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MTOR

Official Full Name
mechanistic target of rapamycin kinase
Organism
Homo sapiens
GeneID
2475
Background
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 kinase is a component of two distinct complexes, mTORC1, which controls protein synthesis, cell growth and proliferation, and mTORC2, which is a regulator of the actin cytoskeleton, and promotes cell survival and cell cycle progression. This protein acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. Inhibitors of mTOR are used in organ transplants as immunosuppressants, and are being evaluated for their therapeutic potential in SARS-CoV-2 infections. Mutations in this gene are associated with Smith-Kingsmore syndrome and somatic focal cortical dysplasia type II. The ANGPTL7 gene is located in an intron of this gene. [provided by RefSeq, Aug 2020]
Synonyms
SKS; FRAP; FRAP1; FRAP2; RAFT1; RAPT1;
Bio Chemical Class
Kinase
Protein Sequence
MLGTGPAAATTAATTSSNVSVLQQFASGLKSRNEETRAKAAKELQHYVTMELREMSQEESTRFYDQLNHHIFELVSSSDANERKGGILAIASLIGVEGGNATRIGRFANYLRNLLPSNDPVVMEMASKAIGRLAMAGDTFTAEYVEFEVKRALEWLGADRNEGRRHAAVLVLRELAISVPTFFFQQVQPFFDNIFVAVWDPKQAIREGAVAALRACLILTTQREPKEMQKPQWYRHTFEEAEKGFDETLAKEKGMNRDDRIHGALLILNELVRISSMEGERLREEMEEITQQQLVHDKYCKDLMGFGTKPRHITPFTSFQAVQPQQSNALVGLLGYSSHQGLMGFGTSPSPAKSTLVESRCCRDLMEEKFDQVCQWVLKCRNSKNSLIQMTILNLLPRLAAFRPSAFTDTQYLQDTMNHVLSCVKKEKERTAAFQALGLLSVAVRSEFKVYLPRVLDIIRAALPPKDFAHKRQKAMQVDATVFTCISMLARAMGPGIQQDIKELLEPMLAVGLSPALTAVLYDLSRQIPQLKKDIQDGLLKMLSLVLMHKPLRHPGMPKGLAHQLASPGLTTLPEASDVGSITLALRTLGSFEFEGHSLTQFVRHCADHFLNSEHKEIRMEAARTCSRLLTPSIHLISGHAHVVSQTAVQVVADVLSKLLVVGITDPDPDIRYCVLASLDERFDAHLAQAENLQALFVALNDQVFEIRELAICTVGRLSSMNPAFVMPFLRKMLIQILTELEHSGIGRIKEQSARMLGHLVSNAPRLIRPYMEPILKALILKLKDPDPDPNPGVINNVLATIGELAQVSGLEMRKWVDELFIIIMDMLQDSSLLAKRQVALWTLGQLVASTGYVVEPYRKYPTLLEVLLNFLKTEQNQGTRREAIRVLGLLGALDPYKHKVNIGMIDQSRDASAVSLSESKSSQDSSDYSTSEMLVNMGNLPLDEFYPAVSMVALMRIFRDQSLSHHHTMVVQAITFIFKSLGLKCVQFLPQVMPTFLNVIRVCDGAIREFLFQQLGMLVSFVKSHIRPYMDEIVTLMREFWVMNTSIQSTIILLIEQIVVALGGEFKLYLPQLIPHMLRVFMHDNSPGRIVSIKLLAAIQLFGANLDDYLHLLLPPIVKLFDAPEAPLPSRKAALETVDRLTESLDFTDYASRIIHPIVRTLDQSPELRSTAMDTLSSLVFQLGKKYQIFIPMVNKVLVRHRINHQRYDVLICRIVKGYTLADEEEDPLIYQHRMLRSGQGDALASGPVETGPMKKLHVSTINLQKAWGAARRVSKDDWLEWLRRLSLELLKDSSSPSLRSCWALAQAYNPMARDLFNAAFVSCWSELNEDQQDELIRSIELALTSQDIAEVTQTLLNLAEFMEHSDKGPLPLRDDNGIVLLGERAAKCRAYAKALHYKELEFQKGPTPAILESLISINNKLQQPEAAAGVLEYAMKHFGELEIQATWYEKLHEWEDALVAYDKKMDTNKDDPELMLGRMRCLEALGEWGQLHQQCCEKWTLVNDETQAKMARMAAAAAWGLGQWDSMEEYTCMIPRDTHDGAFYRAVLALHQDLFSLAQQCIDKARDLLDAELTAMAGESYSRAYGAMVSCHMLSELEEVIQYKLVPERREIIRQIWWERLQGCQRIVEDWQKILMVRSLVVSPHEDMRTWLKYASLCGKSGRLALAHKTLVLLLGVDPSRQLDHPLPTVHPQVTYAYMKNMWKSARKIDAFQHMQHFVQTMQQQAQHAIATEDQQHKQELHKLMARCFLKLGEWQLNLQGINESTIPKVLQYYSAATEHDRSWYKAWHAWAVMNFEAVLHYKHQNQARDEKKKLRHASGANITNATTAATTAATATTTASTEGSNSESEAESTENSPTPSPLQKKVTEDLSKTLLMYTVPAVQGFFRSISLSRGNNLQDTLRVLTLWFDYGHWPDVNEALVEGVKAIQIDTWLQVIPQLIARIDTPRPLVGRLIHQLLTDIGRYHPQALIYPLTVASKSTTTARHNAANKILKNMCEHSNTLVQQAMMVSEELIRVAILWHEMWHEGLEEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLTQAWDLYYHVFRRISKQLPQLTSLELQYVSPKLLMCRDLELAVPGTYDPNQPIIRIQSIAPSLQVITSKQRPRKLTLMGSNGHEFVFLLKGHEDLRQDERVMQLFGLVNTLLANDPTSLRKNLSIQRYAVIPLSTNSGLIGWVPHCDTLHALIRDYREKKKILLNIEHRIMLRMAPDYDHLTLMQKVEVFEHAVNNTAGDDLAKLLWLKSPSSEVWFDRRTNYTRSLAVMSMVGYILGLGDRHPSNLMLDRLSGKILHIDFGDCFEVAMTREKFPEKIPFRLTRMLTNAMEVTGLDGNYRITCHTVMEVLREHKDSVMAVLEAFVYDPLLNWRLMDTNTKGNKRSRTRTDSYSAGQSVEILDGVELGEPAHKKTGTTVPESIHSFIGDGLVKPEALNKKAIQIINRVRDKLTGRDFSHDDTLDVPTQVELLIKQATSHENLCQCYIGWCPFW
Open
Disease
Arteries/arterioles disorder, Bladder cancer, Breast cancer, Chronic myelomonocytic leukaemia, Endometrial cancer, Head and neck cancer, Hydrocephalus, Liver cancer, Lung cancer, Lymphangioleiomyomatosis, Lymphoma, Malignant haematopoietic neoplasm, Malignant mesenchymal neoplasm, Mature T-cell lymphoma, Metastatic lymph node neoplasm, Multiple myeloma, Pain, Pancreatic cancer, Pleural mesothelioma, Postoperative inflammation, Prostate cancer, Pulmonary hypertension, Renal cell carcinoma, Sarcoma, Solid tumour/cancer, Transplant rejection, Ulcerative colitis, Vascular system developmental anomaly
Approved Drug
6 +
Clinical Trial Drug
26 +
Discontinued Drug
3 +

Detailed Information

mTOR (rapamycin target protein) is a serine/threonine kinase. The mTOR signaling pathway promotes substance metabolism, participates in apoptosis, autophagy, and plays a non-negligible role in various diseases. mTOR contains two complexes, mTORC1 and mTORC2. In comparison, mTORC1 plays a more important role, and the signal path formed by mTORC2 is relatively simple. 

The mTOR signalling pathways. Figure 1. The mTOR signalling pathways. (Crino, P. B.. 2016)

mTOR Signaling Pathway

mTOR has been shown to be an important negative regulator of autophagy in cells. The most classical pathway for the mTOR upstream signaling pathway is the PI3K/AKT/mTOR pathway, whose upstream pathway, transmembrane insulin receptor binds to insulin growth factor or tyrosine kinase receptor, then activates PI3K, converting PIP to PIP3, and then PIP3 binds to Akt/PKB and PDK1 and inhibits autophagosome formation. Its downstream pathway, the tuberous sclerosis complex (TSC) protein, inhibits the small G protein Rheb (Ras homolog enriched in brain), thereby inhibiting mTOR function and activating autophagosome formation.

Studies suggest that the direct substrates of mTORC1 downstream are two independent autophagy related genes 4E-BP1 (eukaryotic initiation factor 4E binding protein 1) and S6K, both of which are key regulatory genes for mRNAs translation. There are two different complex forms of TOR: TORC1 and TORC2. Studies have shown that the structures and functions of TORC1 and TORC2 are very conservative and stable. mTORC1 inhibits autophagy by phosphorylating ULK1. Research suggests that Atg1 is located downstream of mTOR and is a negative regulator of mTOR. Atg1 and S6 kinases inhibit autophagy. At present, the role of AKt/mTOR and its downstream signaling molecules 4E-BP1 and p70S6K1 in tumor autophagy is a new research hotspot.

mTOR Inhibitor and Tumor Treatment

Since rapamycin has shown certain effects in a variety of tumor treatments, various rapamycin derivatives have been further developed internationally since the 1990s. Currently, clinical studies or even clinical applications include temsirolimus (CCI-779), everolimus (RAD001), and Ridaforolimus (deforolimus, AP2 3573). Animal experiments show that the addition of Caspase-3 inhibitor DEVD to the use of rapamycin derivative RAD001 will increase the sensitivity of lung cancer radiotherapy, suggesting that there may be a correlation between autophagy in the treatment of tumor effects; The study found that RAD001 and CCI-779 can induce a tumor remission rate of 30% to 40%. Studies suggest that RAD001 can also increase the sensitivity of breast, prostate and bladder cancers to chemoradiotherapy, and that cell death is a non-apoptotic-dependent autophagy-associated cell death.

A new generation of mTOR inhibitors can dually target mTORC1 and mTORC2, negatively regulate the compensatory phosphorylation of AKT, and also significantly inhibit the PI3K/AKT/mTOR pathway. NVP-BEZ235 is a PI3K/mTOR dual target inhibitor that demonstrates the inhibition of NVP-BEZ235 on tumor cell growth and proliferation and induces apoptosis in a variety of tumors. NVP-BEZ235 functions to reversibly inhibit PI3K activity by binding to the ATP-binding domain of PI3K, and NVP-BEZ235 binds to the ATP-binding site in the mTOR kinase domain to down-regulate the activity of mTORC1 and mTORC2.

The mTORC1/mTORC2 inhibitor OSI-027 is also a new generation of mTOR inhibitors. OSI-027 inhibits rapamycin stimulation and IGF-1-induced AKT phosphorylation. In addition, it can down-regulate the proliferation of rapamycin-sensitive and tolerant tumor cells, and induce apoptosis characteristics of tumor cells. AZD8055 inhibits both mTORC1 and mTORC1 complexes, and AZD8055 has been shown to inhibit proliferation and growth of a variety of tumor cells.

References:

  1. Alp, E. , Yilmaz, A. , Onen, H. I. , Menevse, E. S. , Alp, E. , & Yilmaz, A. , et al. (2017). Effects of ef-24, rad001, and paclitaxel on the expression profiles of apoptotic and anti-apoptotic genes. Journal of Cancer Research & Therapeutics, 13(2), 346.
  2. Risberg, K. , Redalen, K. R. , S Nstevold, L. , Bj Rnetr, T. , S?Lvernes, J. , & Ree, A. H. . (2016). Pro-survival responses to the dual inhibition of anti-apoptotic bcl-2 family proteins and mtor-mediated signaling in hypoxic colorectal carcinoma cells. BMC Cancer, 16(1), 531.
  3. Crino, P. B. . (2016). The mtor signalling cascade: paving new roads to cure neurological disease. Nature Reviews Neurology, 12(7).
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