Inhibition of mTOR activation

The mammalian target of Rapamycin (mTOR) is a protein kinase in the PI3K-related kinase family. It plays a crucial role in several cellular processes, including proliferation and survival [1]. This enzyme forms the catalytic subunit of two distinct protein complexes, known as mTOR complex 1 (mTORc1) and 2 (mTORc2).
Besides the mTOR catalytic subunit, mTORc1 consists of Raptor (regulatory associated protein of mTOR) and mLST8 (mammalian lethal with SEC13 protein 8). mTORc1 is Rapamycin-sensitive and plays a critical role in the regulation of cell growth, proliferation, survival, and motility. mTORC1 primarily controls protein synthesis through the direct phosphorylation of S6 Kinase 1 (S6K1) and 4E (eIF4E)-binding protein 1 (4E-BP1). In addition to regulating protein synthesis, mTORc1 activates lipogenesis and negatively regulates autophagy. Specifically, mTORc1 induces phosphorylation of autophagy-related 13 (ATG13) and the Unc-51-like autophagy activating kinase 1 (ULK1) which become unable to positively regulate autophagy.
The mTORc2 complex contains mLST8, Rictor (rapamycin-insensitive companion of mammalian target of rapamycin), and mSin1 (mammalian stress-activated protein kinase (SAPK)-interacting protein 1) [2]. This mTOR complex was originally thought to be Rapamycin-insensitive. However, studies show that prolonged Rapamycin treatment inhibits the assembly and function of mTORc2 in some, but not all, cell lines or tissues [3, 4]. mTORc2 activates several kinases, including Akt, SGK1, and PKC-α which regulate glucose and lipid metabolism and a variety of cellular responses. It has been suggested that the relative expression of FKBP12 and FKBP51, another intracellular receptor, may determine a cell or tissue's ability to respond to Rapamycin [5]. This mTOR complex negatively regulates autophagy through the phosphorylation of Beclin-1, GFAP, and VDAC1 preventing them from activating autophagy.

References:

1. Sabatini D.M., 2017. Twenty-five years of mTOR: Uncovering the link from nutrients to growth. PNAS 114(45):11818-11825.
2. Ballesteros-Álvarez J. & Andersen J.K., 2021. mTORC2: The other mTOR in autophagy regulation. Aging Cell. 20(8):e13431.
3. Sarbassov D.D. et al., 2006. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 22:159–168.
4. Schreiber K.H. et al., 2015.Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging Cell.14(2):265-73.

Chemical structure of Rapamycin:

Chemical structure of Rapamycin

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