MTOR signaling (Homo sapiens)

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Bibliography

1. Syed NA, Horner KN, Misra V, Khandelwal RL.; ''Different cellular localization, translocation, and insulin-induced phosphorylation of PKBalpha in HepG2 cells and hepatocytes.''; PubMed Europe PMC Scholia
2. Inoki K, Ouyang H, Li Y, Guan KL.; ''Signaling by target of rapamycin proteins in cell growth control.''; PubMed Europe PMC Scholia
3. 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.''; PubMed Europe PMC Scholia
4. 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.''; PubMed Europe PMC Scholia
5. Hay N, Sonenberg N.; ''Upstream and downstream of mTOR.''; PubMed Europe PMC Scholia
6. Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM.; ''Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1.''; PubMed Europe PMC Scholia
7. 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.''; PubMed Europe PMC Scholia
8. 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.''; PubMed Europe PMC Scholia
9. 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.''; PubMed Europe PMC Scholia
10. Ali SM, Sabatini DM.; ''Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site.''; PubMed Europe PMC Scholia
11. Katajisto P, Vallenius T, Vaahtomeri K, Ekman N, Udd L, Tiainen M, Mäkelä TP.; ''The LKB1 tumor suppressor kinase in human disease.''; PubMed Europe PMC Scholia
12. 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.''; PubMed Europe PMC Scholia
13. Hardie DG.; ''AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.''; PubMed Europe PMC Scholia
14. 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.''; PubMed Europe PMC Scholia
15. 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.''; PubMed Europe PMC Scholia
16. Guertin DA, Sabatini DM.; ''Defining the role of mTOR in cancer.''; PubMed Europe PMC Scholia
17. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH.; ''Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40.''; PubMed Europe PMC Scholia
18. Zoncu R, Efeyan A, Sabatini DM.; ''mTOR: from growth signal integration to cancer, diabetes and ageing.''; PubMed Europe PMC Scholia
19. Inoki K, Li Y, Xu T, Guan KL.; ''Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling.''; PubMed Europe PMC Scholia
20. 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.''; PubMed Europe PMC Scholia
21. 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.''; PubMed Europe PMC Scholia
22. 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.''; PubMed Europe PMC Scholia
23. 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.''; PubMed Europe PMC Scholia
24. Jung J, Genau HM, Behrends C.; ''Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
ADP	Metabolite	CHEBI:16761 (ChEBI)
AKT1S1	Protein	Q96B36 (Uniprot-TrEMBL)
AKT1S1	Protein	Q96B36 (Uniprot-TrEMBL)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Active mTORC1 complex	Complex	R-HSA-165678 (Reactome)
EEF2K	Protein	O00418 (Uniprot-TrEMBL)
EIF4B	Protein	P23588 (Uniprot-TrEMBL)
EIF4E	Protein	P06730 (Uniprot-TrEMBL)
EIF4EBP1	Protein	Q13541 (Uniprot-TrEMBL)
EIF4E	Protein	P06730 (Uniprot-TrEMBL)
EIF4G1	Protein	Q04637 (Uniprot-TrEMBL)
Energy dependent regulation of mTOR by LKB1-AMPK	Pathway	R-HSA-380972 (Reactome)	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.
GDP	Metabolite	CHEBI:17552 (ChEBI)
GDP	Metabolite	CHEBI:17552 (ChEBI)
GTP	Metabolite	CHEBI:15996 (ChEBI)
GTP	Metabolite	CHEBI:15996 (ChEBI)
LAMTOR1	Protein	Q6IAA8 (Uniprot-TrEMBL)
LAMTOR1	Protein	Q6IAA8 (Uniprot-TrEMBL)
LAMTOR2	Protein	Q9Y2Q5 (Uniprot-TrEMBL)
LAMTOR2	Protein	Q9Y2Q5 (Uniprot-TrEMBL)
LAMTOR3	Protein	Q9UHA4 (Uniprot-TrEMBL)
LAMTOR3	Protein	Q9UHA4 (Uniprot-TrEMBL)
LAMTOR4	Protein	Q0VGL1 (Uniprot-TrEMBL)
LAMTOR4	Protein	Q0VGL1 (Uniprot-TrEMBL)
LAMTOR5	Protein	O43504 (Uniprot-TrEMBL)
LAMTOR5	Protein	O43504 (Uniprot-TrEMBL)
MLST8	Protein	Q9BVC4 (Uniprot-TrEMBL)
MTOR	Protein	P42345 (Uniprot-TrEMBL)
PIP3	Metabolite	CHEBI:16618 (ChEBI)
RHEB	Protein	Q15382 (Uniprot-TrEMBL)
RHEB:GDP	Complex	R-HSA-165191 (Reactome)
RHEB:GTP	Complex	R-HSA-165189 (Reactome)
RPS6KB1	Protein	P23443 (Uniprot-TrEMBL)
RPS6	Protein	P62753 (Uniprot-TrEMBL)
RPTOR	Protein	Q8N122 (Uniprot-TrEMBL)
RRAGA	Protein	Q7L523 (Uniprot-TrEMBL)
RRAGA, RRAGB	Complex	R-HSA-5653946 (Reactome)
RRAGB	Protein	Q5VZM2 (Uniprot-TrEMBL)
RRAGC	Protein	Q9HB90 (Uniprot-TrEMBL)
RRAGC,RRAGD	Complex	R-HSA-5653964 (Reactome)
RRAGD	Protein	Q9NQL2 (Uniprot-TrEMBL)
Rag:GNP heterodimers	Complex	R-HSA-5653945 (Reactome)
Ragulator:Rag:GNP heterodimers	Complex	R-HSA-5653979 (Reactome)
Ragulator	Complex	R-HSA-5653921 (Reactome)
TSC1	Protein	Q92574 (Uniprot-TrEMBL)
TSC1:Inhibited TSC2-1-P	Complex	R-HSA-165180 (Reactome)
TSC1:TSC2	Complex	R-HSA-165175 (Reactome)
TSC2	Protein	P49815 (Uniprot-TrEMBL)
TSC2	Protein	P49815 (Uniprot-TrEMBL)
YWHAB	Protein	P31946 (Uniprot-TrEMBL)
YWHAB	Protein	P31946 (Uniprot-TrEMBL)
eIF4E:4E-BP1-P	Complex	R-HSA-165697 (Reactome)
eIF4E:4E-BP	Complex	R-HSA-72581 (Reactome)
mTORC1 with p-S722,S792-RPTOR:Ragulator:Rag:GNP:RHEB:GTP	Complex	R-HSA-5693284 (Reactome)
mTORC1:RHEB:GTP:AKT1S1	Complex	R-HSA-5672831 (Reactome)
mTORC1:RHEB:GTP:p-S183,T246-AKT1S1:YWHAB	Complex	R-HSA-5672866 (Reactome)
mTORC1:RHEB:GTP:p-T246-AKT1S1	Complex	R-HSA-377420 (Reactome)
mTORC1:Ragulator:Rag:GNP	Complex	R-HSA-5653972 (Reactome)
mTORC1:p-T246-AKT1S1:YWHAB	Complex	R-HSA-5672861 (Reactome)
mTORC1	Complex	R-HSA-377400 (Reactome)
p-5S-RPS6	Protein	P62753 (Uniprot-TrEMBL)
p-S1108,S1148,S1192-EIF4G1	Protein	Q04637 (Uniprot-TrEMBL)
p-S183,T246-AKT1S1	Protein	Q96B36 (Uniprot-TrEMBL)
p-S366-EEF2K	Protein	O00418 (Uniprot-TrEMBL)
p-S371,T389-RPS6KB1	Protein	P23443 (Uniprot-TrEMBL)
p-S422-EIF4B	Protein	P23588 (Uniprot-TrEMBL)
p-S722,S792-RPTOR	Protein	Q8N122 (Uniprot-TrEMBL)
p-S939,S1130,T1462-TSC2	Protein	P49815 (Uniprot-TrEMBL)
p-S939,S1130,T1462-TSC2	Protein	P49815 (Uniprot-TrEMBL)
p-T246-AKT1S1	Protein	Q96B36 (Uniprot-TrEMBL)
p-T308,S473-AKT1	Protein	P31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2	Protein	P31751 (Uniprot-TrEMBL)
p-T309,S474-AKT2:PIP3	Complex	R-HSA-162387 (Reactome)
p-T37,T46-EIF4EBP1	Protein	Q13541 (Uniprot-TrEMBL)
p-T37,T46-EIF4EBP1	Protein	Q13541 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	ADP	Arrow	R-HSA-165162 (Reactome)
	ADP	Arrow	R-HSA-165182 (Reactome)
	ADP	Arrow	R-HSA-165692 (Reactome)
	ADP	Arrow	R-HSA-165718 (Reactome)
	ADP	Arrow	R-HSA-165726 (Reactome)
	ADP	Arrow	R-HSA-165758 (Reactome)
	ADP	Arrow	R-HSA-165766 (Reactome)
	ADP	Arrow	R-HSA-165777 (Reactome)
	ADP	Arrow	R-HSA-377186 (Reactome)
	ADP	Arrow	R-HSA-5672828 (Reactome)
AKT1S1			R-HSA-5672843 (Reactome)
ATP			R-HSA-165162 (Reactome)
ATP			R-HSA-165182 (Reactome)
ATP			R-HSA-165692 (Reactome)
ATP			R-HSA-165718 (Reactome)
ATP			R-HSA-165726 (Reactome)
ATP			R-HSA-165758 (Reactome)
ATP			R-HSA-165766 (Reactome)
ATP			R-HSA-165777 (Reactome)
ATP			R-HSA-377186 (Reactome)
ATP			R-HSA-5672828 (Reactome)
	Active mTORC1 complex	Arrow	R-HSA-165680 (Reactome)
Active mTORC1 complex			R-HSA-5672843 (Reactome)
Active mTORC1 complex		mim-catalysis	R-HSA-165692 (Reactome)
Active mTORC1 complex		mim-catalysis	R-HSA-165718 (Reactome)
EEF2K			R-HSA-165758 (Reactome)
EIF4B			R-HSA-165777 (Reactome)
	EIF4E	Arrow	R-HSA-165708 (Reactome)
EIF4G1			R-HSA-165766 (Reactome)
	GDP	Arrow	R-HSA-165195 (Reactome)
GTP			R-HSA-165195 (Reactome)
LAMTOR1			R-HSA-5653936 (Reactome)
LAMTOR2			R-HSA-5653936 (Reactome)
LAMTOR3			R-HSA-5653936 (Reactome)
LAMTOR4			R-HSA-5653936 (Reactome)
LAMTOR5			R-HSA-5653936 (Reactome)
			R-HSA-165162 (Reactome)	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).
			R-HSA-165182 (Reactome)	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).
			R-HSA-165195 (Reactome)	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.
			R-HSA-165680 (Reactome)	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).
			R-HSA-165692 (Reactome)	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).
			R-HSA-165708 (Reactome)	Phosphorylated EIF4BP1 dissociates from EIF4E.
			R-HSA-165718 (Reactome)	RPS6KB1 (S6K1) contains a TOS motif. mTORC1 requires an intact TOS motif to bind and phosphorylate S6K1 (Ali & Sabatini 2005).
			R-HSA-165726 (Reactome)	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).
			R-HSA-165758 (Reactome)	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.
			R-HSA-165766 (Reactome)	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.
			R-HSA-165777 (Reactome)	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.
			R-HSA-377186 (Reactome)	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.
			R-HSA-5653936 (Reactome)	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).
			R-HSA-5653957 (Reactome)	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).
			R-HSA-5653968 (Reactome)	The Ragulator complex on the lysosomal surface binds Rag heterodimers which in turn bind mTORC1 (Sancak et al. 2010).
			R-HSA-5653974 (Reactome)	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).
			R-HSA-5672824 (Reactome)	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).
			R-HSA-5672828 (Reactome)	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).
			R-HSA-5672843 (Reactome)	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).
RHEB:GDP			R-HSA-165195 (Reactome)
	RHEB:GTP	Arrow	R-HSA-165195 (Reactome)
RHEB:GTP			R-HSA-165680 (Reactome)
RPS6KB1			R-HSA-165718 (Reactome)
RPS6			R-HSA-165726 (Reactome)
RRAGA, RRAGB			R-HSA-5653957 (Reactome)
RRAGC,RRAGD			R-HSA-5653957 (Reactome)
	Rag:GNP heterodimers	Arrow	R-HSA-5653957 (Reactome)
Rag:GNP heterodimers			R-HSA-5653974 (Reactome)
	Ragulator:Rag:GNP heterodimers	Arrow	R-HSA-5653974 (Reactome)
Ragulator:Rag:GNP heterodimers			R-HSA-5653968 (Reactome)
	Ragulator	Arrow	R-HSA-5653936 (Reactome)
Ragulator			R-HSA-5653974 (Reactome)
	TSC1:Inhibited TSC2-1-P	Arrow	R-HSA-165182 (Reactome)
TSC1:TSC2			R-HSA-165182 (Reactome)
TSC2			R-HSA-165162 (Reactome)
YWHAB			R-HSA-5672824 (Reactome)
	eIF4E:4E-BP1-P	Arrow	R-HSA-165692 (Reactome)
eIF4E:4E-BP1-P			R-HSA-165708 (Reactome)
eIF4E:4E-BP			R-HSA-165692 (Reactome)
mTORC1 with p-S722,S792-RPTOR:Ragulator:Rag:GNP:RHEB:GTP		TBar	R-HSA-165718 (Reactome)
	mTORC1:RHEB:GTP:AKT1S1	Arrow	R-HSA-5672843 (Reactome)
mTORC1:RHEB:GTP:AKT1S1			R-HSA-377186 (Reactome)
mTORC1:RHEB:GTP:AKT1S1		TBar	R-HSA-165692 (Reactome)
	mTORC1:RHEB:GTP:p-S183,T246-AKT1S1:YWHAB	Arrow	R-HSA-5672828 (Reactome)
	mTORC1:RHEB:GTP:p-T246-AKT1S1	Arrow	R-HSA-377186 (Reactome)
mTORC1:RHEB:GTP:p-T246-AKT1S1			R-HSA-5672824 (Reactome)
	mTORC1:Ragulator:Rag:GNP	Arrow	R-HSA-5653968 (Reactome)
mTORC1:Ragulator:Rag:GNP			R-HSA-165680 (Reactome)
mTORC1:p-T246-AKT1S1:YWHAB		Arrow	R-HSA-165692 (Reactome)
mTORC1:p-T246-AKT1S1:YWHAB		Arrow	R-HSA-165718 (Reactome)
	mTORC1:p-T246-AKT1S1:YWHAB	Arrow	R-HSA-5672824 (Reactome)
mTORC1:p-T246-AKT1S1:YWHAB			R-HSA-5672828 (Reactome)
mTORC1:p-T246-AKT1S1:YWHAB		mim-catalysis	R-HSA-5672828 (Reactome)
mTORC1			R-HSA-5653968 (Reactome)
	p-5S-RPS6	Arrow	R-HSA-165726 (Reactome)
	p-S1108,S1148,S1192-EIF4G1	Arrow	R-HSA-165766 (Reactome)
	p-S366-EEF2K	Arrow	R-HSA-165758 (Reactome)
	p-S371,T389-RPS6KB1	Arrow	R-HSA-165718 (Reactome)
p-S371,T389-RPS6KB1		mim-catalysis	R-HSA-165726 (Reactome)
p-S371,T389-RPS6KB1		mim-catalysis	R-HSA-165758 (Reactome)
p-S371,T389-RPS6KB1		mim-catalysis	R-HSA-165766 (Reactome)
p-S371,T389-RPS6KB1		mim-catalysis	R-HSA-165777 (Reactome)
	p-S422-EIF4B	Arrow	R-HSA-165777 (Reactome)
	p-S939,S1130,T1462-TSC2	Arrow	R-HSA-165162 (Reactome)
p-T308,S473-AKT1		mim-catalysis	R-HSA-377186 (Reactome)
p-T309,S474-AKT2:PIP3		mim-catalysis	R-HSA-165162 (Reactome)
p-T309,S474-AKT2:PIP3		mim-catalysis	R-HSA-165182 (Reactome)
	p-T37,T46-EIF4EBP1	Arrow	R-HSA-165708 (Reactome)