Twenty-five years of mTOR: Uncovering the link from nutrients to growth

Abstract

In my PNAS Inaugural Article, I describe the development of the mTOR field, starting with efforts to understand the mechanism of action of the drug rapamycin, which ∼25 y ago led to the discovery of the mTOR protein kinase. I focus on insights that we have contributed and on work that has been particularly influential to me, as well as provide some personal reflections and stories. We now appreciate that, as part of two distinct complexes, mTORC1 and mTORC2, mTOR is the major regulator of growth (mass accumulation) in animals and is the key link between the availability of nutrients in the environment and the control of most anabolic and catabolic processes. Nutrients signal to mTORC1 through the lysosome-associated Rag GTPases and their many regulators and associated cytosolic and lysosomal nutrient sensors. mTOR signaling is deregulated in common diseases, like cancer and epilepsy, and mTORC1 is a well-validated modulator of aging in multiple model organisms. There is significant excitement around using mTORC1 inhibitors to treat cancer and neurological disease and, potentially, to improve healthspan and lifespan.

Keywords: Rag GTPase; growth; mTOR; nutrients; rapamycin.

Fig. 1.

(A and B) Established components of mTORC1 (A) and mTORC2 (B). (C) Schematic showing the signals sensed by mTORC1 and mTORC2 and the processes they regulate to control growth.

Fig. 2.

(A) Photograph of Suren Sehgal, the father of rapamycin. (B) Photographs of the discoverers of mTOR and TOR1/2. (B, Upper) Robert T. Abraham (Left), David M. Sabatini (Center), and Stuart L. Schreiber (Right). (B, Lower) Michael N. Hall (Left) and George P. Livi (Right). Ajai Sehgal kindly provided the photograph of Suren Sehgal.

Fig. 3.

(A) Coincidence detector model for how mTORC1 integrates signals from nutrients and growth factors to regulate growth. The Rag GTPases promote the localization of mTORC1 to the lysosomal surface in response to nutrients, and, at the lysosome, the Rheb GTPase activates its kinase activity in response to insulin and energy levels. (B) Schematic showing components of the nutrient-sensing pathway upstream of mTORC1, including the many multiprotein complexes that regulate the Rag GTPases as well as the amino acid sensors Sestrin2, CASTOR1, and SLC38A9, and the SAM sensor SAMTOR.

Fig. 4.

Views of the amino acid binding pocket of Sestrin2 bound to leucine [Protein Data Bank (PDB) ID code 5DJ4] (Left) and of the amino acid binding pocket of CASTOR1 bound to arginine (PDB ID code 5I2C) (Right).