Where is mTOR and what is it doing there?

Abstract

Target of rapamycin (TOR) forms two conserved, structurally distinct kinase complexes termed TOR complex 1 (TORC1) and TORC2. Each complex phosphorylates a different set of substrates to regulate cell growth. In mammals, mTOR is stimulated by nutrients and growth factors and inhibited by stress to ensure that cells grow only during favorable conditions. Studies in different organisms have reported localization of TOR to several distinct subcellular compartments. Notably, the finding that mTORC1 is localized to the lysosome has significantly enhanced our understanding of mTORC1 regulation. Subcellular localization may be a general principle used by TOR to enact precise spatial and temporal control of cell growth.

Figure 1.

Localization of mTORC1 signaling. mTORC1 is in the cytoplasm when amino acids levels are low. Addition of amino acids stimulates the recruitment of mTORC1 in a Rag-dependent manner to the lysosomal surface. Upon growth factor stimulation, PI3K produces PIP₃ in the plasma membrane, which in turn activates PDK1 and Akt. After phosphorylation by PDK1, Akt phosphorylates and thereby inhibits the TSC complex, possibly at the lysosome and the peroxisome. Reduced TSC complex GAP activity leads to an increase in GTP-bound Rheb. Rheb-GTP at the lysosomal surface directly binds to and activates mTORC1. Osmotic stress induces sequestration of mTORC1 in stress granules. Pools of mTORC1 have also been reported at other sites, including mitochondria and the nucleus.

Figure 2.

Localization of mTORC2 signaling. mTORC2 interacts with ribosomes in a PI3K-dependent manner. Upon growth factor stimulation, mTORC2 is recruited to MAMs, presumably from the cytoplasm. mTORC2 has also been observed in the nucleus and on lipid rafts at the plasma membrane.