Fig. 5.

Growth signal activates ATF4 and mitochondrial metabolism. ATF4 activation is induced not only by stress signals that induce eIF2α phosphorylation and translational inhibition but also by growth signals that activate mTORC1 and accelerate translation. Growth signals activate AKT, which phosphorylates a number of substrates in cytoplasm and mitochondria. Phosphorylation of TSC1/2 activates mTORC1, which in turn phosphorylates S6K and 4E-BP to accelerate translation. Notably, mTORC1 activation induces ATF4 expression without eIF2α phosphorylation but likely via the depletion of translation re-initiation factors. ATF4 induces the gene expression in amino acid synthesis/transport and aminoacyl-tRNA synthesis in response to the demand for protein synthesis. 4E-BP, eukaryotic initiation factor 4E binding protein; TSC, tuberous sclerosis.