MTOR
Sisarski cilj za rapamicin (mTOR),[5] znan i kao mehanistički cilj rapamicina, a ponekad i kao FK506-vezujući protein 12-rapamicinu pridruženi protein 1 (FRAP1), jest kinaza koji je kod ljudi kodiran genom MTOR sa hromosoma 1.[6][7] mTOR je član porodice protein-kinaza, fosfatidilinozitol 3-kinaza-vezane kinaze.[8]
mTOR se povezuje sa drugim proteinima i služi kao osnovna komponenta dva različita proteinska kompleksa, mTOR kompleksa 1 i mTOR kompleksa 2, koji regulišu različite ćelijske procese. Konkretno, kao ključna komponenta oba kompleksa, mTOR funkcionira kao serin/treonin protein-kinaza koja regulira ćelijski rast, proliferaciju ćelija, ćelijski motilitet, preživljavanje ćelije, sintezu proteina, autofagiju i transkripciju.[9][10] Kao jezgarna komponenta mTORC2, mTOR također funkcionira kao tirozin protein-kinaza koja promovira aktivaciju insulinskih receptora i insulinolikog receptora faktora rasta 1.[11] mTORC2 je također uključen u kontrolu i održavanje aktinskog citoskeleta.[9][12]
Aminokiselinska sekvenca
[uredi | uredi izvor]Dužina polipeptidnog lanca je 2.549 aminokiselina, a molekulska težina 288.892 Da.[11]
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MLGTGPAAAT | TAATTSSNVS | VLQQFASGLK | SRNEETRAKA | AKELQHYVTM | ||||
ELREMSQEES | TRFYDQLNHH | IFELVSSSDA | NERKGGILAI | ASLIGVEGGN | ||||
ATRIGRFANY | LRNLLPSNDP | VVMEMASKAI | GRLAMAGDTF | TAEYVEFEVK | ||||
RALEWLGADR | NEGRRHAAVL | VLRELAISVP | TFFFQQVQPF | FDNIFVAVWD | ||||
PKQAIREGAV | AALRACLILT | TQREPKEMQK | PQWYRHTFEE | AEKGFDETLA | ||||
KEKGMNRDDR | IHGALLILNE | LVRISSMEGE | RLREEMEEIT | QQQLVHDKYC | ||||
KDLMGFGTKP | RHITPFTSFQ | AVQPQQSNAL | VGLLGYSSHQ | GLMGFGTSPS | ||||
PAKSTLVESR | CCRDLMEEKF | DQVCQWVLKC | RNSKNSLIQM | TILNLLPRLA | ||||
AFRPSAFTDT | QYLQDTMNHV | LSCVKKEKER | TAAFQALGLL | SVAVRSEFKV | ||||
YLPRVLDIIR | AALPPKDFAH | KRQKAMQVDA | TVFTCISMLA | RAMGPGIQQD | ||||
IKELLEPMLA | VGLSPALTAV | LYDLSRQIPQ | LKKDIQDGLL | KMLSLVLMHK | ||||
PLRHPGMPKG | LAHQLASPGL | TTLPEASDVG | SITLALRTLG | SFEFEGHSLT | ||||
QFVRHCADHF | LNSEHKEIRM | EAARTCSRLL | TPSIHLISGH | AHVVSQTAVQ | ||||
VVADVLSKLL | VVGITDPDPD | IRYCVLASLD | ERFDAHLAQA | ENLQALFVAL | ||||
NDQVFEIREL | AICTVGRLSS | MNPAFVMPFL | RKMLIQILTE | LEHSGIGRIK | ||||
EQSARMLGHL | VSNAPRLIRP | YMEPILKALI | LKLKDPDPDP | NPGVINNVLA | ||||
TIGELAQVSG | LEMRKWVDEL | FIIIMDMLQD | SSLLAKRQVA | LWTLGQLVAS | ||||
TGYVVEPYRK | YPTLLEVLLN | FLKTEQNQGT | RREAIRVLGL | LGALDPYKHK | ||||
VNIGMIDQSR | DASAVSLSES | KSSQDSSDYS | TSEMLVNMGN | LPLDEFYPAV | ||||
SMVALMRIFR | DQSLSHHHTM | VVQAITFIFK | SLGLKCVQFL | PQVMPTFLNV | ||||
IRVCDGAIRE | FLFQQLGMLV | SFVKSHIRPY | MDEIVTLMRE | FWVMNTSIQS | ||||
TIILLIEQIV | VALGGEFKLY | LPQLIPHMLR | VFMHDNSPGR | IVSIKLLAAI | ||||
QLFGANLDDY | LHLLLPPIVK | LFDAPEAPLP | SRKAALETVD | RLTESLDFTD | ||||
YASRIIHPIV | RTLDQSPELR | STAMDTLSSL | VFQLGKKYQI | FIPMVNKVLV | ||||
RHRINHQRYD | VLICRIVKGY | TLADEEEDPL | IYQHRMLRSG | QGDALASGPV | ||||
ETGPMKKLHV | STINLQKAWG | AARRVSKDDW | LEWLRRLSLE | LLKDSSSPSL | ||||
RSCWALAQAY | NPMARDLFNA | AFVSCWSELN | EDQQDELIRS | IELALTSQDI | ||||
AEVTQTLLNL | AEFMEHSDKG | PLPLRDDNGI | VLLGERAAKC | RAYAKALHYK | ||||
ELEFQKGPTP | AILESLISIN | NKLQQPEAAA | GVLEYAMKHF | GELEIQATWY | ||||
EKLHEWEDAL | VAYDKKMDTN | KDDPELMLGR | MRCLEALGEW | GQLHQQCCEK | ||||
WTLVNDETQA | KMARMAAAAA | WGLGQWDSME | EYTCMIPRDT | HDGAFYRAVL | ||||
ALHQDLFSLA | QQCIDKARDL | LDAELTAMAG | ESYSRAYGAM | VSCHMLSELE | ||||
EVIQYKLVPE | RREIIRQIWW | ERLQGCQRIV | EDWQKILMVR | SLVVSPHEDM | ||||
RTWLKYASLC | GKSGRLALAH | KTLVLLLGVD | PSRQLDHPLP | TVHPQVTYAY | ||||
MKNMWKSARK | IDAFQHMQHF | VQTMQQQAQH | AIATEDQQHK | QELHKLMARC | ||||
FLKLGEWQLN | LQGINESTIP | KVLQYYSAAT | EHDRSWYKAW | HAWAVMNFEA | ||||
VLHYKHQNQA | RDEKKKLRHA | SGANITNATT | AATTAATATT | TASTEGSNSE | ||||
SEAESTENSP | TPSPLQKKVT | EDLSKTLLMY | TVPAVQGFFR | SISLSRGNNL | ||||
QDTLRVLTLW | FDYGHWPDVN | EALVEGVKAI | QIDTWLQVIP | QLIARIDTPR | ||||
PLVGRLIHQL | LTDIGRYHPQ | ALIYPLTVAS | KSTTTARHNA | ANKILKNMCE | ||||
HSNTLVQQAM | MVSEELIRVA | ILWHEMWHEG | LEEASRLYFG | ERNVKGMFEV | ||||
LEPLHAMMER | GPQTLKETSF | NQAYGRDLME | AQEWCRKYMK | SGNVKDLTQA | ||||
WDLYYHVFRR | ISKQLPQLTS | LELQYVSPKL | LMCRDLELAV | PGTYDPNQPI | ||||
IRIQSIAPSL | QVITSKQRPR | KLTLMGSNGH | EFVFLLKGHE | DLRQDERVMQ | ||||
LFGLVNTLLA | NDPTSLRKNL | SIQRYAVIPL | STNSGLIGWV | PHCDTLHALI | ||||
RDYREKKKIL | LNIEHRIMLR | MAPDYDHLTL | MQKVEVFEHA | VNNTAGDDLA | ||||
KLLWLKSPSS | EVWFDRRTNY | TRSLAVMSMV | GYILGLGDRH | PSNLMLDRLS | ||||
GKILHIDFGD | CFEVAMTREK | FPEKIPFRLT | RMLTNAMEVT | GLDGNYRITC | ||||
HTVMEVLREH | KDSVMAVLEA | FVYDPLLNWR | LMDTNTKGNK | RSRTRTDSYS | ||||
AGQSVEILDG | VELGEPAHKK | TGTTVPESIH | SFIGDGLVKP | EALNKKAIQI | ||||
INRVRDKLTG | RDFSHDDTLD | VPTQVELLIK | QATSHENLCQ | CYIGWCPFW |
Funkcija
[uredi | uredi izvor]mTOR integrira ulaz iz uzvodnih puteva||transdukcija signala|transdukcije signala]], uključujući insulin, faktore rasta (kao što su IGF-1 i IGF-2), i [ [aminokiselina]].[10] mTOR takođe osjeća nivoe ćelijskih hranljivih materija, kisika i energije.[13] mTOR-ski put je centralni regulator metabolizma i fiziologije sisara, s važnom ulogom u funkciji tkiva, uključujući jetru, mišiće, bijelo i smeđe masno tkivo,[14] i mozak; disreguliran je kod ljudskih bolesti, kao što su dijabetes, gojaznost, depresija i određeni karcinomi.[15][16] Rapamicin inhibira mTOR povezujući se sa njegovim unutarčelijskim receptorom FKBP12.[17][18] Kompleks FKBP12–rapamicin vezuje se direktno za FKBP12-rapamicinvezujući (FRB) domen mTOR, inhibirajući njegovu aktivnost.[18]
Kompleksi
[uredi | uredi izvor]mTOR je katalitska podjedinica dva strukturno različita kompleksa: mTORC1 i mTORC2.[19] The two complexes localize to different subcellular compartments, thus affecting their activation and function.[20] Nakon aktivacije Rheb-om, mTORC1 se lokalizira na Ragulator-Rag kompleks na površini lizosoma gdje tada postaje aktivan, u prisustvu dovoljno aminokiselina.[21][22]
Klinički značaj
[uredi | uredi izvor]Starenje
[uredi | uredi izvor]Utvrđeno je da smanjena aktivnost TOR produžava životni vijek u S. cerevisiae, C. elegans, i D. melanogaster.[23][24][25][26] Potvrđeno je da mTOR-ov inhibitor, rapamicin produžava životni vijek miševa.[27][28][29][30][31]
Pretpostavlja se da neki režimi ishrane, kao što su ograničenje kalorija i ograničenje metionina, uzrokuju produženje životnog vijeka, smanjenjem mTOR-ske aktivnosti.[23][24] Neke studije sugerirale su da se signalizacija mTOR-a može povećati tokom starenja, barem u specifičnim tkivima kao što je masno tkivo, a rapamicin može djelovati, djelimično blokirajući ovo povećanje.[32] Alternativna teorija je da je mTOR signalizacija primjer antagonističke plejotropije, a dok je visoka signalizacija mTOR dobra tokom ranog života, održava se na neprikladno visokom nivou u starosti. Restrikcija kalorija i restrikcija metionina mogu djelomično djelovati ograničavanjem nivoa esencijalnih aminokiselina, uključujući leucin i metionin, koji su snažni aktivatori mTOR-a.[33] Pokazalo se da davanje leucina u mozak pacova smanjuje unos hrane i tjelesnu težinu putem aktivacije mTOR puta u hipotalamusu.[34]
Kancer
[uredi | uredi izvor]Prekomjerna aktivacija signalizacije mTOR-a značajno doprinosi započinjanju i razvoju tumora, a otkriveno je da je aktivnost mTOR deregulirana kod mnogih tipova karcinoma uključujući karcinome dojke, pluća, prostate, melanoma, mjehura, mozga i bubrega.[35] Ima nekoliki razloga za konstitutivnu aktivaciju. Među najčešćim su mutacije tumor supresorskog gena PTEN. PTEN-ova fosfataza negativno utiče na signalizaciju mTOR, ometanjem efekta PI3K, uzvodnog efektora mTOR. Osim toga, aktivnost mTOR je deregulirana kod mnogih karcinoma, kao posljedica povećane aktivnosti PI3K ili Akt.[36] Slično tome, prekomjerna ekspresija nizvodnih mTOR efektora 4E-BP1, S6K i eIF4E dovodi do loše prognoze raka.[37] Također, mutacije TSC proteina koje inhibiraju aktivnost mTOR-a mogu dovesti do stanja pod nazivom kompleksne gomoljasate skleroze, koje se ispoljava kao benigne lezije i povećava rizik od karcinomskih ćelija bubrežne skleroze.[38]
Pokazalo se da povećanje aktivnosti mTOR-a pokreće progresiju ćelijskog ciklusa i povećava ćelijsku proliferaciju uglavnom zbog njegovog efekta na sintezu proteina. Štaviše, aktivni mTOR podržava rast tumora takođe indirektno inhibirajući autofagiju.[39] Konstitutivno aktivirani mTOR funkcionira u opskrbi karcinomskih ćelija kisikom i hranjivim tvarima, povećanjem translacije HIF1A i podržavanjem angiogeneze.[40] mTOR također pomaže u još jednoj metaboličkoj adaptaciji kancerogenih ćelija, kako bi podržao njihovu povećanu stopu rasta – aktivaciju glikolitskog metabolizma. Akt2, supstrat mTOR-a, posebno mTORC2, pojačava ekspresiju glikolitskog enzima PKM2 doprinoseći tako Warburgovom efektu.[41]
Poremećaji centralnog nervnog sistema / Funkcija mozga
[uredi | uredi izvor]Autizam
[uredi | uredi izvor]mTOR je umiješan u neuspjeh mehanizma 'orezivanja' ekscitatornih sinapsi kod poremećaja iz autističkog spektra.[42]
Alzheimerova bolest
[uredi | uredi izvor]mTOR signalizacija se ukršta sa nekoliko aspekata patoloških prfomjena kod Alzhemerovw bolesti (AD), sugerirajući njegovu potencijalnu ulogu kao doprinosa progresiji bolesti. Općenito, nalazi pokazuju hiperaktivnost signalizacije mTORa u mozgu sa AD. Naprimjer, postmortem studije ljudskog mozga sa AD otkrivaju disregulaciju u PTEN, Akt, S6K i mTOR.[43][44][45] Signalizacija mTOR-a povezana je usko s prisustvom rastvorljivih beta (Aβ) i tau proteina, koji se agregiraju i formiraju dva obilježja bolesti, Aβ plakove i neurofibrilne čvorove.[46] In vitro studije pokazale su da je Aβ aktivator PI3K/AKT put, koji zauzvrat aktivira mTOR.[47] Osim toga, primjena Aβ na N2K ćelije povećava ekspresiju p70S6K, nizvodne mete mTOR-a, za koju se zna da ima veću ekspresiju u neuronima koji na kraju razvijaju neurofibrilske zaplete.[48][49] Ćelije jajnika kineskog hrčka transficirane 7PA2 porodičnom AD mutacijom također pokazuju povećanu aktivnost mTOR-a u odnosu na kontrole, a hiperaktivnost je blokirana pomoću inhibitora gama-sekretaze.[50][51] Ove in vitro studije ukazuju na to da povećanje koncentracije Aβ povećava signalizaciju mTOR-a; međutim, smatra se da značajno velike, citotoksične koncentracije Aβ smanjuju tu signalizaciju.[52]
U skladu sa podacima uočenim in vitro, pokazalo se da su aktivnost mTOR-a i aktivirani p70S6K značajno povećani u korteksu i hipokampusu životinjskih modela AD, u poređenju sa kontrolama.[51][53] Farmakološko ili genetičko uklanjanje Aβ u životinjskim modelima AD eliminira poremećaj normalne aktivnosti mTOR-a, ukazujući na direktnu uključenost Aβ u njegovu signalizaciju.[53] Osim toga, ubrizgavanjem Aβ oligomera u hipokampus normalnih miševa, uočena je hiperaktivnost mTOR-a.[53] Čini se da su kognitivna oštećenja karakteristična za AD posredovana fosforilacijom PRAS-40, koja se odvaja od mTOR-ovoj hiperaktivnosti i omogućava mTOR-sku hiperaktivnost kada je fosforiliran; inhibiranje fosforilacije PRAS-40 sprečava hiperaktivnost mTOR-a izazvanu putem Aβ.[53][54][55] S obzirom na ove nalaze, čini se da je signalni put mTOR-a jedan od mehanizama Aβ-indukovane toksičnosti u AD. .
Limfoproliferativne bolesti
[uredi | uredi izvor]Hiperaktivni putevi mTOR-a su identificirani kod određenih limfoproliferativnih bolesti, kao što su autoimunski limfoproliferativni sindrom (ALPS),[56] multicentrična Castlemanova bolest,[57] i posttransplantacijski limfoproliferativni poremećaj (PTLD).[58]
Sinteza proteina i rast ćelija
[uredi | uredi izvor]Aktivacija mTORC1 potrebna je za sintezu proteina mišićnih miofibrila i skeletnu hipertrofiju mišića kod ljudi. kao odgovor i na fizičke vježbe i uzimanje određenih aminokiselina ili njihovih derivata.[59][60] Trajna inaktivacija signalizacije mTORC1 u skeletnim mišićima olakšava gubitak mišićne mase i snage tokom gubljenja mišića u starosti, kaheksije raka i atrofije zbog fizičke neaktivnosti.[59][60][61] Čini se da aktivacija mTORC2 posreduje u izrastanj neurita u diferenciranoj neuro2a ćeliji miša.[62] Intermitentna aktivacija mTOR-a u prefrontalnim neuronima pomoću β-hidroksi β-metilbutirata inhibira kognitivni pad koji je povezan sa starenjem i povezan sa dendritskim orezivanjem kod životinja, što je fenomen koji se također primjećuje kod ljudi.[63]
Mnoge aminokiseline izvedene iz proteina hrane podstiču aktivaciju mTORC1 i povećavaju sintezu proteina signalizacijom putem Rag GTPaza.
Skraćenice i prikazi:| • PLD: fosfolipaza D
• PA: fosfatidna kiselina
• mTOR: mehanička meta rapamicina
• AMP: adenozin monofosfat
• ATP: adenozin trifosfat
• AMPK: AMP-aktivirana protein kinaza
• PGC-1α: peroksizomski proliferator aktiviran receptor gama koaktivator-1α
• S6K1: p70S6 kinaza
• 4EBP1: eukariotski faktor inicijacije translacije 4E- vezujući protein 1
• eIF4E: eukariotski faktor inicijacije translacije 4E
• RPS6: ribosomalni protein S6
• eEF2: eukariotski faktor elongacije 2
• RE: vježba otpora; EE: vježba izdržljivosti
• Mio: miofibrilski; Mito: mitohondrijel
• AA: aminokiseline
• HMB: β-hidroksi β-metilbuterna kiselina
• ↑ predstavlja activaciju
•
T-inhibicije
Sklerodermija
[uredi | uredi izvor]Skleroderma, također poznata kao sistemska skleroza, je hronična sistemska autoimunska bolest koju karakteriše otvrdnuće (sklero) kože (derma ) koje u težim oblicima zahvata unutrašnje organe.[65][66] mTOR ima ulogu u bolestima fibroza i autoimunosti, a blokada mTORC puta se istražuje kao tretman za sklerodermu.[8]
Bolest skladištenja glikogena
[uredi | uredi izvor]Neki članci navode da rapamicin može inhibirati mTORC1 tako da se fosforilacija GS (glikogen-sintaze) može povećati u skeletnim mišićima. Ovo otkriće predstavlja potencijalni novi terapijski pristup za bolest skladištenja glikogena koja uključuje akumulaciju glikogena u mišićima.
Anti-kancer
[uredi | uredi izvor]Postoje dva primarna nhibitoramTOR-a i koji se koriste u liječenju karcinoma kod ljudi, temsirolimus i everolimus. mTOR inhibitori su našli primenu u liječenju različitih malignosti, uključujući karcinom bubrežnih ćelija (temsirolimus) i rak gušterače, rak dojke i karcinom bubrežnih ćelija (everolimus).[67] Kompletan mehanizam ovih agenasa nije jasan, ali se smatra da funkcionišu tako što ometaju angiogenezu tumora i uzrokuju oštećenje G1/S tranzicije.[68]
Protiv starenja
[uredi | uredi izvor]Inhibitori mTOR-a mogu biti korisni za liječenje/prevenciju nekoliko stanja povezanih s godinama,[69] uključujući neurodegenerativne bolesti, kao što su Alzheimerova i Parkinsonova bolest.[70] Nakon kratkotrajnog tretmana inhibitorima mTORa, kao što su dactolisib i everolimus, kod starijih osoba (65 i više godina), liječeni su imali smanjen broj infekcija u toku jedne godine.[71]
Za razne prirodne spojeve, uključujući epigalokatehin-galat (EGCG), kofein, kurkumin, berberin, kvercetin, resveratrol i pterostilben, prijavljeno je da inhibiraju mTOR kada se primjenjuju na izolirane ćelije u kulturi.[72][73][74] Još uvijek ne postoje visokokvalitetni dokazi da ove tvari inhibiraju signalizaciju mTOR-a ili produžuju životni vijek kada ih ljudi uzimaju kao dodatke ishrani, uprkos ohrabrujućim rezultatima kod životinja kao što su vinske mušice i miševi. Razne prosudbe su u toku.[75][76]
Interakcije
[uredi | uredi izvor]Pokazalo se da mehancistička meta rapamicina reaguje sa:[77]
- ABL1,[78]
- AKT1,[79][80]
- IGF-IR,[11]
- InsR,[11]
- CLIP1,[81]
- EIF3F[82]
- EIF4EBP1,[83][84][85][86][87][88][89]
- FKBP1A,[12][90][91][92][93]
- GPHN,[94]
- KIAA1303,[83][84][85][95][96][97][98][99][100][101][102][103][104][105][106]
- PRKCD,[107]
- PS6KB1,[84][86][87][88][102][105][108][109][110][111][112][113][114][115]
- RHEB,[116][117][118]
- RICTOR,[97][103][105][106]
- STAT1,[119]
- STAT3,[120][121]
- TPCN1;
- TPCN2,[122] i
- UBQLN1.[123]
Reference
[uredi | uredi izvor]- ^ a b c GRCh38: Ensembl release 89: ENSG00000198793 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028991 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT (Jan 1995). "Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells". J. Biol. Chem. 270 (2): 815–22. doi:10.1074/jbc.270.2.815. PMID 7822316.
- ^ Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL (juni 1994). "A mammalian protein targeted by G1-arresting rapamycin-receptor complex". Nature. 369 (6483): 756–8. Bibcode:1994Natur.369..756B. doi:10.1038/369756a0. PMID 8008069. S2CID 4359651.
- ^ Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT (januar 1995). "Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells". The Journal of Biological Chemistry. 270 (2): 815–22. doi:10.1074/jbc.270.2.815. PMID 7822316.
- ^ a b Mitra A, Luna JI, Marusina AI, Merleev A, Kundu-Raychaudhuri S, Fiorentino D, Raychaudhuri SP, Maverakis E (novembar 2015). "Dual mTOR Inhibition Is Required to Prevent TGF-β-Mediated Fibrosis: Implications for Scleroderma". The Journal of Investigative Dermatology. 135 (11): 2873–6. doi:10.1038/jid.2015.252. PMC 4640976. PMID 26134944.
- ^ a b c Lipton JO, Sahin M (oktobar 2014). "The neurology of mTOR". Neuron. 84 (2): 275–291. doi:10.1016/j.neuron.2014.09.034. PMC 4223653. PMID 25374355.
The mTOR signaling pathway acts as a molecular systems integrator to support organismal and cellular interactions with the environment. The mTOR pathway regulates homeostasis by directly influencing protein synthesis, transcription, autophagy, metabolism, and organelle biogenesis and maintenance. It is not surprising then that mTOR signaling is implicated in the entire hierarchy of brain function including the proliferation of neural stem cells, the assembly and maintenance of circuits, experience-dependent plasticity and regulation of complex behaviors like feeding, sleep and circadian rhythms. ...
mTOR function is mediated through two large biochemical complexes defined by their respective protein composition and have been extensively reviewed elsewhere(Dibble and Manning, 2013; Laplante and Sabatini, 2012)(Figure 1B). In brief, common to both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) are: mTOR itself, mammalian lethal with sec13 protein 8 (mLST8; also known as GβL), and the inhibitory DEP domain containing mTOR-interacting protein (DEPTOR). Specific to mTORC1 is the regulator-associated protein of the mammalian target of rapamycin (Raptor) and proline-rich Akt substrate of 40 kDa (PRAS40)(Kim et al., 2002; Laplante and Sabatini, 2012). Raptor is essential to mTORC1 activity. The mTORC2 complex includes the rapamycin insensitive companion of mTOR (Rictor), mammalian stress activated MAP kinase-interacting protein 1 (mSIN1), and proteins observed with rictor 1 and 2 (PROTOR 1 and 2)(Jacinto et al., 2006; Jacinto et al., 2004; Pearce et al., 2007; Sarbassov et al., 2004)(Figure 1B). Rictor and mSIN1 are both critical to mTORC2 function.
Figure 1: Domain structure of the mTOR kinase and components of mTORC1 and mTORC2
Figure 2: The mTOR Signaling Pathway - ^ a b Hay N, Sonenberg N (august 2004). "Upstream and downstream of mTOR". Genes & Development. 18 (16): 1926–45. doi:10.1101/gad.1212704. PMID 15314020.
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Dopunska literatura
[uredi | uredi izvor]- Saxton RA, Sabatini DM (mart 2017). "mTOR Signaling in Growth, Metabolism, and Disease". Cell. 168 (6): 960–976. doi:10.1016/j.cell.2017.02.004. PMC 5394987. PMID 28283069.
Vanjski linkovi
[uredi | uredi izvor]- mTOR protein na US National Library of Medicine Medical Subject Headings (MeSH)
- "mTOR Signaling Pathway in Pathway Interaction Database". National Cancer Institute. Arhivirano s originala, 18. 3. 2013. Pristupljeno 18. 10. 2015.
- P42345