mTORC1

mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis. mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8), PRAS40 and DEPTOR. This complex embodies the classic functions of mTOR, namely as a nutrient/energy/redox sensor and controller of protein synthesis. The activity of this complex is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.g., L-leucine and β-hydroxy β-methylbutyric acid), mechanical stimuli, and oxidative stress. The role of mTORC1 is to activate translation of proteins. In order for cells to grow and proliferate by manufacturing more proteins, the cells must ensure that they have the resources available for protein production. Thus, for protein production, and therefore mTORC1 activation, cells must have adequate energy resources, nutrient availability, oxygen abundance, and proper growth factors in order for mRNA translation to begin. Almost all of the variables required for protein synthesis affect mTORC1 activation by interacting with the TSC1/TSC2 protein complex. TSC2 is a GTPase activating protein (GAP). Its GAP activity interacts with a G protein called Rheb by hydrolyzing the GTP of the active Rheb-GTP complex, converting it to the inactive Rheb-GDP complex. The active Rheb-GTP activates mTORC1 through unelucidated pathways. Thus, many of the pathways that influence mTORC1 activation do so through the activation or inactivation of the TSC1/TSC2 heterodimer. This control is usually performed through phosphorylation of the complex. This phosphorylation can cause the dimer to dissociate and lose its GAP activity, or the phosphorylation can cause the heterodimer to have increased GAP activity, depending on which amino acid residue becomes phosphorylated. Thus, the signals that influence mTORC1 activity do so through activation or inactivation of the TSC1/TSC2 complex, upstream of mTORC1. mTORC1 interacts at the Ragulator-Rag complex on the surface of the lysosome in response to amino acid levels in the cell. Even if a cell has the proper energy for protein synthesis, if it does not have the amino acid building blocks for proteins, no protein synthesis will occur. Studies have shown that depriving amino acid levels inhibits mTORC1 signaling to the point where both energy abundance and amino acids are necessary for mTORC1 to function. When amino acids are introduced to a deprived cell, the presence of amino acids causes Rag GTPase heterodimers to switch to their active conformation. Active Rag heterodimers interact with Raptor, localizing mTORC1 to the surface of late endosomes and lysosomes where the Rheb-GTP is located. This allows mTORC1 to physically interact with Rheb. Thus the amino acid pathway as well as the growth factor/energy pathway converge on endosomes and lysosomes. Thus the Ragulator-Rag complex recruits mTORC1 to lysosomes to interact with Rheb. Rag activity is regulated by at least two highly conserved complexes: the 'GATOR1' complex containing DEPDC5, NPRL2 and NPRL3 and the ''GATOR2' complex containing Mios, WDR24, WDR59, Seh1L, Sec13. GATOR1 inhibits Rags (it is a GTPase-activating protein for Rag subunits A/B) and GATOR2 activates Rags by inhibiting DEPDC5. Insulin-like growth factors can activate mTORC1 through the receptor tyrosine kinase (RTK)-Akt/PKB signaling pathway. Ultimately, Akt phosphorylates TSC2 on serine residue 939, serine residue 981, and threonine residue 1462. These phosphorylated sites will recruit the cytosolic anchoring protein 14-3-3 to TSC2, disrupting the TSC1/TSC2 dimer. When TSC2 is not associated with TSC1, TSC2 loses its GAP activity and can no longer hydrolyze Rheb-GTP. This results in continued activation of mTORC1, allowing for protein synthesis via insulin signaling.