mTOR: a pharmacologic target for autophagy regulation

Abstract

mTOR, a serine/threonine kinase, is a master regulator of cellular metabolism. mTOR regulates cell growth and proliferation in response to a wide range of cues, and its signaling pathway is deregulated in many human diseases. mTOR also plays a crucial role in regulating autophagy. This Review provides an overview of the mTOR signaling pathway, the mechanisms of mTOR in autophagy regulation, and the clinical implications of mTOR inhibitors in disease treatment.

Figure 2. Regulation of autophagy by mTORC1.

Activation of mTORC1 by nutrients and growth factors leads to inhibition of autophagy through the phosphorylation of multiple autophagy-related proteins, such as ULK1, ATG13, AMBRA1, and ATG14L, which promote autophagy initiation and autophagosome nucleation. mTORC1 also phosphorylates and prevents nuclear localization of the transcription factor TFEB, a master regulator of lysosomal and autophagy gene expression. Proper lysosome function is essential for autophagy completion.

Figure 1. The mTOR signaling network.

mTOR forms two distinct signaling complexes, mTORC1 and mTORC2. mTORC1 integrates nutrient and growth factor signaling to promote anabolic metabolism, such as protein synthesis and lipid synthesis, and to inhibit catabolic pathways, such as lysosome biogenesis and autophagy. Growth factors activate RTKs and the downstream signaling cascades PI3K/AKT and Ras/Erk, resulting in inhibition of the TSC complex, which functions as a GAP for the mTORC1 upstream effector Rheb GTPase. In contrast, cellular stressors, such as low energy levels and hypoxia, activate the TSC complex via AMPK and REDD1. AMPK also directly inhibits mTORC1 activity by phosphorylating RAPTOR. In the presence of amino acids, Rag GTPases recruit mTORC1 to the lysosomal surface, where it can be activated by Rheb GTPase. Growth factor/RTK/PI3K signaling also activates mTORC2, which regulates cell survival, metabolism, and cytoskeletal organization via AGC family kinases. mTORC1 activation exerts feedback inhibition on RTK/PI3K/AKT signaling via the inhibition of IRS and activation of GRB10. S6K, an mTORC1 downstream effector, also inhibits IRS and mTORC2 via inhibitory phosphorylation.