticoid-induced protein kinase (SGK) to
regulate the cytoskeleton, metabolism and ion transport and promote cell
survival. CAD, carbamoyl-phosphate synthetase 2, apartate transcarbamoylase,
dihydroorotase; 4E-BP, 4E-binding protein; eIF4, eukaryotic translation
initiation factor 4; GSK3b, glycogen synthase kinase 3b; MTHFD2,
methylenetetrahydrofolate dehydrogenase 2; PDCD4, programmed cell death 4; Pol
I/Pol III, RNA polymerase I/RNA polymerase III; S6K1, p70 S6 kinase 1; TFE3,
transcription factor E3; TIF-1A, transcription initiation factor 1A; TSC2,
tuberous sclerosis complex 2; UBF, upstream binding factor; ULK1, unc-51-like
autophagy-activating kinase 1.