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MTOR

GeneName

MTOR

Summary

MTOR, also known as Tor or FRAP, is a 289 kDa serine/threonine protein kinase that plays a central role in regulating cell growth, proliferation, and survival. It is predominantly expressed in the cytoplasm and is localised to various cellular compartments including the endoplasmic reticulum, lysosomes, and the plasma membrane. MTOR is a key component of the mTORC1 and mTORC2 complexes, which integrate signals from nutrients, growth factors, and cellular stress to modulate various biological processes such as autophagy, metabolism, and protein synthesis. Its activity is crucial for the cellular response to amino acid availability and nutrient levels, influencing pathways involved in cellular homeostasis and development.

Importance

MTOR is relevant to: - Cancer research due to its role in cell growth and metabolism, making it a target for therapeutic interventions. - Metabolic disorders as it regulates nutrient sensing and energy homeostasis. - Neurodegenerative diseases through its involvement in autophagy and neuronal health. - Cardiovascular diseases since it influences cardiac muscle development and function. - Immune responses by modulating T cell activation and differentiation.

Top Products

For researchers investigating MTOR, we recommend two excellent primary antibodies. The first is the well-cited polyclonal antibody, Anti-mTOR antibody (ab2732), which has garnered 408 citations, highlighting its reliability in the field. This antibody is particularly effective for Western blotting (WB), immunocytochemistry (ICC), and immunoprecipitation (IP). Additionally, we offer the recombinant antibody, Anti-mTOR antibody [Y391] (ab32028). This monoclonal antibody has been validated for use in Western blotting (WB), immunohistochemistry (IHC), and immunoprecipitation (IP), making it a versatile option for various applications. With 304 citations, it is also well-regarded among researchers. Both products provide robust options for studying MTOR, catering to different experimental needs. The Anti-mTOR antibody ELISA Kit (ab2732), supported by 408 citations, is an excellent option for researchers looking to accurately measure mTOR levels in their samples.

Abcam Product Citation Summary

The data indicates a significant focus on the MTOR target across various species, particularly in Rattus norvegicus and human cells. The applications primarily involve Western blotting, highlighting the importance of MTOR in diverse biological contexts such as cancer, signaling pathways, and metabolic processes. Studies often explore the implications of MTOR in conditions like heart failure, cancer progression, and responses to treatments, suggesting its critical role in cellular regulation and disease mechanisms.

Abcam Product Citation Table

ab134903
Rat
WB
PI3K/AKT/mTOR signaling pathway
29018330
ab134903
Human
WB
Cell death induced by ZnONPs
28749469
ab134903
Rat
WB
CTGF induction
30135653
ab134903
Human
WB
Normal tissue vs primary PSCC specimens
29662627
ab134903
Human
WB
Glycolysis and cell proliferation
33994864
ab134903
Mouse
WB
Heart failure
39141645
ab2732
Human
WB
PI3K/Akt/mTOR pathway
31091245
ab2732
Mouse
WB
Effects of TMP on protein expressions
28491104
ab2732
Mouse
WB
Regulation of Foxp3 expression
23301798
ab2732
Human
WB
TC progression
32231464
ab2732
Rat
WB
Oocyte autophagy
29423092
ab2732
Human
WB
Autophagy and EMT
32385195
ab2732
Human
WB
LPS-induced injury
32071922
ab2732
Human
IHC
Gastric cancer tissue
29233126
ab32028
Human
WB
Drug responses in gliomas
35646111
ab32028
Rat
WB
Effects of rapamycin
27780926

Domain

The kinase domain (PI3K/PI4K) is intrinsically active but has a highly restricted catalytic center.

The FAT domain forms three discontinuous subdomains of alpha-helical TPR repeats plus a single subdomain of HEAT repeats. The four domains pack sequentially to form a C-shaped a-solenoid that clamps onto the kinase domain (PubMed:23636326).

Function

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, PubMed:29150432, PubMed:29236692, PubMed:31112131, PubMed:31601708, PubMed:32561715, PubMed:34519269, PubMed:37751742). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins (PubMed:15268862, PubMed:15467718, PubMed:17517883, PubMed:18372248, PubMed:18497260, PubMed:18925875, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704, PubMed:30171069, PubMed:29236692, PubMed:37751742). Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15268862, PubMed:15467718, PubMed:18497260, PubMed:18925875, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704, PubMed:29424687, PubMed:29567957, PubMed: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 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, PubMed:29150432, PubMed:29236692, PubMed:31112131, PubMed:34519269). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (PubMed:24403073, PubMed: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 PDCD4 (PubMed:12087098, PubMed:12150925, PubMed:18925875, PubMed:29150432, PubMed: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 complex (PubMed:23429703, PubMed:23429704). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (PubMed:20516213). Activates dormant ribosomes by mediating phosphorylation of SERBP1, leading to SERBP1 inactivation and reactivation of translation (PubMed:36691768). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (PubMed:23426360). 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 ULK1 (PubMed:32561715). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (PubMed:32561715). 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). The mTORC1 complex is inhibited in response to starvation and amino acid depletion (PubMed:12150925, PubMed:12150926, PubMed:24403073, PubMed: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 inactivation (PubMed:22343943, PubMed:22576015, PubMed:22692423, PubMed:24448649, PubMed:32612235, PubMed:36608670, PubMed:36697823). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:22343943, PubMed:22576015, PubMed:22692423, PubMed:24448649, PubMed:32612235, PubMed:36608670). The mTORC1 complex regulates pyroptosis in macrophages by promoting GSDMD oligomerization (PubMed:34289345). 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 output (PubMed:15268862, PubMed:15467718, PubMed:24670654, PubMed:29424687, PubMed:29567957, PubMed: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 SGK1 (PubMed:15268862, PubMed:15467718, PubMed:21376236, PubMed:24670654, PubMed:29424687, PubMed:29567957, PubMed:35926713). In contrast to mTORC1, mTORC2 is nutrient-insensitive (PubMed:15467718). 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 activation (PubMed:15718470, PubMed:21376236, PubMed:24670654, PubMed:29424687, PubMed:29567957). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed: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 RAC1B (PubMed:15268862). 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 vivo (PubMed:26584640). 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).

Involvement in disease

Smith-Kingsmore syndrome

SKS

An autosomal dominant syndrome characterized by intellectual disability, macrocephaly, seizures, umbilical hernia, and facial dysmorphic features.

None

The disease is caused by variants affecting the gene represented in this entry.

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.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Autophosphorylates when part of mTORC1 or mTORC2 (PubMed:15467718, PubMed:20022946, PubMed:9434772). Phosphorylation at Ser-1261, Ser-2159 and Thr-2164 promotes autophosphorylation (PubMed:19487463). Phosphorylated at Ser-2448 by RPS6KB1 (PubMed:15899889, PubMed:15905173, PubMed:19145465). Phosphorylation in the kinase domain modulates the interactions of MTOR with RPTOR and AKT1S1/PRAS40 and leads to increased intrinsic mTORC1 kinase activity (PubMed:15905173, PubMed:19145465, PubMed:21576368). Phosphorylation at Ser-2159 by TBK1 in response to growth factors and pathogen recognition receptors promotes mTORC1 activity (PubMed:29150432). Phosphorylation at Ser-2159 by TBK1 in response to EGF growth factor promotes mTORC2 activity, leading to AKT1 phosphorylation and activation (By similarity). Phosphorylation at Thr-2173 in the ATP-binding region by AKT1 strongly reduces kinase activity (PubMed:24247430).

Ubiquitinated at Lys-2066 by the SCF(FBXO22) complex via 'Lys-27'-linked ubiquitination prevents mTORC1 substrate recruitment.

Sequence Similarities

Belongs to the PI3/PI4-kinase family.

Tissue Specificity

Expressed in numerous tissues, with highest levels in testis.

Cellular localization

Alternative names

FRAP, FRAP1, FRAP2, RAFT1, RAPT1, MTOR, Serine/threonine-protein kinase mTOR, FK506-binding protein 12-rapamycin complex-associated protein 1, FKBP12-rapamycin complex-associated protein, Mammalian target of rapamycin, Mechanistic target of rapamycin, Rapamycin and FKBP12 target 1, Rapamycin target protein 1, Tyrosine-protein kinase mTOR, mTOR

swissprot:P42345 omim:601231 entrezGene:2475 swissprot:Q9BVC4 swissprot:Q8N122

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