mTOR

mTOR, or mechanistic target of rapamycin, is a highly conserved serine/threonine kinase that serves as a central regulator of cell growth and metabolism. It integrates signals from nutrients, energy status, growth factors, and stress to control anabolic and catabolic processes, including protein synthesis, lipid synthesis, and autophagy. mTOR activity promotes growth when nutrients are plentiful and suppresses growth under adverse conditions.

mTOR functions in two multi-protein complexes, mTORC1 and mTORC2, with distinct components and outputs. mTORC1, containing RAPTOR, S6K, and 4E-BP1, stimulates protein synthesis and inhibits autophagy; mTORC2, containing RICTOR, regulates the actin cytoskeleton and promotes cell survival and metabolism via AKT, PKC, and SGK1. mTORC1 is acutely inhibited by the drug rapamycin and is activated by amino acids via Rag GTPases and Ragulator recruiting the complex to the lysosome, where Rheb-GTP can activate it in response to growth factor signaling that inhibits TSC1/2.

Activation of mTOR signaling is driven by PI3K-AKT signaling relieving TSC1/2-mediated suppression of Rheb. mTORC1 substrates include S6K1 and 4E-BP1; mTORC2 phosphorylates AKT at Ser473. Dysregulation of mTOR signaling is implicated in cancer, tuberous sclerosis complex, metabolic disorders, and neurodegenerative diseases. mTOR inhibitors, including rapamycin and rapalogs such as temsirolimus and everolimus, are used clinically for cancer therapy and prevention of transplant rejection; they mainly target mTORC1 and can cause immunosuppression and metabolic side effects.

mTOR was identified as the target of rapamycin, a natural product produced by Streptomyces hygroscopicus. The name reflects its rapamycin target in yeast and other eukaryotes. The pathway is conserved across eukaryotes and remains an active area of biomedical research, including aging and metabolism studies.