mTORC1pathway

mTORC1, or the mTOR complex 1 pathway, is a central regulator of cell growth and metabolism in eukaryotic cells. It comprises the serine/threonine kinase mTOR, the scaffolding protein Raptor, the mLST8 (GβL) subunit, and regulatory partners such as PRAS40 and DEPTOR. The complex responds to nutrients, energy status, oxygen, and growth factors to control anabolic processes and catabolic inhibition.

Activation of mTORC1 requires signals from growth factors through PI3K/AKT, which inhibit the TSC1/2 tumor suppressor complex, relieving its suppression of the small GTPase Rheb. GTP-bound Rheb binds and activates mTORC1 at lysosomal membranes. Amino acids regulate mTORC1 independently of growth factors by promoting recruitment of mTORC1 to lysosomes via Rag GTPases in combination with Ragulator and the v-ATPase. Energy stress activates AMPK, which inhibits mTORC1 by phosphorylating TSC2 and Raptor, while hypoxia can induce REDD1 to dampen signaling.

Localization to the lysosome is a key feature of mTORC1 regulation; lysosomal surface serves as a signaling platform integrating inputs from Rag GTPases and Rheb to determine mTORC1 activity.

Active mTORC1 phosphorylates S6K1 and 4E-BP1, promoting cap-dependent translation and ribosome biogenesis while inhibiting autophagy through ULK1 suppression. It also influences lipid synthesis, nucleotide production, and mitochondrial biogenesis in some contexts.

Dysregulation links to cancer, tuberous sclerosis complex, and metabolic disorders. Therapeutic inhibition with rapalogs such as sirolimus and everolimus targets mTORC1, though many cancers develop resistance; second-generation ATP-competitive inhibitors target both mTOR complexes. mTORC1 is distinct from mTORC2, which regulates cytoskeletal organization and cell survival and is not acutely sensitive to rapamycin.