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Expanding mTOR signaling
Expanding mTOR signaling
Qian Yang1,2, Kun-Liang Guan1,2,3
1Life Sciences Institute; 2Department of Biological Chemistry; 3Institute of Gerontology, University of Michigan, Ann Arbor, MI
Cell Research (2007) 17:666-681.
© 2007 IBCB, SIBS, CAS All rights reserved 1001-0602/07 $ 30.00
The mammalian target of rapamycin (mTOR) has drawn much attention recently because of its essential role in cell
growth control and its involvement in human tumorigenesis. Great endeavors have been made to elucidate the functions
and regulation of mTOR in the past decade. The current prevailing view is that mTOR regulates many fundamental bio-
logical processes, such as cell growth and survival, by integrating both intracellular and extracellular signals, including
growth factors, nutrients, energy levels, and cellular stress. The significance of mTOR has been highlighted most recently
by the identification of mTOR-associated proteins. Amazingly, when bound to different proteins, mTOR forms distinctive
complexes with very different physiological functions. These findings not only expand the roles that mTOR plays in cells
but also further complicate the regulation network. Thus, it is now even more critical that we precisely understand the
underlying molecular mechanisms in order to directly guide the development and usage of anti-cancer drugs targeting the
mTOR signaling pathway. In this review, we will discuss different mTOR-associated proteins, the regulation of mTOR
complexes, and the consequences of mTOR dysregulation under pathophysiological conditions.
Keywords: mTOR, rapamycin, S6K1, Akt, cancer, obesity, diabetes
Cell Research (2007) 17:666-681. doi: 10.1038/cr.2007.64; published online 7 August 2007
Easter Island is a small triangular-shaped Chilean island
located in the South Pacific Ocean. This island, known as
Rapa Nui in the native language, is world famous for its
numerous moai or large stone head statues, which are listed
as one of the New Seven Wonders of the World. However,
most of people do not realize that it is also the humble origin
of the wondrous story of TOR (target of rapamycin).
Roughly three decades ago, a bacterial strain, Streptomy-
ces hygroscopicus, was first isolated from this island. These
bacteria secrete a potent anti-fungal macrolide that was
named rapamycin after Rapa Nui, the location of its discov-
ery. Rapamycin was initially developed as an anti-fungal
agent. However, its major application quickly changed after
rapamycin was proven to have immunosuppressive and
anti-proliferative properties. To date, rapamycin (sirolimus
as the trade name) has become an FDA (Food and Drug
Administration) approved drug for immunosuppression
Correspondence: Kun-Liang Guan
Tel: +1-734-763-3030; Fax: +1-734-647-9702
for organ transplantation, prevention of restenosis post-
angioplasty, and chemotherapy for soft-tissue and bone
It soon became realized that the anti-proliferative prop-
erties of rapamycin were a very powerful tool to study
cell growth regulation. In the 1990s, yeast genetic screens
identified two rapamycin target genes, mutations of which
allowed yeast to escape the cell cycle arrest caused by
rapamycin treatment [4, 5]. These two genes were named
the target of rapamycin 1 and 2 (TOR1 and TOR2). Further
studies revealed the molecular mechanism of rapamycin
inhibition on TOR [6-8]. Upon entering the cells, rapamycin
binds a small protein receptor called FKBP12 (FK506-
binding protein 12 kDa). The rapamycin/FKBP12 complex
specifically binds to TOR and potently interferes with its
function, causing cell growth arrest. Extensive genetic stud-
ies in yeast established that TOR plays essential roles in cell
growth regulation, particularly in response to nutrients. The
identification of TOR genes in yeast led to the subsequent
discovery of TOR genes in higher eukaryotes, including
mammals. The high degree of conservation among spe-
cies strongly suggests that TOR is an essential cell growth
controller. In addition, the mechanism by which rapamycin
inhibits TOR in higher eukaryotes also appears to be con-
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Qian Yang and Kun-Liang Guan
served [9-12]. Recognition of the importance of TOR and
the availability of rapamycin led to studies in yeast, flies,
worms, and mammals to elucidate a basic understanding
of TOR biology.
The mammalian TOR, mTOR, is an atypical serine/
threonine protein kinase, belonging to the phosphatidylino-
sitol kinase-related kinase (PIKK) family, with a predicted
molecular weight of 290 kDa [13, 14]. The physiological
importance of mTOR is undoubtedly demonstrated by the
fact that the knockout of mTOR in mice is primordially
embryonic lethal [15-17]. Structurally, mTOR possesses up
to 20 tandem HEAT (a protein-protein interaction structure
of two tandem anti-parallel α-helices found in huntingtin,
elongation factor 3, PR65/A and TOR) repeats at the amino-
terminal region, followed by an FAT (FRAP, ATM, and
TRRAP, all PIKK family members) domain (Figure 1A)
. The kinase domain is between the FRB (FKBP12/ra-
pamycin binding) domain, which is C-terminal to the FAT
domain, and the FATC (FAT C-terminus) domain, located
at the C-terminus of the protein. It is speculated that the
HEAT repeats serve to mediate protein-protein interactions,
the FRB domain as suggested by its name provides a dock-
ing site for the FKBP12/rapamycin complex, and the FAT
and FATC domains modulate mTOR kinase activity via
The binding of rapamycin/FKBP12 to the mTOR FRB
domain in vivo clearly blocks some of the physiological
functions of mTOR. However, whether rapamycin directly
inhibits mTOR’s intrinsic kinase activity is not clear. While
some scientists believe that the binding mainly prevents
Figure 1 Schematic of mTOR complex components. HEAT: a protein-protein interaction structure of two tandem anti-parallel a-
helices found in huntingtin, elongation factor 3, PR65/A and TOR; FAT: a domain structure shared by FRAP, ATM and TRRAP, all
of which are PIKK family members; FRB: FKBP12/rapamycin binding domain; FATC: FAT C-terminus; RNC: Raptor N-terminal
conserved domain; WD40: about 40 amino acids with conserved W and D forming four anti-parallel beta strands; CRIM: conserved
region in the middle; RBD: Ras binding domain.
FAT FRB Kinase FATC
RNC HEAT WD40 repeats
Conserved domain structure
CRIM RBD PH
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Expanding mTOR signaling
mTOR from interacting with its substrates, others have
shown that mTOR autophosphorylation (intrinsic mTOR
activity) is inhibited by rapamycin [19-21]. Further studies
on mTOR phosphorylation are needed to reveal whether ra-
pamycin does, indeed, contribute to the regulation of mTOR
intrinsic kinase activity. So far, quite a few phosphorylation
sites have been identified in mTOR and many more are
expected to come [22-26]. While the phosphorylation of
Ser2481 in mTOR has been considered the major indica-
tor of mTOR intrinsic kinase activity, the contributions of
other phosphorylation sites towards mTOR activity are not
The earliest identified and best-studied mTOR down-
stream effectors are S6K1 (p70 ribosomal protein S6 kinase
1) and 4EBP1 (eIF4E binding protein 1) . Under basal
conditions, S6K1 and 4EBP1 are bound to eIF3 (eukaryotic
initiation factor 3) and remain inactive . Upon growth
stimulations, mTOR binds to eIF3 and phosphorylates
S6K1 and 4EBP1. The phosphorylation of S6K1 releases
it from eIF3 and activates the kinase. The active S6K1
promotes translation and growth by phosphorylating cel-
lular substrates, such as S6 [28, 29]. 4EBP1 inhibits cap-
dependent mRNA translation via binding to the translation
initiator eIF4E (eukaryotic translation initiation factor 4E)
. The phosphorylation of 4EBP1 by mTOR frees it from
eIF4E, relieves its inhibitory effect and stimulates transla-
tion initiation. Together, active mTOR enhances cell growth
by promoting protein translation and increasing cell mass.
Cells with hyperactive mTOR often gain growth advantages
and display a larger size [13, 31, 32].
Tuberous sclerosis complex inhibits mTOR activity
Much earlier than the discovery of rapamycin and
mTOR, hamartoma syndromes have been documented
along the course of human pathological history. These
diseases are characterized by multiple benign tumors oc-
curring in a variety of organs. Hamartomas are formed by
normally differentiated but structurally disorganized cells,
which are often enlarged. Among different hamartoma syn-
dromes, tuberous sclerosis complex (TSC) is an autosomal
disorder with a population prevalence of 1/5 000 to 1/10 000
. TSC tumors can be found in many organs, including
brain, heart, kidney, muscles and skin. Like typical ham-
artoma syndromes, TSC tumors are normally benign, but
their presence in these tissues may result in severe clinical
manifestations. Although the first documentation of TSC
can be traced back to the 19th century, the cause of this
disease remained unknown until the recent identification
of the TSC1 and TSC2 tumor suppressor genes. Mutation
of either one of these genes is sufficient to cause TSC. This
was later explained by biochemical evidence demonstrat-
ing that TSC1 and TSC2 form a physical and functional
complex in vivo. TSC1 stabilizes the complex, while TSC2
exerts GTPase activating protein (GAP) activity towards
The seemingly parallel TSC syndrome and the mTOR-
controlled cell growth were tied together in 2002, when
our laboratory together with others [34-37], inspired by
the TSC genetic studies in Drosophila [38-41], showed
that the major function of TSC1/TSC2 is to inhibit mTOR.
This finding provided the first piece of evidence for mTOR
involvement in human tumorigenesis and opened the door
for a plethora of studies on the regulation and functions of
the TSC-mTOR signaling network.
The TSC1/TSC2 complex (TSC1/2) has been established
as the major upstream inhibitory regulator of mTOR [42,
43]. Functioning as a rheostat, TSC1/2 suppresses mTOR’s
activity to restrain cell growth under stress conditions, and
releases its inhibition when conditions are favorable for
growth. In TSC syndrome patients, TSC mutations (loss
of mTOR inhibition) lead to a hyperactive mTOR, caus-
ing cell overgrowth and tumor formation. Interestingly,
elevated mTOR activity has been detected in many other
hamartoma syndromes. Together, these results implicate a
possible common cause underlying different benign tumor
syndromes, and place mTOR under the spotlight as an
anti-cancer drug target. Naturally, rapamycin immediately
became the ideal candidate to treat TSC syndrome due to
its exquisitely specific and potent inhibition of mTOR. In-
deed, three rapamycin analogs, CCI-779 (Wyeth), RAD001
(Novartis), and AP23573 (Ariad Pharmaceuticals Inc.) are
currently in clinical trials for cancer treatment.
The emergence of mTOR complex 1
TOR is a large protein with many domains known to
mediate protein-protein interactions. By gel filtration
chromatography, TOR elutes in a fraction corresponding
to a molecular weight much larger than its predicted size,
which prompted many research groups to purify TOR
binding partners. In 2002, seminal works from Hall’s group
first identified multiple TOR-associated proteins in yeast,
including KOG1, AVO1, AVO2, AVO3 (AVO1/2/3) and
LST8 . Curiously, either TOR1 or TOR2 can complex
with KOG1 and LST8 to form a rapamycin-sensitive com-
plex, termed TOR complex 1 (TORC1), while only TOR2
binds AVO1/2/3 and LST8 to form a rapamycin-insensi-
tive complex, termed TOR complex 2 (TORC2). Almost
at the same time, Raptor (regulatory associated protein of
mTOR) was also identified as an mTOR-binding protein
[45, 46]. Amino-acid alignment reveals that Raptor is the
mammalian homolog of the yeast KOG1. mTOR, Raptor,
and the later identified mammalian LST8 (mLST8) 
form a complex that is sensitive to rapamycin inhibition,
termed mTOR complex 1 (mTORC1).
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Expanding mTOR signaling
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