S. cerevisiae encodes two TOR paralogs, Tor1 and Tor2. Biochemical purification of these
proteins demonstrated that they assemble into two distinct multiprotein complexes named TOR
complex 1 (TORC1) and TORC2 (see Glossary) [6,7]. Both complexes are widely conserved
[6,8–11] but only TOR in TORC1 is bound and inhibited by FKBP12–rapamycin. Importantly,
mammalian TORC1 (MTORC1; for clarity, mammalian factors are written in small Caps) is a
validated drug target as rapamycin was eventually approved for clinical use in both immuno-
1
suppression and oncology. Rapamycin has additionally been a valuable tool to study TORC1 Department of Molecular Biology, and
Institute of Genetics and Genomics of
signaling; and, over the years, it has become abundantly clear that both TORC1 regulators Geneva (iGE3), University of Geneva,
and effectors are robustly conserved from yeast to human [12–15]. By contrast, in the absence 30 quai Ernest Ansermet, CH1211
of a specific inhibitor, the utility of MTORC2 inhibition as a therapeutic option remains unclear and Geneva, Switzerland
2
National Centre of Competence in
the molecular characterization of TORC2 signaling has comparatively lagged. Research “Chemical Biology”,
University of Geneva, Geneva CH-
However, new tools are starting to become available to study TORC2. For example, ATP- 1211, Switzerland
competitive MTOR inhibitors that inhibit MTORC2 (and MTORC1) have been described [3] and
reverse chemical genetic approaches enable the specific inhibition of TORC2 in yeast *Correspondence:
[16–18]. These chemical tools are complemented by tissue-specific MTORC2 knockout mouse Robbie.Loewith@unige.ch (R. Loewith).
532 Trends in Biochemical Sciences, June 2016, Vol. 41, No. 6 http://dx.doi.org/10.1016/j.tibs.2016.04.001
© 2016 Elsevier Ltd. All rights reserved.
lines. Furthermore, several exciting structural insights have recently been made. Building on Glossary
these advances, in this review we detail the current understanding of the functions of individual AGC kinase: a family of
TORC2 subunits. We then try to summarize the often controversial literature describing the approximately 60 related protein
localization and regulation of MTORC2. Lastly, we close with a discussion of what these studies kinases named after protein kinase A,
protein kinase G, and protein kinase
suggest regarding MTORC2 inhibition as a clinical strategy. C. A common prerequisite for AGC
kinase activation are phosphorylation
Common Architecture of the Two TOR Complexes events mediated by PDK, in the
TORC1 and TORC2 are similarly large, weighing in at 1.2 and 1.4 MDa, respectively. TORC1/ activation loop of the kinase domain,
and TOR, in C-terminal motifs.
mTORC1 contains TOR/MTOR, Lst8/MLST8, Kog1/RAPTOR, Tco89 (which is yeast-specific), and ATM: ataxia telangiectasia mutated
DEPTOR (which is vertebrate-specific). TORC2/MTORC2 contains TOR/MTOR, Lst8/MLST8, Avo3/ plays important roles in DNA repair
RICTOR, Avo1/hSIN1, Bit61 and Bit2/PROTOR-1 and PROTOR-2, Avo2 (which is yeast-specific), and and is recruited to double-strand
breaks (DSBs) via the MRE11–RAD50–
DEPTOR (which again is vertebrate-specific) (Figure 1A). A search of subunit paralogs in published
NBS1 (MRN) complex. Loss of kinase
genomes suggests that TOR complexes are broadly conserved in eukaryotes with notable activity results in ataxia telangiectasia
absences in some parasites, including Microsporidia and Plasmodia [12], and, curiously, a lack (A-T), an autosomal recessive
of TORC2 in Planta [19] (Figure 1A). disorder.
ATR: ataxia telangiectasia and RAD3-
related protein serves essential
In recent years there have been five major structural insights into TOR complex structure and functions in maintaining genomic
function: a low-resolution cryo-electron microscopy (cryo-EM) reconstruction of MTORC1 integrity and binds to replication
[20]; a high-resolution cryo-EM reconstruction of MTORC1 including a docked crystal structure of protein A (RPA) at sites of DNA
damage via interaction with ATRIP.
the RAPTOR subunit [21]; a low-resolution negative-stain EM reconstruction of yeast TORC2 [16]
cryo-EM (cryo-electron
(Figure 2A); an atomic resolution crystal structure of the kinase domain of MTOR in complex with microscopy): is a structural biology
MLST8 [22] (Figure 1B); and, most recently, a high-resolution cryo-EM reconstruction of full-length technique used to image single
Tor–Lst8 complex from the thermotolerant yeast Kluyveromyces marxianus [23]. A comparison particle specimens without the need
for crystals. Owing to recent
of the EM reconstructions demonstrates that the two TOR Complexes have in common some technological advances, it is possible
interesting design features, suggesting that they share fundamental structure–function proper- to determine the structure of
ties. In both MTORC1 and TORC2 there are two copies of each subunit. These subunits are macromolecular complexes and
divided into one of two protomers, which are themselves related by C2 rotational (pseudo-) proteins at near atomic resolution.
DEP: the DEP (dishevelled, egl-10,
symmetry. Together the two protomers give an overall parallelepiped (3D rhomboid) structure to pleckstrin) domain folds into a
each complex and delineate a relatively large central cavity that could potentially accommodate a globular structure of approximately
globular protein up to 60 kDa in size [16]. The function of this cavity is unknown but it has been 80 amino acid residues, which is
found in proteins that regulate G
proposed to provide an interaction surface for upstream regulators [16]. Both TOR complexes
protein signaling.
are known to interact with membranes and it is likely one of the broad faces of the parallelepiped DNA–PKcs: this DNA-dependent
that is membrane proximal [16]. protein kinase catalytic subunit forms
the DNA–PK holoenzyme with the
Ku70/80 heterodimer to mediate
Several of the TORC2 subunits can be localized within the TORC2 EM reconstruction, which
non-homologous end joining, the
helps to define their otherwise enigmatic functions (Figure 2). Furthermore, the arrangements of main pathway used in mammals to
the MTOR and MLST8 subunits, which are shared between the two complexes, were well defined in repair double-strand DNA breaks.
the high-resolution cryo-EM MTORC1 reconstruction [21] and the high-resolution cryo-EM DNA–PKcs is the largest of all PIKKs.
Eisosome: plasma membrane
KmTor–Lst8 reconstruction [23]. Using this same orientation, these two subunits can be
invaginations that may serve as
tentatively placed within the low-resolution TORC2 reconstruction (Figure 2B [21]). This place- plasma membrane reservoirs in yeast
ment questions the accuracy of the previous positioning of the Avo1 subunit but supports the and appear to act analogously to
notion that, as with MTORC1 [21], access to the deeply recessed active sites of TORC2 is gained caveolae in mammalian cells.
FAT: FRAP–ATM–TRRAP is a 600-residue
from the external periphery [16]. domain made up of /-helical bundles
located adjacent to the N terminus of
Structure–Function of TORC2 Subunits the kinase domain in PIKKs.
TOR/MTOR and Lst8/MLST8 FRB: the FKBP12–rapamycin binding
domain folds into a bundle of four
TOR and its binding partner Lst8 form the core of both TORC1 and TORC2. TOR is the founding /-helices within the kinase domain,
member of the phosphatidylinositol 3-kinase (PI3K)-related kinases (PIKK) family [24]. Included in thereby extending the N-lobe side of
this family are the mammalian PIKKs: DNA–PKcs, ATM,ATR,SMG1, and (the catalytically inactive) the kinase cleft.
TRRAP. Like TOR, all of these proteins are similarly large and possess common domain structures HEAT: HUNTINGTON, EF3A, PP2A, TOR is
a repeat motif consisting of /-helices
including a serine–threonine kinase domain that shares a curious resemblance to the catalytic that fold into flexible super helical
domains of PI3Ks (Figure 1B). Lst8 is composed entirely of WD40 repeats, which fold into a
TRRAP) domain (Figure 1B). In the high-resolution MTORC1 reconstruction [21], the two HEAT paralog PRR5L.
PH: pleckstrin homology domains are
repeats form /-solenoid superstructures named the ‘horn’ and ‘bridge’, whereas the TPRs of approximately 100 amino acid
the FAT domain form a compact structure that cradles the kinase domain [21,22]. The ‘horn’ and residues in length and serve as
‘bridge’ pack against one another but also form part of the solvent-exposed surface of MTORC1. membrane targeting modules; they
The ‘horn’ additionally interacts with an adjacent FAT domain to form an interlocking structure bind to a diverse set of lipids
including phosphatidylinositol
sufficient to mediate the observed dimerization of two protomers in MTORC1 [21]. Given the phosphates.
structural similarities between MTORC1 and TORC2, it is reasonable to suspect that the HEAT and PIKK: phosphatidylinositol-3 kinase-
TPR repeats of TOR also mediate dimerization of TORC2. Such a structural role does not related kinases form a family of
serine–threonine kinases, which
preclude additional functions for these repeats in the recruitment of regulators, for example, nor
comprises six members in mammals:
does it preclude scaffolding roles for other subunits in the complex. SMG1, ATM, ATR, DNA–PKc, MTOR, and
TRRAP. The concerted activity of all
BITs/PRRs
The last remaining conserved TORC2 subunit is known as Bit61 in yeast [7] and PRR5 (PROTOR-1)
in mammals [42,43]. Each has a paralog–Bit2 and PRR5L (PROTOR-2)–that also associates with
TORC2/MTORC2. The BITs are not essential and the specific functions of neither the BITs nor the
PRRs are known. They bind TORC2 peripherally via Avo3/RICTOR and Avo1/SIN1 but are not
themselves required for complex assembly [16,26,44]. They possess a conserved domain
shared with the Aspergillus nidulans protein HbrB (Figure 1E) [45,46]. HbrB plays a role in
filamentous growth in A. nidulans but how this relates to BIT/PRR function in TORC2/MTORC2 is
unclear.
Avo2
Avo2 is a nonessential, yeast-specific TORC2 subunit. It has a peripheral localization within
TORC2 [16] and is predicted to contain ankyrin repeats (Figure 1F) [46]. Together with the BITs
[47], it may bind to the TORC2 regulators Slm1 and Slm2, which are described in the next
section. Otherwise, the molecular function of Avo2 within TORC2 is unknown.
DEPTOR
DEPTOR is a vertebrate-specific subunit of both MTORC2 and MTORC1 [48]. It possesses two tandem
DEP (dishevelled, egl-10, pleckstrin) motifs at its N terminus in addition to a PDZ (postsynaptic
density 95, discs large, zonula occludens-1) domain (Figure 1G). DEP domains provide spatial
control to diverse signaling pathways by recruiting signaling modules to cellular membranes [49].
PDZ domains are often implicated in protein binding and DEPTOR seems to bind MTOR via its PDZ
domain. DEPTOR interferes with the signaling output of the two MTOR complexes through unknown
mechanisms [48].
Regulation of TORC2
TORC2 Localizes to the Plasma Membrane and Is Regulated by Membrane Tension
TORC2 localizes to puncta at the plasma membrane that are named membrane compartments
containing TORC2 (MCTs) [50]. MCTs are adjacent to, but never overlapping with, distinct
membrane nanodomains known as eisosomes. Eisosomes contain dozens of different pro-
teins, the major ones being the Bin/Amphiphysin/Rvs (BAR) domain containing proteins Lsp1
and Pil1 [51]. Lsp1 and Pil1 contour eisosomes, and the underlying plasma membrane, into
canoe-shaped structures that invaginate into the cytoplasm. This puckering of the membrane
could potentially serve to sense membrane tension [52].
Eisosomes regulate TORC2 signaling via the Slm1 and Slm2 paralogs [50] (Figure 3A). In
rapidly growing cells, the Slm1/2 proteins are partitioned approximately equally between
eisosomes and MCTs. However, upon an increase in plasma membrane tension, triggered
by inhibition of endogenous lipid biosynthesis, hypotonic shock or direct mechanical
FRB KD
Red algae conservaon
100%
Ciliates
Trypanosomes 200 aa
100%
Sequence
conservaon
0
FATC
0
Sequence
conservaon
100%
(C) 100%
(D) 100%
Sequence
Sequence
conservaon
0
conservaon 0
0 0
Sequence Sequence
conservaon conservaon
100% 100%
100%
Sequence
(E) conservaon (F) (G) 100%
0 Sequence
conservaon
0
Protor-1 HbrB 370 aa
Avo2 ANK 426 aa Deptor DEP DEP PDZ 409 aa
100%
Sequence
Bit2 HbrB 543 aa conservaon
0
0
Sequence
conservaon
100%
Figure 1. Conservation of TORC2 Subunits. (A) Conservation of TORC2 subunits across the eukaryotic kingdom. Names of mammalian and budding yeast proteins
are included in the table. TOR and Lst8 form the core of both TORC1 and TORC2 and are conserved in all eukaryotes with the exception of a few intracellular parasites
[12]. PROTOR-1/2 paralogs are present in most vertebrates but their yeast orthologs Bit2/61 are conserved in only a minority of fungi. (B–G) Sequence conservation
diagrams of yeast and mammalian TORC2 subunits. The plots indicate the percentage conservation across orthologs found in representative eukaryote species. The
protein sequence alignment was generated with Clustal using default parameters. Insertions/deletions between the cartooned yeast and the mammalian orthologs are
shown by light gray sectors delimited by broken lines. (B) Structure and conservation of Tor2/MTOR and Lst8/MLST8. Illustrated are the HEAT (HUNTINGTON, EF3A, PP2A, TOR),
FAT (FRAP–ATM–TRRAP), FRB (FKBP12–rapamycin binding), Kinase, and FATC (found in the C terminus of FAT-containing proteins) domains of TOR and the WD40 repeats
of Lst8. Also shown is the atomic resolution structure [22] of the C-terminal portion of MTOR in complex with MLST8 via the small LBE (Lst8 binding element). Note how
access to the active site (where ATP is bound) is restricted by MLST8 and the FRB domain. (C) The amino- and carboxy-terminal tails of Avo3/RICTOR are poorly conserved,
do not display any known domain, and show many species-specific sequence insertions/deletions. These variable tails frame a conserved central domain consisting of an
ARM (Armadillo-like) and RAS–GEFN domains. (D) The overall sequence of Avo1/SIN1 is variable in size, poorly conserved, and displays many insertions/deletions
(Figure legend continued on the bottom of the next page.)
Acve site
10 nm
26Å cryo-EM reconstrucon, 2010 5.9Å cryo-EM reconstrucon, 2016 Atomic model of mTOR and mLst8
(B) TORC2
mLst8
FAT Acve site
Bit61/2 FRB
90°
Avo2 HEAT
KD
Avo1 PH FATC
26Å negave stain EM reconstrucon, 2015 Atomic model of mTOR and mLst8 placed into TORC2 reconstrucon
Figure 2. Comparison of TORC2 and MTORC1 Electron Microscopy (EM) Reconstructions. (A) From left to right, EM maps, generated in Chimera, showing a
low resolution (26 Å) reconstruction of mTORC1 [20] (EMD ID: 5197), a high resolution (5.9 Å) reconstruction of mTORC1 [21] (EMD ID: 3213) and the corresponding
atomic model (PDB ID: 5FLC) placed within this reconstruction. (B) Left: Low resolution (26 Å) reconstruction of TORC2 [16] (EMD ID: 2990). The PH domain of Avo1
(which tethers TORC2 to the plasma membrane), Avo2 and Bit61/2 are indicated. Center and right: Atomic model of MTOR and MLST8 (PDB ID: 5FLC) was placed within the
TORC2 reconstruction using Chimera. The domains within MTOR are colour-coded: HEAT repeats are in gray, FAT in green, kinase domain in orange, FRB in yellow and
FATC in red. In this placement, MLST8, represented in purple, sits in the ‘thumb’ of TORC2 presumably just below the PH domain of Avo1. This simple placement does not
account for spatial constraints that TORC2-specific subunits will undoubtedly evoke.
manipulation, Slm1/2 exit eisosomes and accumulate in MCTs. In MCTs, Slm1/2 activate
TORC2 signaling output, potentially by corecruitment of the major TORC2 substrate Ypk1
[50,53].
Regulation of MTORC2
As several potential mechanisms have been proposed in the literature (Figure 3B), the regulation
of MTORC2 is currently debated. There is some evidence to support the notion that MTORC2,
similarly to TORC2 in yeast, is regulated by membrane tension. Specifically, stretching mam-
malian cells triggers MTORC2-dependent phosphorylation of AKT [54–57]. Intriguingly, this signal-
ing requires CAVEOLIN, the defining protein of caveolae, which are vertebrate-specific membrane
invaginations thought to function as membrane reservoirs and may function analogously to
eisosomes in yeast. Furthermore, as in yeast, hyperosmotic stress, which decreases membrane
tension, inhibits MTORC2 activity [58,59].
between orthologs. The CRIM (conserved region in the middle), RB (Ras binding), and PH (pleckstrin homology) domains are indicated. (E) Bit2/61–Protor1/2 contains a
conserved HbrB (hyperbranching) domain of unknown function. (F) Avo2 is a small subunit, found only in fungi, containing a domain composed of ANK (Ankyrin) repeats.
(G) DEPTOR displays two DEP (dishevelled, egl-10, pleckstrin) domains and associates with MTOR, in both MTORC1 and MTORC2, through its very well-conserved PDZ
(postsynaptic density protein, Drosophila disc large tumor suppressor, and zonula occludens-1 protein) domain.
Ypk1/2
P P Ypk1/2
P P hypotonic shock
mechanical stress
YPK Pkc1 impaired lipid biosynthesis
methylglyoxal
turgor pressure
plasma membrane tension
acn polarizaon
cell wall integrity pathway
G2/M cell cycle transion
genome integrity
pentose phosphate pathway
(B) Rac1
Ribosome
Rit1
A
A acetyl coenzyme A
A
A A
PtdIns(3,4,5)P3 SIN1 RICTOR
mTOR
PROTOR
DEPTOR mLST8
Ypk1/2
Ypk1/2
P P
hyperosmoc XPLN AGC
stress kinase
methylglyoxal
Figure 3. Upstream Regulators and Downstream Effectors of Yeast (A) and Mammalian TORC2 (B). (A)
Membrane tension, which triggers the translocation of the Slm1/2 proteins into MCT (membrane compartments containing
TORC2) is the best described regulator of TORC2 in yeast. Ypk1, and to a lesser extent Ypk2 and Pkc1, are the best
described substrates of TORC2 in yeast. (B) Many upstream regulators of MTORC2 have been proposed. The best described
substrates of MTORC2 are the AGC kinases AKT/PKB, SGK, and various PKC isoforms. See text for details and abbreviations.
Localization to the plasma membrane would support a role for MTORC2 downstream of mem-
brane tension; however, here too the literature is unclear because MTORC2 is reportedly localized
to the plasma membrane, but also mitochondria, the endoplasmic reticulum (ER), mitochondria–
ER junctions, the lysosome, and other locales [60,61]. Why the localization of MTORC2 is so
Consistent with the latter proposition, MTORC2 is reportedly activated upon binding to PtdIns
(3,4,5)P3 produced at the plasma membrane downstream of growth factor signaling [62,63].
This recruitment is mediated by the PH domain in SIN1. Moreover, in this report it was suggested
that, in the absence of lipids, the PH domain of SIN1 binds to the kinase domain of MTOR and
inhibits its activity. Binding of PtdIns(3,4,5)P3 was thus proposed to not only recruit MTORC2 to the
plasma membrane where it would meet its substrates but to also reorient the PH domain of SIN1
such that substrates could gain access to the kinase pocket.
a
Numbering refers to human sequences.
Methylglyoxal is another potential link between metabolic status and MTORC2 activity. A reactive
intermediate produced during glycolysis, methylglyoxal was recently reported to activate TORC2
in budding yeast as well as MTORC2 [69].
In addition to GTPases, other MTORC2 protein binding partners have been described as regu-
lators of MTORC2 activity. These include XPLN, a guanine nucleotide exchange factor (GEF) for Rho
GTPases that antagonizes MTORC2 signaling [75], and the ribosome, which activates MTORC2
signaling downstream of growth factor signaling [76,77]. The mechanisms by which these
MTORC2 partners influence MTORC2 signaling output are not known.
TORC2 Effectors
The best characterized substrates of yeast and mammalian TORC2 are the AGC family kinases,
which are activated downstream of TORC2 by phosphorylation on the so-called turn and
hydrophobic motifs found in their C termini [78].
The first obstacle in the interrogation of MTORC2 effector pathways lies in the curious fact that, in
mammalian cells, phosphorylation of the turn and hydrophobic motifs by MTORC2 seems to be
required only for maximal activity and thus influences only substrate specificity of the down-
stream AGC kinase (reviewed in [39,87]). This means that known AGC kinase substrates are
not necessarily MTORC2 distal effectors even if the AGC kinase in question is a substrate of
MTORC2. Neglecting this fact has greatly confused the study of MTORC2 effectors. For example, in
mouse embryonic fibroblasts, loss of MTORC2-mediated phosphorylation on Ser473 in the
hydrophobic motif of AKT diminishes AKT-mediated phosphorylation of the FOXO1/3A (forkhead
box O1/3a) transcription factor but not TSC2 (a GTPase activating protein that acts on the
MTORC1-activating GTPase RHEB) nor GSK3-b (glycogen synthase kinase). Thus, it is inappropri-
ate to cartoon MTORC2 ! AKT ! TSC2 ! RHEB as a mechanism of MTORC1 regulation as is often
done in MTOR reviews.
The second obstacle in the interrogation of MTORC2 effector pathways is the absence of small
molecules that specifically and acutely inhibit this complex. This problem has recently been
surmounted in yeast using reverse chemical genetics (reviewed in [81]), but analogous systems
have yet to be developed in mammalian systems. Although ATP competitive MTOR inhibitors are
available [3], these compounds inhibit both MTOR complexes which makes it difficult to assign
functions to one complex over the other.
Because of these challenges, MTORC2 functions have most commonly been ascertained through
genetic studies, typically involving deletion of the gene encoding the essential RICTOR subunit.
However, unlike acute inhibition attainable through pharmacological approaches, genetic stud-
ies, due to their chronic nature, often permit adaptive events to occur, which can confound
results. A potential example of this can be seen in two studies where RICTOR was deleted in
muscle. In one study [88], RICTOR-deficient muscle exhibited decreased insulin-stimulated glu-
cose uptake, decreased AKT Ser473 phosphorylation and the mice displayed glucose intolerance.
While in another study [89], RICTOR-deficient muscle was indistinguishable from wild-type con-
trols, although one should note that the ex vivo analyses of RICTOR-deficient muscle was relatively
less rigorous in this study. One possible mechanism of adaptation is the reacquisition of AKT
Ser473 phosphorylation in RICTOR-deficient cells as was observed in the latter study. Indeed,
DNA–PKcs [90] among other kinases have been proposed to phosphorylate AKT Ser
473
, the so-
called PDK2 site, independently of MTORC2. Other possible confounding factors can of course be
the choice of promoter driving the conditional knockout [91], or inherent differences in the mouse
genetic backgrounds.
Other, tissue-specific RICTOR knockouts have now been reported. Global deletion of RICTOR
causes lethality during embryonic development likely due to defects in the fetal vasculature
energy expenditure in obese people. However, fat cell-specific RICTOR ablation provoked glucose
Continuing improvements on the 3D
intolerance, hyperinsulinemia, and hepatic steatosis. Beta-cell-specific RICTOR ablation also structure of mTORC2 will hopefully facil-
provoked hyperglycemia and glucose intolerance [100]. Furthermore, RICTOR deletion in the liver itate the rational design of compounds
[101–103] was found to perturb glucose metabolism leading to hyperglycemia and hyper- that (i) prevent or disrupt mTORC2
assembly, (ii) block access of substrates
insulinemia. Interestingly, however, these mice also presented reduced serum cholesterol and to the active site, (iii) prevent the interac-
reduced hepatic steatosis. In summary, these observations suggest that MTORC2 inhibitors tion of upstream activators, or (iv) pre-
would trigger both desired as well as unwanted metabolic consequences. vent membrane association (via the PH
domain of SIN1).
predict that MTORC2 inhibitors may provoke unwanted metabolic issues. Indeed, some of the
How is mTORC2 regulated?
undesirable side effects of prolonged rapamycin treatment, including impaired sugar metabo-
lism, are attributed to inhibition of MTORC2, although these might be mitigated with optimized Presently, the regulation of mTORC2
treatment regimens [104,105]. Furthermore, RICTOR deletion in mouse heart results in cardiac is fairly controversial. Structural data to
date suggest that the kinase domain per
dysfunction [106] and RICTOR deletion in mouse liver or induced systemically in all mouse cells se is in a constitutively active conforma-
late in life specifically reduces male lifespan [107]. It will be interesting to see how well these tion. This would suggest that signaling
mouse studies will resonate with human clinical studies. Targeted drug delivery to affected output is regulated by recruitment of
organs may also help assuage eventual side effects. substrate to mTORC2, or, recruitment
of mTORC2 to substrate. Key to this
will be a definitive determination of
Although loss of MTORC2 appears to affect basal AKT activity only modestly, elegant genetic mTORC2 localization within the cell.
experiments in flies demonstrate that dTORC2 activity is absolutely required for pathologies Also important will be a molecular under-
standing of why the TOR complexes
stemming from dAkt hyperactivation [108]. The requirement for MTORC2 in pathologies driven by
are dimeric and why they possess such
hyperactive AKT has also been reported. For example, in mice, RICTOR deletion is sufficient to block a large central cavity.
aberrant fibroblast growth factor (FGF)2- or tumor-induced neovascularization, and tumor
development induced by loss of the PTEN tumor suppressor [93,94,109]. These observations
suggest that it would be interesting to evaluate MTORC2-specific inhibitors in the treatment of any
pathology associated with hyperactive AKT, which includes many cancers with PIK3CA mutations
[110]. Lastly, according to the COSMIC (Catalog of Somatic Mutations in Cancer) databasei,
RICTOR appears to be amplified in a large percentage of cancers, suggesting that MTORC2 itself
Acknowledgments
The authors thank Georgia Konstantinidou and the anonymous reviewers for their critical reading of the manuscript and
apologize to authors of relevant studies that were not cited owing to space restrictions. The Loewith lab receives funding
from the Canton of Geneva, the Swiss National Science Foundation, and the European Research Council Consolidator
Grant Programme.
Resources
i
http://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=RICTOR
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