Serine/threonine-protein kinase mTOR

Serine/threonine-protein kinase 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 signals12087098,12150925,12150926,12231510,12718876,14651849,15268862,15467718,15545625,15718470,18497260,18762023,18925875,20516213,20537536,21659604,23429703,23429704,25799227,26018084,29150432,29236692,31112131,31601708,32561715,34519269,37751742. MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins15268862,15467718,17517883,18372248,18497260,18925875,20516213,21576368,21659604,23429704,30171069,29236692,37751742. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2)15268862,15467718,18497260,18925875,20516213,21576368,21659604,23429704,29424687,29567957,35926713. In response to nutrients, growth factors or amino acids, mTORC1 is recruited to the lysosome membrane and promotes protein, lipid and nucleotide synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis12087098,12150925,12150926,12231510,12718876,14651849,15268862,15467718,15545625,15718470,18497260,18762023,18925875,20516213,20537536,21659604,23429703,23429704,25799227,26018084,29150432,29236692,31112131,34519269. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E)24403073,29236692. 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 PDCD412087098,12150925,18925875,29150432,29236692. 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 complex23429703,23429704. Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor20516213. Activates dormant ribosomes by mediating phosphorylation of SERBP1, leading to SERBP1 inactivation and reactivation of translation36691768. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN123426360. To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). In the same time, mTORC1 inhibits catabolic pathways: negatively regulates autophagy through phosphorylation of ULK132561715. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK132561715. Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP20537536. Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions30704899. Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA23524951,25438055. mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor21659604. Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules12231510. The mTORC1 complex is inhibited in response to starvation and amino acid depletion12150925,12150926,24403073,31695197. The non-canonical mTORC1 complex, which acts independently of RHEB, specifically mediates phosphorylation of MiT/TFE factors MITF, TFEB and TFE3 in the presence of nutrients, promoting their cytosolic retention and inactivation22343943,22576015,22692423,24448649,32612235,36608670,36697823. Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity22343943,22576015,22692423,24448649,32612235,36608670. The mTORC1 complex regulates pyroptosis in macrophages by promoting GSDMD oligomerization34289345. MTOR phosphorylates RPTOR which in turn inhibits mTORC1 (By similarity). As part of the mTORC2 complex, MTOR transduces signals from growth factors to pathways involved in proliferation, cytoskeletal organization, lipogenesis and anabolic output15268862,15467718,24670654,29424687,29567957,35926713. In response to growth factors, mTORC2 phosphorylates and activates AGC protein kinase family members, including AKT (AKT1, AKT2 and AKT3), PKC (PRKCA, PRKCB and PRKCE) and SGK115268862,15467718,21376236,24670654,29424687,29567957,35926713. In contrast to mTORC1, mTORC2 is nutrient-insensitive15467718. mTORC2 plays a critical role in AKT1 activation by mediating phosphorylation of different sites depending on the context, such as 'Thr-450', 'Ser-473', 'Ser-477' or 'Thr-479', facilitating the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDPK1/PDK1 which is a prerequisite for full activation15718470,21376236,24670654,29424687,29567957. mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'18925875. 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 RAC1B15268862. The mTORC2 complex also phosphorylates various proteins involved in insulin signaling, such as FBXW8 and IGF2BP1 (By similarity). May also regulate insulin signaling by acting as a tyrosine protein kinase that catalyzes phosphorylation of IGF1R and INSR; additional evidence are however required to confirm this result in vivo26584640. 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)

Quoted from UniProt’s FUNCTION annotation for P42345 (reviewed). The superscript numbers are UniProt’s own PubMed citations, kept in the sentence and in order, each linking to the paper it names.

What it acts with

STRING’s highest-confidence human functional partners. The combined score mixes several kinds of evidence, so each channel is shown separately — a partner supported by experiment is a different claim from one supported only by text mining, and for a receptor this is where its coupling appears as evidence rather than as assertion.

Where it sits in the cell

• Golgi apparatus
• Cytosol

Human Protein Atlas, by antibody immunofluorescence in cell lines — a different assay from the expression figures below, which are RNA.

UniProt, curated Lysosome membrane · Endoplasmic reticulum membrane · Golgi apparatus membrane · Cell membrane · Mitochondrion outer membrane · Cytoplasm · Nucleus · Nucleus, PML body · Microsome membrane · Cytoplasmic vesicle, phagosome