Function
MTOR is a serine/threonine protein kinase that serves as a pivotal regulator of cellular metabolism, growth, and survival in response to signals from hormones, growth factors, nutrients, energy, and stress. It directly or indirectly regulates the phosphorylation of at least 800 proteins. MTOR functions within two structurally and functionally distinct signaling complexes: mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2). Activated mTORC1 upregulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1, releasing its inhibitory effect on the elongation initiation factor 4E (eiF4E). Additionally, it phosphorylates and activates RPS6KB1 and RPS6KB2, promoting protein synthesis by modulating the activity of their downstream targets, including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4. This also includes the mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3. Under nutrient-rich conditions, mTORC1 mediates phosphorylation of TFEB and TFE3, leading to their cytosolic retention and inactivation. However, upon starvation or lysosomal stress, mTORC1 inhibition triggers dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity. MTOR stimulates the pyrimidine biosynthesis pathway through both acute regulation via RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation through transcriptional enhancement of the pentose phosphate pathway. This pathway produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis. This function is dependent on the mTORC1 complex. MTOR regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1, an RNA polymerase III-repressor. Along with protein synthesis, MTOR also regulates lipid synthesis via SREBF1/SREBP1 and LPIN1. To maintain energy homeostasis, mTORC1 can regulate mitochondrial biogenesis through the regulation of PPARGC1A. Additionally, mTORC1 negatively regulates autophagy by phosphorylating ULK1. Under nutrient-sufficient conditions, it phosphorylates ULK1 at Ser-758, disrupting its interaction with AMPK and preventing activation of ULK1. MTOR also inhibits autophagy by phosphorylating the autophagy inhibitor DAP. It further prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions. MTOR prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting its ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA. MTOR exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10, an INSR-dependent signaling suppressor. Among other potential targets, MTOR may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex, MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. It plays a critical role in the phosphorylation at Ser-473 of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. MTORc2 may regulate the actin cytoskeleton through phosphorylation of PRKCA, PXN, and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. MTORc2 also regulates the phosphorylation of SGK1 at Ser-422. MTOR regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms. It plays a significant regulatory role in the circadian clock function; regulating period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks. MTOR phosphorylates SQSTM1, promoting interaction between SQSTM1 and KEAP1 and subsequent inactivation of the BCR(KEAP1) complex.