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mTOR at A Glance PDF
mTOR at A Glance PDF
mTOR signaling at a proliferation and survival. Discoveries that have mTOR structure and organization
been made over the last decade show that the into multi-protein complexes
glance mTOR pathway is activated during various The mTOR protein is a 289-kDa serine-
cellular processes (e.g. tumor formation and threonine kinase that belongs to the phospho-
Mathieu Laplante1,2 and David M.
angiogenesis, insulin resistance, adipogenesis inositide 3-kinase (PI3K)-related kinase family
Sabatini1,2,3,*
and T-lymphocyte activation) and is deregulated and is conserved throughout evolution. The
1
Whitehead Institute for Biomedical Research, Nine in human diseases such as cancer and type 2 poster depicts an overview of mTOR structural
Cambridge Center, Cambridge, MA 02142, USA
2
Howard Hughes Medical Institute, Department of diabetes. These observations have attracted domains. mTOR nucleates at least two distinct
Biology, Massachusetts Institute of Technology, broad scientific and clinical interest in mTOR. multi-protein complexes, mTOR complex 1
Cambridge, MA 02139, USA
3
Koch Center for Integrative Cancer Research at MIT,
This is highlighted by the growing use of (mTORC1) and mTOR complex 2 (mTORC2)
77 Massachusetts Avenue, Cambridge, MA 02139, mTOR inhibitors [rapamycin and its (reviewed by Guertin and Sabatini, 2007).
USA analogues (rapalogues)] in pathological settings,
*Author for correspondence ([email protected]) including the treatment of solid tumors, organ mTORC1
Journal of Cell Science 122, 3589-3594 transplantation, coronary restenosis and mTORC1 has five components: mTOR, which
Published by The Company of Biologists 2009 rheumatoid arthritis. Here, we highlight is the catalytic subunit of the complex;
doi:10.1242/jcs.051011
and summarize the current understanding of regulatory-associated protein of mTOR
how mTOR nucleates distinct multi-protein (Raptor); mammalian lethal with Sec13
The mammalian target of rapamycin (mTOR) complexes, how intra- and extracellular signals protein 8 (mLST8, also known as GbL); proline-
signaling pathway integrates both intracellular are processed by the mTOR complexes, and rich AKT substrate 40 kDa (PRAS40); and
and extracellular signals and serves as a how such signals affect cell metabolism, DEP-domain-containing mTOR-interacting
central regulator of cell metabolism, growth, growth, proliferation and survival. protein (Deptor) (Peterson et al., 2009). The
Journal of Cell Science
exact function of most of the mTOR-interacting processes such as autophagy. Much of the organelles and protein complexes through
proteins in mTORC1 still remains elusive. It has knowledge about mTORC1 function comes autophagy provides biological material to
been proposed that Raptor might affect from the use of the bacterial macrolide sustain anabolic processes such as protein
mTORC1 activity by regulating assembly of the rapamycin. Upon entering the cell, rapamycin synthesis and energy production. Studies have
complex and by recruiting substrates for mTOR binds to FK506-binding protein of 12 kDa shown that mTORC1 inhibition increases
(Hara et al., 2002; Kim et al., 2002). The role of (FKBP12) and interacts with the FKBP12- autophagy, whereas stimulation of mTORC1
mLST8 in mTORC1 function is also unclear, as rapamycin binding domain (FRB) of mTOR, reduces this process (reviewed by Codogno and
deletion of this protein does not affect mTORC1 thus inhibiting mTORC1 functions (reviewed Meier, 2005). We have observed that mTORC1
activity in vivo (Guertin et al., 2006). PRAS40 by Guertin and Sabatini, 2007). In contrast to its controls autophagy through an unknown
and Deptor have been characterized as effect on mTORC1, FKBP12-rapamycin cannot mechanism that is essentially insensitive to
distinct negative regulators of mTORC1 physically interact with or acutely inhibit inhibition by rapamycin (Thoreen et al., 2009).
(Peterson et al., 2009; Sancak et al., 2007; mTORC2 (Jacinto et al., 2004; Sarbassov et al., It was recently shown by three independent
Vander Haar et al., 2007). When the activity of 2004). On the basis of these observations, groups that mTORC1 controls autophagy
mTORC1 is reduced, PRAS40 and Deptor are mTORC1 and mTORC2 have been respectively through the regulation of a protein complex
recruited to the complex, where they promote characterized as the rapamycin-sensitive and composed of unc-51-like kinase 1 (ULK1),
the inhibition of mTORC1. It was proposed that rapamycin-insensitive complexes. However, autophagy-related gene 13 (ATG13) and focal
PRAS40 regulates mTORC1 kinase activity by this paradigm might not be entirely accurate, as adhesion kinase family-interacting protein of
functioning as a direct inhibitor of substrate chronic rapamycin treatment can, in some cases, 200 kDa (FIP200) (Ganley et al., 2009;
binding (Wang et al., 2007). Upon activation, inhibit mTORC2 activity by blocking its Hosokawa et al., 2009; Jung et al., 2009). These
mTORC1 directly phosphorylates PRAS40 and assembly (Sarbassov et al., 2006). In addition, studies have revealed that mTORC1 represses
Deptor, which reduces their physical interaction recent reports suggest that important mTORC1 autophagy by phosphorylating and thereby
with mTORC1 and further activates mTORC1 functions are resistant to inhibition by repressing ULK1 and ATG13.
signaling (Peterson et al., 2009; Wang et al., rapamycin (Choo et al., 2008; Feldman et al.,
2007). 2009; Garcia-Martinez et al., 2009; Thoreen Lipid synthesis
Journal of Cell Science
activate mTORC1 signaling (Chen et al., 2008; of PRAS40 from mTORC1 (Sancak et al., 2007; processes when oxygen, but not growth factors,
Cunningham et al., 2007). Additionally, Vander Haar et al., 2007; Wang et al., 2007). is scarce. Additionally, promyelocytic leukemia
conditional deletion of Raptor in mouse skeletal The binding of insulin to its cell-surface (PML) tumor suppressor and BCL2/adenovirus
muscle reduces the expression of genes involved receptor promotes the tyrosine kinase activity of E1B 19 kDa protein-interacting protein 3
in mitochondrial biogenesis (Bentzinger et al., the insulin receptor, the recruitment of insulin (BNIP3) reduce mTORC1 signaling during
2008). Cunningham and colleagues have receptor substrate 1 (IRS1), the production hypoxia by disrupting the interaction between
discovered that mTORC1 controls the transcrip- of phosphatidylinositol (3,4,5)-triphosphate mTOR and its positive regulator Rheb (Bernardi
tional activity of PPARg coactivator 1 [PtdIns(3,4,5)P3] through the activation of et al., 2006; Li et al., 2007).
(PGC1-a), a nuclear cofactor that plays a key PI3K, and the recruitment and activation
role in mitochondrial biogenesis and oxidative of AKT at the plasma membrane. In many cell Amino acids
metabolism, by directly altering its physical types, activation of mTORC1 strongly represses Amino acids represent a strong signal that
interaction with another transcription factor, the PI3K-AKT axis upstream of PI3K. positively regulates mTORC1 (reviewed by
namely yin-yang 1 (YY1) (Cunningham et al., Activation of S6K1 by mTORC1 promotes the Guertin and Sabatini, 2007). It was recently
2007). phosphorylation of IRS1 and reduces its shown that leucine, an essential amino acid
stability (reviewed by Harrington et al., 2005). required for mTORC1 activation, is transported
Many roads lead to mTORC1: This auto-regulatory pathway, characterized as into cells in a glutamine-dependent fashion
overview of a complex signaling the S6K1-dependent negative feedback loop, (Nicklin et al., 2009). Glutamine, which is
network has been shown to have profound implications imported into cells through SLC1A5 [solute
mTORC1 integrates four major signals – growth for both metabolic diseases and tumorigenesis carrier family 1 (neutral amino acid transporter)
factors, energy status, oxygen and amino acids – (reviewed by Manning, 2004). Other pathways member 5], is exchanged to import leucine via a
to regulate many processes that are involved in that are independent of IRS1 are also likely to heterodimeric system composed of SLC7A5
the promotion of cell growth. One of the most contribute to the retro-inhibition of mTORC1. [antiport solute carrier family 7 (cationic amino
important sensors involved in the regulation of For example, loss of TSC1/2 suppresses acid transporter, y+ system, member 5] and
mTORC1 activity is the tuberous sclerosis platelet-derived growth factor receptor SLC3A2 [solute carrier family 3 (activators of
Journal of Cell Science
complex (TSC), which is a heterodimer that (PDGFR) expression in a rapamycin-sensitive dibasic and neutral amino acid transport)
comprises TSC1 (also known as hamartin) and manner (Zhang et al., 2007). How mTOR member 2]. The mechanism by which
TSC2 (also known as tuberin). TSC1/2 functions signaling controls PDGFR expression remains intracellular amino acids then signal to mTORC1
as a GTPase-activating protein (GAP) for the to be determined. remained obscure for many years. The activation
small Ras-related GTPase Rheb (Ras homolog of mTORC1 by amino acids is known to be
enriched in brain). The active, GTP-bound form Energy status independent of TSC1/2, because the mTORC1
of Rheb directly interacts with mTORC1 to The energy status of the cell is signaled to pathway remains sensitive to amino acid
stimulate its activity (Long et al., 2005; Sancak mTORC1 through AMP-activated protein deprivation in cells that lack TSC1 or TSC2
et al., 2007). The exact mechanism by which kinase (AMPK), a master sensor of intracellular (Nobukuni et al., 2005). Some studies have
Rheb activates mTORC1 remains to be energy status (reviewed by Hardie, 2007). In implicated human vacuolar protein-sorting-
determined. As a Rheb-specific GAP, TSC1/2 response to energy depletion (low ATP:ADP associated protein 34 (VPS34) in nutrient
negatively regulates mTORC1 signaling by ratio), AMPK is activated and phosphorylates sensing (Nobukuni et al., 2005); however, the
converting Rheb into its inactive GDP-bound TSC2, which increases the GAP activity precise role of human VPS34 in this process still
state (Inoki et al., 2003; Tee et al., 2003). of TSC2 towards Rheb and reduces mTORC1 remains to be established (Juhasz et al., 2008).
Consistent with a role of TSC1/2 in the negative activation (Inoki et al., 2003). Additionally, Recently, two independent teams, including
regulation of mTORC1, inactivating mutations AMPK can reduce mTORC1 activity in ours, have shown that the Rag proteins, a family
or loss of heterozygosity of TSC1/2 give rise to response to energy depletion by directly of four related small GTPases, interact with
tuberous sclerosis, a disease associated with the phosphorylating Raptor (Gwinn et al., 2008). mTORC1 in an amino acid-sensitive manner and
presence of numerous benign tumors that are are necessary for the activation of the mTORC1
composed of enlarged and disorganized cells Oxygen levels pathway by amino acids (Kim et al., 2008;
(reviewed by Crino et al., 2006). Oxygen levels affect mTORC1 activity through Sancak et al., 2008). In the presence of amino
multiple pathways (reviewed by Wouters and acids, Rag proteins bind to Raptor and promote
Growth factors Koritzinsky, 2008). Under conditions of mild the relocalization of mTORC1 from discrete
Growth factors stimulate mTORC1 through the hypoxia, the reduction in ATP levels activates locations throughout the cytoplasm to a
activation of the canonical insulin and Ras AMPK, which promotes TSC1/2 activation and perinuclear region that contains its activator Rheb
signaling pathways. The stimulation of these inhibits mTORC1 signaling as described in the (Sancak et al., 2008). The physical dissociation of
pathways increases the phosphorylation of TSC2 previous section (Arsham et al., 2003; Liu et al., mTORC1 and Rheb with amino acid deprivation
by protein kinase B (PKB, also known as AKT) 2006). Hypoxia can also activate TSC1/2 might explain why activators of Rheb, such as
(Inoki et al., 2002; Potter et al., 2002), by through transcriptional regulation of DNA growth factors, cannot stimulate mTORC1
extracellular-signal-regulated kinase 1/2 damage response 1 (REDD1) (Brugarolas et al., signaling in the absence of amino acids.
(ERK1/2) (Ma et al., 2005), and by p90 ribosomal 2004; Reiling and Hafen, 2004). REDD1 blocks
S6 kinase 1 (RSK1) (Roux et al., 2004), and leads mTORC1 signaling by releasing TSC2 from its Other cellular conditions and signals
to the inactivation of TSC1/2 and thus to growth-factor-induced association with 14-3-3 In addition to the key signals described above,
the activation of mTORC1. Additionally, AKT proteins (DeYoung et al., 2008). This ability of other cellular conditions and signals, such as
activation by growth factors can activate REDD1 to reduce mTORC1 signaling by genotoxic stress, inflammation, Wnt ligand and
mTORC1 in a TSC1/2-independent manner by disrupting the interaction of TSC2 and 14-3-3 PA, have all been shown to regulate mTORC1
promoting the phosphorylation and dissociation has probably evolved to limit energy-consuming signaling. Genotoxic stress reduces
3592 Journal of Cell Science 122 (20)
mTORC1 activity through many mechanisms. AKT, which positively regulates these processes stimulation, AKT is phosphorylated at the cell
For instance, the activation of p53 in response to through the phosphorylation of various effectors membrane through the binding of
DNA damage rapidly activates AMPK through (reviewed by Manning and Cantley, 2007). Full PtdIns(3,4,5)P3 to its pleckstrin homology (PH)
an unknown process, which in turn activation of AKT requires its phosphorylation domain. Under these conditions, PDK1 is also
phosphorylates and thereby activates TSC2 at two sites: Ser308, by phosphoinositide- recruited to the membrane through its PH
(Feng et al., 2005). Additionally, p53 negatively dependent kinase 1 (PDK1), and Ser473, by a domain and phosphorylates AKT at Ser308
controls mTORC1 signaling by increasing the kinase that remained unidentified for many (reviewed by Lawlor and Alessi, 2001).
transcription of phosphatase and tensin homolog years, but was demonstrated to be mTORC2 by Interestingly, the mTORC2 component mSIN1
deleted on chromosome 10 (PTEN) and TSC2, our group in 2005 (Sarbassov et al., 2005). Other possesses a PH domain at its C-terminus,
two negative regulators of the pathway (Feng studies have subsequently observed that suggesting that mSIN1 can promote the
et al., 2005; Stambolic et al., 2001). ablation of various mTORC2 components translocation of mTORC2 to the membrane and
Inflammatory mediators also signal to mTORC1 specifically blocks AKT phosphorylation at the phosphorylation of AKT at Ser473.
via the TSC1/2 complex. Pro-inflammatory Ser473 and the downstream phosphorylation of Additional work is needed to support this model
cytokines, such as TNFa, activate IkB kinase-b some, but not all, AKT substrates (Guertin et al., and to identify other cellular signals that play a
(IKKb), which physically interacts with and 2006; Jacinto et al., 2006). Inhibition of AKT role in the regulation of mTORC2.
inactivates TSC1, leading to mTORC1 following mTORC2 depletion reduces the phos-
activation (Lee et al., 2007). This positive phorylation of, and therefore activates, the Perspectives
relationship between inflammation and forkhead box protein O1 (FoxO1) and FoxO3a Over the last decade, knowledge of the mTOR
mTORC1 activation is thought to be important in transcription factors, which control the signaling pathway has greatly progressed,
tumor angiogenesis (Lee et al., 2007) and in the expression of genes involved in stress enabling researchers to better understand the
development of insulin resistance (Lee et al., resistance, metabolism, cell-cycle arrest and mechanism of diseases such as cancer and
2008). Wnt signaling also increases mTORC1 apoptosis (reviewed by Calnan and Brunet, type 2 diabetes. Despite these advances, our
activity through the inactivation of TSC1/2. 2008). By contrast, the phosphorylation state of understanding of this signaling network is far
Stimulation of the Wnt pathway inhibits TSC2 and GSK3 is not affected by mTORC2 from complete and many important questions
Journal of Cell Science
glycogen synthase kinase 3 (GSK3), a kinase inactivation. Recently, serum- and remain to be answered. For example, how is
that promotes TSC1/2 activity by directly phos- glucocorticoid-induced protein kinase 1 mTORC2 regulated and which biological
phorylating TSC2 (Inoki et al., 2006). Finally, (SGK1), which shares homology with AKT, processes does it control? How are the
PA has been identified as another activator of was also shown to be regulated by mTORC2 mTORC1 and mTORC2 signaling pathways
mTORC1. Many groups have shown that (Garcia-Martinez and Alessi, 2008). In contrast integrated with each other? What are the
exogenous PA or overexpression of PA- to AKT, which retains a basal activity when functions of these complexes in adult tissues
producing enzymes such as phospholipase D1 mTORC2 is inhibited, SGK1 activity is totally and organs and what are the implications of
(PLD1) and PLD2 significantly increases abrogated under these conditions. Because their dysfunction or dysregulation in health and
mTORC1 signaling (reviewed by Foster, 2007). SGK1 and AKT phosphorylate FoxO1 and disease? Are there additional mTOR complexes
A recent study suggests that PA affects mTOR FoxO3a on common sites, it is possible that the that regulate other biological processes?
signaling by facilitating the assembly of mTOR lack of SGK1 activity in mTORC2-deficient Finding answers to these important questions
complexes, or stabilizing the complexes (Toschi cells is responsible for the inhibition of will advance our understanding of cellular
et al., 2009). phosphorylation of FoxO1 and FoxO3a. biology, and will also help the development of
therapeutic avenues to treat many human
mTORC2 still has many secrets to Cytoskeletal organization diseases.
reveal mTORC2 regulates cytoskeletal organization. We apologize to those authors whose primary work we
In contrast to mTORC1, for which many Many independent groups have observed that did not reference directly in the text. We thank the
upstream signals and cellular functions have knocking down mTORC2 components affects Sabatini laboratory for critical reading of the
manuscript and NIH and HHMI for funding. M.L. held
been defined (see above), relatively little is actin polymerization and perturbs cell a postdoctoral fellowship from the Canadian Institutes
known about mTORC2 biology. The early morphology (Jacinto et al., 2004; Sarbassov of Health Research. Deposited in PMC for release after
lethality caused by the deletion of mTORC2 et al., 2004). These studies have suggested that 12 months.
components in mice, as well as the absence of mTORC2 controls the actin cytoskeleton by
mTORC2 inhibitors, have complicated the promoting protein kinase Ca (PKCa) phospho- References
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