mTORC1

Mechanistic target of rapamycin complex 1 (mTORC1) is a large protein kinase complex that coordinates cell growth and metabolism in response to nutrient availability, energy status, oxygen, and growth signals. It consists of the catalytic subunit mTOR, the scaffolding protein Raptor, and the auxiliary subunit mLST8. Regulatory proteins such as PRAS40 and Deptor modulate activity; the complex is located on the lysosomal surface where signaling inputs converge.

Activation requires Rheb-GTP, produced when the TSC1/TSC2 complex is inhibited by growth factor signaling (via PI3K-AKT) or other cues. Amino acid sufficiency promotes recruitment of mTORC1 to lysosomes through Rag GTPases and Ragulator; leucine and arginine are among key amino acids. Energy stress activates AMPK, which inhibits mTORC1 by activating TSC2 and by directly phosphorylating Raptor. Hypoxia also suppresses mTORC1 through REDD1 and related pathways.

mTORC1 promotes protein synthesis by phosphorylating S6K1 and 4E-BP1, enhances lipid and nucleotide biosynthesis, and supports ribosome biogenesis and growth. It inhibits autophagy by phosphorylation of ULK1 and other autophagy regulators when nutrients are sufficient. The complex thereby couples anabolic metabolism to environmental cues and supports cell growth, proliferation, and metabolic homeostasis.

Dysregulation of mTORC1 signaling is linked to cancer, tuberous sclerosis complex, and other disorders. Rapamycin and rapalogs inhibit mTORC1 and have therapeutic use in tuberous sclerosis-related tumors, some cancers, and transplant immunosuppression. Evidence suggests mTORC1 also influences aging, metabolism, and immune function, with ongoing research into selective inhibitors and combination therapies.