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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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).
The sodium-coupled neutral amino acid transporter 9 (SLC38A9 aka URLC11) is a lysosomal membrane protein mediating the transport of amino acids. It is proposed SLC38A9 acts as an amino acid sensor of the Ragulator and Rag GTPases complexes which are involved in the activation of mTORC1. The serine/threonine kinase mTORC1 regulates cellular homeostasis in response to many stimuli, such as nutrient status (for example via the transport of amino acids by SLC38A9) and energy level. SLC38A9 has been established to be an integral part of the Ragulator:Rag GTPase complex (Rebsamen et al. 2015, Wang et al. 2015, Jung et al. 2015).
The sodium-coupled neutral amino acid transporter 9 (SLC38A9 aka URLC11) is a lysosomal membrane protein mediating the transport of amino acids, especially L-arginine (Wang et al. 2015). It is proposed SLC38A9 acts as an amino acid sensor of the Ragulator and Rag GTPases complexes which are involved in the activation of mTORC1. The serine/threonine kinase mTORC1 regulates cellular homeostasis in response to many stimuli, such as nutrient status (for example via the transport of amino acids by SLC38A9) and energy level. SLC38A9 has been established to be an integral part of the Ragulator:Rag GTPase complex (Rebsamen et al. 2015, Wang et al. 2015, Jung et al. 2015).
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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