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mTOR
The full mechanism of action of rapamycin remained elusive until 1994 when biochemical studies identified the mechanistic (formerly “mammalian”) Target of Rapamycin (mTOR) as the direct target of the rapamycin-FKBP12 complex in mammals. mTOR is a serine/threonine protein kinase in the PI3K-related kinase (PIKK) family that forms the catalytic subunit of two distinct protein complexes, known as mTOR Complex 1 (mTORC1) and 2 (mTORC2). mTORC1 is defined by its three core components: mTOR, Raptor (regulatory protein associated with mTOR), and mLST8 (mammalian lethal with Sec13 protein 8, also known as GβL).
mTORC1 promotes protein synthesis largely through the phosphorylation of two key effectors, p70S6 Kinase 1 (S6K1) and eIF4E Binding Protein (4EBP), mTORC1 increases the ATF4-dependent expression of MTHFD2, a key component of the mitochondrial tetrahydrofolate cycle that provides one-carbon units for purine synthesis and mTORC1 increases the translation of the transcription factor HIF1α which drives the expression of several glycolytic enzymes such as phospho-fructo kinase (PFK). While mTORC1 regulates cell growth and metabolism, mTORC2 instead controls proliferation and survival primarily by phosphorylating several members of the AGC (PKA/PKG/PKC) family of protein kinases. The first mTORC2 substrate to be identified was PKCα, a regulator of the actin cytoskeleton.
More recently, mTORC2 has also been shown to phosphorylate several other members of the PKC family, including PKCδ, PKCζ, as well as PKCγ and PKCε, all of which regulate various aspects of cytoskeletal remodeling and cell migration. The most important role of mTORC2 however is likely the phosphorylation and activation of Akt, a key effector of insulin/PI3K signaling. Once active, Akt promotes cell survival, proliferation, and growth through the phosphorylation and inhibition of several key substrates including the FoxO1/3a transcription factors, the metabolic regulator GSK3β, and the mTORC1 inhibitor TSC2. The major focus of mTOR research going forward however will be to address whether these molecular insights can improve the therapeutic targeting of mTOR in the clinic.
References
1.Saxton RA, Sabatini DM. Cell. 2017;168(6):960–976.
mTORC1 promotes protein synthesis largely through the phosphorylation of two key effectors, p70S6 Kinase 1 (S6K1) and eIF4E Binding Protein (4EBP), mTORC1 increases the ATF4-dependent expression of MTHFD2, a key component of the mitochondrial tetrahydrofolate cycle that provides one-carbon units for purine synthesis and mTORC1 increases the translation of the transcription factor HIF1α which drives the expression of several glycolytic enzymes such as phospho-fructo kinase (PFK). While mTORC1 regulates cell growth and metabolism, mTORC2 instead controls proliferation and survival primarily by phosphorylating several members of the AGC (PKA/PKG/PKC) family of protein kinases. The first mTORC2 substrate to be identified was PKCα, a regulator of the actin cytoskeleton.
More recently, mTORC2 has also been shown to phosphorylate several other members of the PKC family, including PKCδ, PKCζ, as well as PKCγ and PKCε, all of which regulate various aspects of cytoskeletal remodeling and cell migration. The most important role of mTORC2 however is likely the phosphorylation and activation of Akt, a key effector of insulin/PI3K signaling. Once active, Akt promotes cell survival, proliferation, and growth through the phosphorylation and inhibition of several key substrates including the FoxO1/3a transcription factors, the metabolic regulator GSK3β, and the mTORC1 inhibitor TSC2. The major focus of mTOR research going forward however will be to address whether these molecular insights can improve the therapeutic targeting of mTOR in the clinic.
References
1.Saxton RA, Sabatini DM. Cell. 2017;168(6):960–976.
