Target of rapamycin (mTOR) is a highly-conserved serine/threonine kinase that regulates cell growth and division in response to energy levels, growth signals, and nutrients (Zoncu et al. 2011). Control of mTOR activity is critical for the cell since its dysregulation leads to cancer, metabolic disease, and diabetes (Laplante & Sabatini 2012). In cells, mTOR exists as two structurally distinct complexes termed mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), each one with specificity for different sets of effectors. mTORC1 couples energy and nutrient abundance to cell growth and proliferation by balancing anabolic (protein synthesis and nutrient storage) and catabolic (autophagy and utilization of energy stores) processes.
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Syed NA, Horner KN, Misra V, Khandelwal RL.; ''Different cellular localization, translocation, and insulin-induced phosphorylation of PKBalpha in HepG2 cells and hepatocytes.''; PubMedEurope PMCScholia
Inoki K, Ouyang H, Li Y, Guan KL.; ''Signaling by target of rapamycin proteins in cell growth control.''; PubMedEurope PMCScholia
Andjelković M, Maira SM, Cron P, Parker PJ, Hemmings BA.; ''Domain swapping used to investigate the mechanism of protein kinase B regulation by 3-phosphoinositide-dependent protein kinase 1 and Ser473 kinase.''; PubMedEurope PMCScholia
Rebsamen M, Pochini L, Stasyk T, de Araújo ME, Galluccio M, Kandasamy RK, Snijder B, Fauster A, Rudashevskaya EL, Bruckner M, Scorzoni S, Filipek PA, Huber KV, Bigenzahn JW, Heinz LX, Kraft C, Bennett KL, Indiveri C, Huber LA, Superti-Furga G.; ''SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1.''; PubMedEurope PMCScholia
Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM.; ''Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1.''; PubMedEurope PMCScholia
Oshiro N, Takahashi R, Yoshino K, Tanimura K, Nakashima A, Eguchi S, Miyamoto T, Hara K, Takehana K, Avruch J, Kikkawa U, Yonezawa K.; ''The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1.''; PubMedEurope PMCScholia
Zhang H, Zha X, Tan Y, Hornbeck PV, Mastrangelo AJ, Alessi DR, Polakiewicz RD, Comb MJ.; ''Phosphoprotein analysis using antibodies broadly reactive against phosphorylated motifs.''; PubMedEurope PMCScholia
Wang S, Tsun ZY, Wolfson RL, Shen K, Wyant GA, Plovanich ME, Yuan ED, Jones TD, Chantranupong L, Comb W, Wang T, Bar-Peled L, Zoncu R, Straub C, Kim C, Park J, Sabatini BL, Sabatini DM.; ''Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1.''; PubMedEurope PMCScholia
Ali SM, Sabatini DM.; ''Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site.''; PubMedEurope PMCScholia
Katajisto P, Vallenius T, Vaahtomeri K, Ekman N, Udd L, Tiainen M, Mäkelä TP.; ''The LKB1 tumor suppressor kinase in human disease.''; PubMedEurope PMCScholia
Kovacina KS, Park GY, Bae SS, Guzzetta AW, Schaefer E, Birnbaum MJ, Roth RA.; ''Identification of a proline-rich Akt substrate as a 14-3-3 binding partner.''; PubMedEurope PMCScholia
Hardie DG.; ''AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.''; PubMedEurope PMCScholia
Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM.; ''Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids.''; PubMedEurope PMCScholia
Andjelković M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M, Cron P, Cohen P, Lucocq JM, Hemmings BA.; ''Role of translocation in the activation and function of protein kinase B.''; PubMedEurope PMCScholia
Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH.; ''Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40.''; PubMedEurope PMCScholia
Zoncu R, Efeyan A, Sabatini DM.; ''mTOR: from growth signal integration to cancer, diabetes and ageing.''; PubMedEurope PMCScholia
Inoki K, Li Y, Xu T, Guan KL.; ''Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling.''; PubMedEurope PMCScholia
Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM.; ''PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase.''; PubMedEurope PMCScholia
Wang L, Harris TE, Lawrence JC.; ''Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation.''; PubMedEurope PMCScholia
Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K.; ''Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action.''; PubMedEurope PMCScholia
Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM.; ''The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.''; PubMedEurope PMCScholia
Jung J, Genau HM, Behrends C.; ''Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9.''; PubMedEurope PMCScholia
Upon formation of a trimeric LKB1:STRAD:MO25 complex, LKB1 phosphorylates and activates AMPK. This phosphorylation is immediately removed in basal conditions by PP2C, but if the cellular AMP:ATP ratio rises, this activation is maintained, as AMP binding by AMPK inhibits the dephosphorylation. AMPK then activates the TSC complex by phosphorylating TSC2. Active TSC activates the intrinsic GTPase activity of Rheb, resulting in GDP-loaded Rheb and inhibition of mTOR pathway.
PKB phosphorylates TSC2 decreasing its activity and disrupting TSC1:TSC2 heterodimer formation (Hay & Sonenberg 2004) which induces ubiquination of the free TSC2 (Inoki et al. 2002).
Phosphorylation of TSC2 by PKB disrupts TSC1:TSC2 heterodimer formation (Hay & Sonenberg 2004) inducing ubiquination and degradation of both TSC1 and TSC2 through the proteosome pathway (Inoki et al. 2002, Dan et al. 2002, Proud 2002). Degradation of TSC2 is not always seen; dissociation of TSC2 from the lysosomal membrane has been suggested as an alternative mechanism (Menon et al. 2014).
Rheb is a GTP binding protein that exhibits GTPase activity. GDP is exchanged for GTP in the [Rheb:GDP] complex to form [Rheb:GTP], which binds and activates the mTORC1 complex. The GDP-bound form of Rheb also binds mTORC1 but does not lead to activation. This exchange may be catalysed by an as yet unidentified guanine exchange factor (GEF); the intrinsic exchange activity of Rheb may be sufficient in the absence of a GEF.
mTOR forms a functional protein complex with at least two proteins: RPTOR (Raptor, Regulated Associated Protein of mTOR) and MLST8. This complex is called mammalian TOR complex 1 (mTORC1). RPTOR serves as a scaffolding protein to bridge the interaction between mTOR and its substrates, defining the substrate specificity of mTORC1 (Dunlop et al. 2008). MLST8 enhances the association of mTOR with RPTOR. The complex is activated by association with RHEB, a small guanosine triphosphate (GTP)–binding protein that potently activates the protein kinase activity of mTORC1 in vivo (Long et al. 2005, Sarbassov et al. 2005) and in vitro (Sancak et al. 2007). Rheb interacts with and activates mTORC1 (reviewed in Laplante & Sabatini 2009, Wang & Proud 2011) and is necessary for the activation of mTORC1 by all signals. Besides binding directly to mTOR, RHEB can bind RPTOR and MLST8 (Hara et al. 2002, Inoki et al. 2005). RHEB-GTP charging does not promote the RHEB:mTOR interaction, but GTP-charged RHEB is required for activation of mTOR catalytic activity (Avruch et al. 2009). Studies in fission yeast strongly suggest that RHEB must bind mTOR for activation of catalytic activity (Urano et al. 2005) and this has also been demonstrated in mammals (Sancak et al. 2007) though this has been questioned (Wang & Proud 2011). It is unclear whether active mTORC1 remains bound to Rheb or, alternatively, once activated, can dissociate from Rheb. mTORC1 activity has been reported at many cellular localizations but some of these reports may be identifying mTOR as part of mTORC2. mTORC1 is predominantly lysosomal, though under amino acid starvation conditions it exhibits a diffuse, cytoplasmic distribution. It may have different functions when active in the cytoplasm. mTORC1 associates with the general translation initiation complex eIF3 and phosphorylates the translation inhibitor 4E-BP upon stimulation by growth factors and nutrients, promoting translation initiation (Proud 2009, Sonenberg & Hinnebusch 2009). These events presumably take place in the cytoplasm (Betz & Hall 2013).
Raptor recruits mTOR to non-phosphorylated 4E-BP1 bound to eIF4E and positively modulates phosphorylation of 4E-BP1 by mTOR. 4E-BP1 is further phosphorylated on multiple sites by other unknown kinases, also contributing to the dissociation of 4E-BP1 from eIF4E. Thus mTORC1 relieves the inhibitory effect of 4E-BP1 on eIF4E dependent translation initiation (Inoki et al. 2005, Gingras et al. 1999, 2001).
Once phosphorylated, S6K1-P phosphorylates and activates ribosomal protein S6 (rpS6), which in turn selectively increases the translation of 5'-TOP mRNAs. These mRNAs encode exclusively for components of the translation machinery (PMID 15809305).
Phosphorylation of eEF2 kinase by S6K1-P results in decreased activity of this kinase. eEF2 kinase normally phosphorylates and deactivates eEF2, preventing its binding to the ribosome.
Phosphorylated S6K1 in turn phosphorylates eIF4G, a component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome.
eIF4B is a physiologically relevant target of S6K1. Once phosphorylated and activated by S6K1, eIF4B specifically stimulates the ATPase and RNA helicase activities of eIF4A.
AKT1 phosphorylates AKT1S1 (PRAS40, Proline Rich Akt Substrate 40 kDa) at Thr-246. AKT1S1 is an inhibitory accessory protein of mTORC1. Phosphorylation of AKT1S1 by AKT releases the inhibition of mTORC1.
A complex of LAMTOR1 to 5, known as Ragulator, interacts with Rag GTPases recruiting them to lysosomes, an essential step in mTORC1 activation (Sancak et al. 2010). LAMTOR1 is probably myristoylated and/or palmitoylated to enhance its assocation with the lysosomal surface, acting as a platform for the other members of the compex. Lamtor1 (Nada et al. 2009) and Lamtor2 (Teis et al. 2006) knockout mice exhibit severe growth retardation, severe defects in intracellular organelle organization and embryonic lethality. Partial reduction of LAMTOR2 in humans leads to reduced height (Bohn et al. 2007).
Rag proteins are Ras-family GTP-binding proteins. Amino acid nutrient signaling is mediated by the Rag family (Kim & Guan 2009). Mammals express four Rag proteins (RRAGA-D) that form heterodimers. RRAGA (RagA) and RRAGB (RagB) can both form a heterodimer with one of RRAGC (RagC) or RRAGD (RagD), which are functionally redundant (Hirose et al. 1998, Sancak et al. 2008, Schurmann et al. 1995, Sekiguchi et al., 2001). Rag heterodimers containing GTP-bound RagB interact with mTORC1, and amino acids induce the mTORC1-Rag interaction by promoting the loading of RagB with GTP, which enables it to directly interact with the raptor component of mTORC1. RagB mutated to constitutively bind GTP immunoprecipitated raptor and mTOR more strongly than complexes containing wild-type RagB or RagB:GDP. The GDP-bound form of RagC increased the amount of copurifying mTORC1, so that a heterodimer complex of RagB:GTP and RagC:GDP recovered more mTORC1 than any other heterodimer (Sancak et al. 2008). It is not clear how Rag GTPases are regulated by the availability of amino acids (Jung et al. 2010, Betz & Hall 2013). Signalling may start at the cell membrane where specific SLC membrane transport proteins regulate amino acid levels and mTOR activity (Nicklin et al. 2009).
A complex of LAMTOR1-5, known as Ragulator, interacts with Rag GTPases, recruiting them to lysosomes, an essential step in mTORC1 activation by amino acids (Sancak et al. 2010).
AKT1S1 (PRAS40) phosphorylation by AKT at Thr246, or at Ser183 by mTORC1, leads to the binding of YWHAB (14-3-3 beta) (Zhang et al. 2002, Kovacina et al. 2003, Oshiro et al. 2007). As AKT1S1 suppresses mTORC1 phosphorylation of physiological substrates S6K1 and 4E-BP1 (Oshiro et al. 2007) binding of YWHAB is proposed to relieve this inhibition (Wang et al. 2012).
AKT1S1 (PRAS40) is phosphorylated by AKT at Thr246, which leads to the binding of YWHAB (14-3-3 beta) (Zhang et al. 2002, Kovacina et al. 2003. AKT1S1 is phosphorylated at Ser183 by mTORC1 (Oshiro et al. 2007); mutation of Ser183 decreases the affinity of AKT1S1 with YWHAB. As AKT1S1 suppresses mTORC1 phosphorylation of S6K1 and 4E-BP1 (Oshiro et al. 2007), binding of YWHAB is proposed to relieve this inhibition (Wang et al. 2012).
AKT1S1 (PRAS40, proline-rich Akt/PKB substrate 40 kDa) is an mTORC1 accessory protein that binds the mTOR kinase domain. The interaction with mTOR is induced under conditions that inhibit mTOR signalling, such as nutrient or serum deprivation or mitochondrial metabolic inhibition. AKT1S1 binding suppresses mTORC1 phosphorylation of S6K1 and 4E-BP1 (Sancak et al. 2007, Vander Haar et al. 2008, Oshiro et al. 2007) and suppresses constitutive activation of mTOR in cells lacking TSC2. AKT1S1 silencing inactivates insulin-receptor substrate-1 (IRS-1) and Akt, and uncouples the response of mTOR to Akt signals. Furthermore, AKT1S1 phosphorylation by Akt and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mTOR (Sancak et al. 2007, Vander Haar et al. 2008). PRAS40 is also a substrate of the mTOR complex (Kovacina et al. 2003, Oshiro et al. 2007).
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regulation of mTOR
by LKB1-AMPKwith
p-S722,S792-RPTOR:Ragulator:Rag:GNP:RHEB:GTPAnnotated Interactions
with
p-S722,S792-RPTOR:Ragulator:Rag:GNP:RHEB:GTP