KinaseMD - MTOR

MTOR Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15268862, PubMed:15467718, PubMed:18925875, PubMed:18497260, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (By similarity). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote 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 (PubMed:12150925, PubMed:12087098, PubMed:18925875). This also includes mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3: in the presence of nutrients, mediates phosphorylation of TFEB and TFE3, promoting their cytosolic retention and inactivation (PubMed:22576015, PubMed:22343943, PubMed:22692423). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:22576015, PubMed:22343943, PubMed:22692423). Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which 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 (PubMed:23429704, PubMed:23429703). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (PubMed:20516213). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (By similarity). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). mTORC1 also negatively regulates autophagy through phosphorylation of ULK1 (By similarity). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (By similarity). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (PubMed:20537536). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (PubMed:30704899). mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor (PubMed:21659604). Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules (PubMed:12231510). As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton (PubMed:15268862, PubMed:15467718). 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 (PubMed:15718470). 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 (PubMed:15268862). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed:18925875). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (By similarity). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (By similarity). Phosphorylates SQSTM1, promoting interaction between SQSTM1 and KEAP1 and subsequent inactivation of the BCR(KEAP1) complex (By similarity). View more >>

GO - Biological processes (BP): 'de novo' pyrimidine nucleobase biosynthetic process, activation of protein kinase B activity, anoikis, brain development, cardiac muscle cell development, cardiac muscle contraction, cell aging, cell cycle arrest, cellular response to amino acid starvation, cellular response to amino acid stimulus, cellular response to hypoxia, cellular response to leucine, cellular response to leucine starvation, cellular response to nutrient levels, cellular response to starvation, energy reserve metabolic process, germ cell development, heart morphogenesis, heart valve morphogenesis, long-term memory, maternal process involved in female pregnancy, mRNA stabilization, multicellular organism growth, negative regulation of autophagy, negative regulation of calcineurin-NFAT signaling cascade, negative regulation of cell size, negative regulation of cholangiocyte apoptotic process, negative regulation of iodide transmembrane transport, negative regulation of macroautophagy, negative regulation of muscle atrophy, negative regulation of protein phosphorylation, negative regulation of protein ubiquitination, peptidyl-serine phosphorylation, peptidyl-threonine phosphorylation, phosphorylation, positive regulation of actin filament polymerization, positive regulation of cell growth involved in cardiac muscle cell development, positive regulation of cholangiocyte proliferation, positive regulation of cytoplasmic translational initiation, positive regulation of dendritic spine development, positive regulation of eating behavior, positive regulation of endothelial cell proliferation, positive regulation of epithelial to mesenchymal transition, positive regulation of gene expression, positive regulation of glial cell proliferation, positive regulation of granulosa cell proliferation, positive regulation of keratinocyte migration, positive regulation of lamellipodium assembly, positive regulation of lipid biosynthetic process, positive regulation of myotube differentiation, positive regulation of neuron death, positive regulation of neuron maturation, positive regulation of nitric oxide biosynthetic process, positive regulation of oligodendrocyte differentiation, positive regulation of peptidyl-tyrosine phosphorylation, positive regulation of phosphoprotein phosphatase activity, positive regulation of protein kinase B signaling, positive regulation of protein phosphorylation, positive regulation of sensory perception of pain, positive regulation of skeletal muscle hypertrophy, positive regulation of smooth muscle cell proliferation, positive regulation of stress fiber assembly, positive regulation of transcription by RNA polymerase III, positive regulation of transcription of nucleolar large rRNA by RNA polymerase I, positive regulation of translation, positive regulation of wound healing, spreading of epidermal cells, post-embryonic development, protein autophosphorylation, protein catabolic process, protein phosphorylation, regulation of actin cytoskeleton organization, regulation of brown fat cell differentiation, regulation of carbohydrate utilization, regulation of cell growth, regulation of cell size, regulation of cellular response to heat, regulation of circadian rhythm, regulation of fatty acid beta-oxidation, regulation of glycogen biosynthetic process, regulation of GTPase activity, regulation of locomotor rhythm, regulation of macroautophagy, regulation of membrane permeability, regulation of myelination, regulation of osteoclast differentiation, regulation of response to food, regulation of translation at synapse, modulating synaptic transmission, response to activity, response to amino acid, response to cocaine, response to insulin, response to morphine, response to nutrient, response to nutrient levels, rhythmic process, ruffle organization, social behavior, spinal cord development, T-helper 1 cell lineage commitment, TORC1 signaling, TOR signaling, visual learning, voluntary musculoskeletal movement, wound healing View more >>

GO - Molecular function (MF): View more >>

GO - Cellular component (CC): View more >>

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KinaseMD: Kinase mutations and drug responses

MTOR

Entrez ID: 2475

Full name: mechanistic target of rapamycin kinase

External links: HGNC UniprotKB Ensembl RefSeq COSMIC

Family: Atypical: PIKK: FRAP

Chromosomal location: 1p36.22

Substructure location: Gatekeeper: A-loop: G-loop: αC-helix:

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Kaplan plot for MTOR in