MTOR

The protein encoded by this gene belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stresses such as DNA damage and nutrient deprivation. This protein acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. The ANGPTL7 gene is located in an intron of this gene. [provided by RefSeq, Sep 2008]

Mechanistic Target Of Rapamycin Kinase

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).

Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA (PubMed:23524951, PubMed:25438055).

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).

de novo' pyrimidine nucleobase biosynthetic process Source: Ensembl
Activation of protein kinase B activity Source: Reactome
Anoikis Source: ParkinsonsUK-UCL
Behavioral response to pain Source: Ensembl
Cardiac muscle cell development Source: Ensembl
Cardiac muscle contraction Source: Ensembl
Cellular response to amino acid starvation Source: UniProtKB
Cellular response to amino acid stimulus Source: CAFA
Cellular response to DNA damage stimulus Source: ComplexPortal
Cellular response to hypoxia Source: UniProtKB
Cellular response to leucine Source: CAFA
Cellular response to leucine starvation Source: CAFA
Cellular response to nutrient levels Source: UniProtKB
Cellular response to osmotic stress Source: ComplexPortal
Cellular response to starvation Source: UniProtKB
Cytoskeleton organization Source: ComplexPortal
Energy reserve metabolic process Source: Ensembl
Germ cell development Source: Ensembl
Heart morphogenesis Source: Ensembl
Heart valve morphogenesis Source: Ensembl
Inflammatory response Source: Ensembl
Lysosome organization Source: UniProtKB
Multicellular organism growth Source: Ensembl
Negative regulation of apoptotic process Source: ComplexPortal
Negative regulation of autophagy Source: UniProtKB
Negative regulation of calcineurin-NFAT signaling cascade Source: Ensembl
Negative regulation of cell size Source: Ensembl
Negative regulation of macroautophagy Source: MGI
Neuronal action potential Source: Ensembl
Nucleus localization Source: UniProtKB
Peptidyl-serine phosphorylation Source: UniProtKB
Peptidyl-threonine phosphorylation Source: Ensembl
Phosphorylation Source: UniProtKB
Positive regulation of actin filament polymerization Source: Ensembl
Positive regulation of cell growth Source: ComplexPortal
Positive regulation of cytoplasmic translational initiation Source: ARUK-UCL
Positive regulation of epithelial to mesenchymal transition Source: BHF-UCL
Positive regulation of gene expression Source: UniProtKB
Positive regulation of glycolytic process Source: ComplexPortal
Positive regulation of keratinocyte migration Source: BHF-UCL
Positive regulation of lamellipodium assembly Source: Ensembl
Positive regulation of lipid biosynthetic process Source: UniProtKB
Positive regulation of myotube differentiation Source: Ensembl
Positive regulation of oligodendrocyte differentiation Source: Ensembl
Positive regulation of pentose-phosphate shunt Source: ComplexPortal
Positive regulation of peptidyl-tyrosine phosphorylation Source: Ensembl
Positive regulation of phosphoprotein phosphatase activity Source: ARUK-UCL
Positive regulation of stress fiber assembly Source: Ensembl
Positive regulation of transcription by RNA polymerase III Source: UniProtKB
Positive regulation of transcription of nucleolar large rRNA by RNA polymerase I Source: UniProtKB
Positive regulation of translation Source: UniProtKB
Positive regulation of wound healing, spreading of epidermal cells Source: BHF-UCL
Post-embryonic development Source: Ensembl
Protein autophosphorylation Source: MGI
Protein catabolic process Source: UniProtKB
Protein phosphorylation Source: UniProtKB
Regulation of actin cytoskeleton organization Source: UniProtKB
Regulation of cell growth Source: UniProtKB
Regulation of cell size Source: CAFA
Regulation of cellular response to heat Source: Reactome
Regulation of circadian rhythm Source: UniProtKB
Regulation of GTPase activity Source: Ensembl
Regulation of locomotor rhythm Source: UniProtKB
Regulation of macroautophagy Source: Reactome
Regulation of membrane permeability Source: Ensembl
Regulation of myelination Source: Ensembl
Regulation of osteoclast differentiation Source: UniProtKB
Regulation of protein kinase B signaling Source: Ensembl
Regulation of signal transduction by p53 class mediator Source: Reactome
Response to amino acid Source: UniProtKB
Response to heat Source: Ensembl
Response to insulin Source: Ensembl
Response to nutrient Source: UniProtKB
Response to nutrient levels Source: UniProtKB
Rhythmic process Source: UniProtKB-KW
Ruffle organization Source: Ensembl
T-helper 1 cell lineage commitment Source: Ensembl
TORC1 signaling Source: UniProtKB
TOR signaling Source: UniProtKB
Voluntary musculoskeletal movement Source: Ensembl

Cytoplasm 2 Publications
Endoplasmic reticulum
Endoplasmic reticulum membrane
Microsome membrane
Nucleus
PML body
Mitochondrion
Mitochondrion outer membrane
Lysosome
Lysosome membrane
Golgi apparatus
Golgi apparatus membrane
Other locations
phagosome
Note: Shuttles between cytoplasm and nucleus. Accumulates in the nucleus in response to hypoxia (By similarity). Targeting to lysosomes depends on amino acid availability and RRAGA and RRAGB (PubMed:18497260, PubMed:20381137). Lysosome targeting also depends on interaction with MEAK7. Translocates to the lysosome membrane in the presence of TM4SF5 (PubMed:30956113).By similarity4 Publications

Smith-Kingsmore syndrome (SKS):
An autosomal dominant syndrome characterized by intellectual disability, macrocephaly, seizures, umbilical hernia, and facial dysmorphic features.
Focal cortical dysplasia 2 (FCORD2):
A form of focal cortical dysplasia, a malformation of cortical development that results in medically refractory epilepsy in the pediatric population and in adults. FCORD2 is a severe form, with onset usually in childhood, characterized by disrupted cortical lamination and specific cytological abnormalities. It is classified in 2 subtypes: type IIA characterized by dysmorphic neurons and lack of balloon cells; type IIB with dysmorphic neurons and balloon cells.

Autophosphorylates when part of mTORC1 or mTORC2. Phosphorylation at Ser-1261, Ser-2159 and Thr-2164 promotes autophosphorylation. Phosphorylation in the kinase domain modulates the interactions of MTOR with RPTOR and PRAS40 and leads to increased intrinsic mTORC1 kinase activity. Phosphorylation at Thr-2173 in the ATP-binding region by AKT1 strongly reduces kinase activity.