Mtor
entrez
56717
canonical
uniprot
Q9JLN9
canonical
ensembl
ENSMUSG00000028991
resolver
ensp
ENSMUSP00000099510
resolver
genesymbol
Mtor
resolver
genesymbol_syn
Frap
resolver
genesymbol_syn
Frap1
resolver
uniprot
Q2KHT0
resolver
uniprot
Q811J5
resolver
uniprot
Q9CST1
resolver
uniprot_entry
MTOR_MOUSE
resolver
uniprot_sec
Q2KHT0
resolver
uniprot_sec
Q811J5
resolver
uniprot_sec
Q9CST1
resolver
activity_regulation
ACTIVITY REGULATION: The mTORC1 complex is activated in response to nutrients, growth factors or amino acids: activation requires relocalization of the mTORC1 complex to lysosomes that is mediated by the Ragulator complex, SLC38A9, and the Rag GTPases RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and RagD/RRAGD (By similarity). Activation of mTORC1 by growth factors such as insulin involves AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase a potent activator of the protein kinase activity of mTORC1 (By similarity). Insulin-stimulated and amino acid-dependent phosphorylation at Ser-1261 promotes autophosphorylation and the activation of mTORC1 (PubMed:19487463). On the other hand, low cellular energy levels can inhibit mTORC1 through activation of PRKAA1 while hypoxia inhibits mTORC1 through a REDD1-dependent mechanism which may also require PRKAA1 (PubMed:15545625). The kinase activity of MTOR within the mTORC1 complex is positively regulated by MLST8 (By similarity). The kinase activity of MTOR is inhibited by DEPTOR and AKT1S1 (By similarity). The non-canonical mTORC1 complex is independent of the RHEB GTPase and specifically mediates phosphorylation of MiT/TFE factors TFEB and TFE3 but not other mTORC1 substrates: it is activated by FLCN, which activates Rag GTPases RagC/RRAGC and RagD/RRAGD (By similarity). MTOR is the target of the immunosuppressive and anti-cancer drug rapamycin which acts in complex with FKBP1A/FKBP12, and specifically inhibits its kinase activity (PubMed:7809080). mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive (By similarity). mTORC2 associates and is directly activated by ribosomes (PubMed:21045808). mTORC2 may also be regulated by RHEB but in an indirect manner through the PI3K signaling pathway (By similarity). {ECO:0000250|UniProtKB:P42345, ECO:0000269|PubMed:15545625, ECO:0000269|PubMed:19487463, ECO:0000269|PubMed:21045808, ECO:0000269|PubMed:7809080}.
uniprot
proteins
amino_acid_sequence
MLGTGPAVATASAATSSNVSVLQQFASGLKSRNEETRAKAAKELQHYVTMELREMSQEESTRFYDQLNHHIFELVSSSDANERKGGILAIASLIGVEGGNSTRIGRFANYLRNLLPSSDPVVMEMASKAIGRLAMAGDTFTAEYVEFEVKRALEWLGADRNEGRRHAAVLVLRELAISVPTFFFQQVQPFFDNIFVAVWDPKQAIREGAVAALRACLILTTQREPKEMQKPQWYRHTFEEAEKGFDETLAKEKGMNRDDRIHGALLILNELVRISSMEGERLREEMEEITQQQLVHDKYCKDLMGFGTKPRHITPFTSFQAVQPQQPNALVGLLGYSSPQGLMGFGTSPSPAKSTLVESRCCRDLMEEKFDQVCQWVLKCRSSKNSLIQMTILNLLPRLAAFRPSAFTDTQYLQDTMNHVLSCVKKEKERTAAFQALGLLSVAVRSEFKVYLPRVLDIIRAALPPKDFAHKRQKTVQVDATVFTCISMLARAMGPGIQQDIKELLEPMLAVGLSPALTAVLYDLSRQIPQLKKDIQDGLLKMLSLVLMHKPLRHPGMPKGLAHQLASPGLTTLPEASDVASITLALRTLGSFEFEGHSLTQFVRHCADHFLNSEHKEIRMEAARTCSRLLTPSIHLISGHAHVVSQTAVQVVADVLSKLLVVGITDPDPDIRYCVLASLDERFDAHLAQAENLQALFVALNDQVFEIRELAICTVGRLSSMNPAFVMPFLRKMLIQILTELEHSGIGRIKEQSARMLGHLVSNAPRLIRPYMEPILKALILKLKDPDPDPNPGVINNVLATIGELAQVSGLEMRKWVDELFIIIMDMLQDSSLLAKRQVALWTLGQLVASTGYVVEPYRKYPTLLEVLLNFLKTEQNQGTRREAIRVLGLLGALDPYKHKVNIGMIDQSRDASAVSLSESKSSQDSSDYSTSEMLVNMGNLPLDEFYPAVSMVALMRIFRDQSLSHHHTMVVQAITFIFKSLGLKCVQFLPQVMPTFLNVIRVCDGAIREFLFQQLGMLVSFVKSHIRPYMDEIVTLMREFWVMNTSIQSTIILLIEQIVVALGGEFKLYLPQLIPHMLRVFMHDNSQGRIVSIKLLAAIQLFGANLDDYLHLLLPPIVKLFDAPEVPLPSRKAALETVDRLTESLDFTDYASRIIHPIVRTLDQSPELRSTAMDTLSSLVFQLGKKYQIFIPMVNKVLVRHRINHQRYDVLICRIVKGYTLADEEEDPLIYQHRMLRSSQGDALASGPVETGPMKKLHVSTINLQKAWGAARRVSKDDWLEWLRRLSLELLKDSSSPSLRSCWALAQAYNPMARDLFNAAFVSCWSELNEDQQDELIRSIELALTSQDIAEVTQTLLNLAEFMEHSDKGPLPLRDDNGIVLLGERAAKCRAYAKALHYKELEFQKGPTPAILESLISINNKLQQPEAASGVLEYAMKHFGELEIQATWYEKLHEWEDALVAYDKKMDTNKEDPELMLGRMRCLEALGEWGQLHQQCCEKWTLVNDETQAKMARMAAAAAWGLGQWDSMEEYTCMIPRDTHDGAFYRAVLALHQDLFSLAQQCIDKARDLLDAELTAMAGESYSRAYGAMVSCHMLSELEEVIQYKLVPERREIIRQIWWERLQGCQRIVEDWQKILMVRSLVVSPHEDMRTWLKYASLCGKSGRLALAHKTLVLLLGVDPSRQLDHPLPTAHPQVTYAYMKNMWKSARKIDAFQHMQHFVQTMQQQAQHAIATEDQQHKQELHKLMARCFLKLGEWQLNLQGINESTIPKVLQYYSAATEHDRSWYKAWHAWAVMNFEAVLHYKHQNQARDEKKKLRHASGANITNATTAATTAASAAAATSTEGSNSESEAESNENSPTPSPLQKKVTEDLSKTLLLYTVPAVQGFFRSISLSRGNNLQDTLRVLTLWFDYGHWPDVNEALVEGVKAIQIDTWLQVIPQLIARIDTPRPLVGRLIHQLLTDIGRYHPQALIYPLTVASKSTTTARHNAANKILKNMCEHSNTLVQQAMMVSEELIRVAILWHEMWHEGLEEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLTQAWDLYYHVFRRISKQLPQLTSLELQYVSPKLLMCRDLELAVPGTYDPNQPIIRIQSIAPSLQVITSKQRPRKLTLMGSNGHEFVFLLKGHEDLRQDERVMQLFGLVNTLLANDPTSLRKNLSIQRYAVIPLSTNSGLIGWVPHCDTLHALIRDYREKKKILLNIEHRIMLRMAPDYDHLTLMQKVEVFEHAVNNTAGDDLAKLLWLKSPSSEVWFDRRTNYTRSLAVMSMVGYILGLGDRHPSNLMLDRLSGKILHIDFGDCFEVAMTREKFPEKIPFRLTRMLTNAMEVTGLDGNYRTTCHTVMEVLREHKDSVMAVLEAFVYDPLLNWRLMDTNTKGNKRSRTRTDSYSAGQSVEILDGVELGEPAHKKAGTTVPESIHSFIGDGLVKPEALNKKAIQIINRVRDKLTGRDFSHDDTLDVPTQVELLIKQATSHENLCQCYIGWCPFW
uniprot
proteins
ec_number
2.7.10.2
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
function
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:15467718, PubMed:15485918, PubMed:15545625, PubMed:16221682, PubMed:16915281, PubMed:16962653, PubMed:18046414, PubMed:19440205, PubMed:21659604). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins (PubMed:15467718, PubMed:15545625, PubMed:16221682, PubMed:16915281, PubMed:16962653, PubMed:18046414, PubMed:19440205, PubMed:21659604). Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15467718, PubMed:16962653, PubMed:21659604). 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:15485918). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (PubMed:15485918). 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:15485918). 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 (By similarity). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (By similarity). Activates dormant ribosomes by mediating phosphorylation of SERBP1, leading to SERBP1 inactivation and reactivation of translation (By similarity). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (PubMed:11792863). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (PubMed:18046414). In the same time, mTORC1 inhibits catabolic pathways: negatively regulates autophagy through phosphorylation of ULK1 (PubMed:21258367). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (PubMed:21258367). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (By similarity). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (By similarity). Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA (By similarity). 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 (By similarity). The mTORC1 complex is inhibited in response to starvation and amino acid depletion (By similarity). The non-canonical mTORC1 complex, which acts independently of RHEB, specifically mediates phosphorylation of MiT/TFE factors TFEB and TFE3 in the presence of nutrients, promoting their cytosolic retention and inactivation (PubMed:27913603). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:27913603). The mTORC1 complex regulates pyroptosis in macrophages by promoting GSDMD oligomerization (PubMed:34289345). MTOR phosphorylates RPTOR which in turn inhibits mTORC1 (PubMed:19346248). As part of the mTORC2 complex, MTOR transduces signals from growth factors to pathways involved in proliferation, cytoskeletal organization, lipogenesis and anabolic output (PubMed:18566586, PubMed:21045808, PubMed:21321111, PubMed:24670654, PubMed:29232555, PubMed:31548312, PubMed:33850054). 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:18566587, PubMed:18566586, PubMed:21045808, PubMed:21321111, PubMed:24670654, PubMed:31548312, PubMed:33850054). In contrast to mTORC1, mTORC2 is nutrient-insensitive. 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:18566586, PubMed:21321111, PubMed:24670654, PubMed:33850054). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (By similarity). 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 (By similarity). The mTORC2 complex also phosphorylates various proteins involved in insulin signaling, such as FBXW8 and IGF2BP1 (PubMed:23142081, PubMed:23388827). May also regulate insulin signaling by acting as a tyrosine protein kinase that catalyzes phosphorylation of IGF1R and INSR (By similarity). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (PubMed:19440205). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (PubMed:29750810). {ECO:0000250|UniProtKB:P42345, ECO:0000269|PubMed:11792863, ECO:0000269|PubMed:15467718, ECO:0000269|PubMed:15485918, ECO:0000269|PubMed:15545625, ECO:0000269|PubMed:16221682, ECO:0000269|PubMed:16915281, ECO:0000269|PubMed:16962653, ECO:0000269|PubMed:18046414, ECO:0000269|PubMed:18566586, ECO:0000269|PubMed:18566587, ECO:0000269|PubMed:19346248, ECO:0000269|PubMed:19440205, ECO:0000269|PubMed:21045808, ECO:0000269|PubMed:21258367, ECO:0000269|PubMed:21321111, ECO:0000269|PubMed:21659604, ECO:0000269|PubMed:23142081, ECO:0000269|PubMed:23388827, ECO:0000269|PubMed:24670654, ECO:0000269|PubMed:27913603, ECO:0000269|PubMed:29232555, ECO:0000269|PubMed:29750810, ECO:0000269|PubMed:31548312, ECO:0000269|PubMed:33850054, ECO:0000269|PubMed:34289345}.
uniprot
proteins
mass_dalton
288789
uniprot
proteins
mutagenesis
MUTAGEN 2035; /note="S->R: Abolishes interaction with the FKBP1A-rapamycin complex."; /evidence="ECO:0000269|PubMed:7809080"; MUTAGEN 2159; /note="S->A: Knockin macrophages display reduced mTORC1 activity. Knockin mice show decreased mTORC2 activity and ability to phosphorylate and activate AKT1."; /evidence="ECO:0000269|PubMed:29150432, ECO:0000269|PubMed:34245780
uniprot
proteins
post_translational_modification
PTM: Autophosphorylates when part of mTORC1 or mTORC2 (By similarity). Phosphorylation at Ser-1261, Ser-2159 and Thr-2164 promotes autophosphorylation (PubMed:19487463). Phosphorylated at Ser-2448 by RPS6KB1 (By similarity). Phosphorylation in the kinase domain modulates the interactions of MTOR with RPTOR and AKT1S1/PRAS40 and leads to increased intrinsic mTORC1 kinase activity (By similarity). 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 (PubMed:34245780). Phosphorylation at Thr-2173 in the ATP-binding region by AKT1 strongly reduces kinase activity (By similarity). {ECO:0000250|UniProtKB:P42345, ECO:0000269|PubMed:19487463, ECO:0000269|PubMed:29150432, ECO:0000269|PubMed:34245780}.; PTM: Ubiquitinated at Lys-2066 by the SCF(FBXO22) complex via 'Lys-27'-linked ubiquitination prevents mTORC1 substrate recruitment. {ECO:0000250|UniProtKB:P42345}.
uniprot
proteins
protein_family
PI3/PI4-kinase family
uniprot
proteins
pubmed
11792863
uniprot
proteins
pubmed
11930000
uniprot
proteins
pubmed
14970221
uniprot
proteins
pubmed
15467718
uniprot
proteins
pubmed
15485918
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15545625
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
16221682
uniprot
proteins
pubmed
16915281
uniprot
proteins
pubmed
16962653
uniprot
proteins
pubmed
17242355
uniprot
proteins
pubmed
18046414
uniprot
proteins
pubmed
18566586
uniprot
proteins
pubmed
18566587
uniprot
proteins
pubmed
19346248
uniprot
proteins
pubmed
19440205
uniprot
proteins
pubmed
19468303
uniprot
proteins
pubmed
19487463
uniprot
proteins
pubmed
19704009
uniprot
proteins
pubmed
20801936
uniprot
proteins
pubmed
21045808
uniprot
proteins
pubmed
21183079
uniprot
proteins
pubmed
21258367
uniprot
proteins
pubmed
21321111
uniprot
proteins
pubmed
21659604
uniprot
proteins
pubmed
23027611
uniprot
proteins
pubmed
23142081
uniprot
proteins
pubmed
23388827
uniprot
proteins
pubmed
24187137
uniprot
proteins
pubmed
24670654
uniprot
proteins
pubmed
26359501
uniprot
proteins
pubmed
27913603
uniprot
proteins
pubmed
29150432
uniprot
proteins
pubmed
29232555
uniprot
proteins
pubmed
29750810
uniprot
proteins
pubmed
31548312
uniprot
proteins
pubmed
31786107
uniprot
proteins
pubmed
33850054
uniprot
proteins
pubmed
34245780
uniprot
proteins
pubmed
34289345
uniprot
proteins
pubmed
7809080
uniprot
proteins
sequence_length
2549
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000250|UniProtKB:P42345}; Peripheral membrane protein {ECO:0000250|UniProtKB:P42345}; Cytoplasmic side {ECO:0000250|UniProtKB:P42345}. Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:P42345}; Peripheral membrane protein {ECO:0000250|UniProtKB:P42345}; Cytoplasmic side {ECO:0000250|UniProtKB:P42345}. Golgi apparatus membrane {ECO:0000250|UniProtKB:P42345}; Peripheral membrane protein {ECO:0000250|UniProtKB:P42345}; Cytoplasmic side {ECO:0000250|UniProtKB:P42345}. Cell membrane {ECO:0000250|UniProtKB:P42345}; Peripheral membrane protein {ECO:0000250|UniProtKB:P42345}. Mitochondrion outer membrane {ECO:0000269|PubMed:11930000}; Peripheral membrane protein {ECO:0000250|UniProtKB:P42345}; Cytoplasmic side {ECO:0000250|UniProtKB:P42345}. Cytoplasm {ECO:0000269|PubMed:11930000, ECO:0000269|PubMed:16915281}. Nucleus {ECO:0000269|PubMed:16915281}. Nucleus, PML body {ECO:0000269|PubMed:16915281}. Microsome membrane {ECO:0000250|UniProtKB:P42345}. Cytoplasmic vesicle, phagosome {ECO:0000250|UniProtKB:P42345}. Note=Shuttles between cytoplasm and nucleus (PubMed:16915281). Accumulates in the nucleus in response to hypoxia (PubMed:16915281). Targeting to lysosomes depends on amino acid availability and RRAGA and RRAGB (By similarity). Lysosome targeting also depends on interaction with MEAK7 (By similarity). Translocates to the lysosome membrane in the presence of TM4SF5 (By similarity). The mTORC2 complex localizes to membranes: mTORC2 is active at the plasma membrane, endoplasmic reticulum membrane and lysosomes (By similarity). {ECO:0000250|UniProtKB:P42345, ECO:0000269|PubMed:16915281}.
uniprot
proteins