Mtor Review

8/2/2019 Mtor Review

1/9

Review

The mTOR pathway and its role in human genetic diseases

Margit Rosner, Michaela Hanneder, Nicol Siegel, Alessandro Valli,Christiane Fuchs, Markus Hengstschlager *

Medical Genetics, Obstetrics and Gynecology, Medical University of Vienna, Wahringer Gurtel 18-20, 1090 Vienna, Austria

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

1.1. The mTOR pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

1.2. Localization of mTOR pathway components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

2. The mTOR pathway and specific human genetic diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

2.1. Tuberous sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

2.2. Peutz-Jeghers syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

2.3. Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, Lhermitte-Duclos disease. . . . . . . . . . . . . . . . . . . . . . 287

2.4. von Hippel-Lindau disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

2.5. Neurofibromatosis type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288

2.6. Polycystic kidney disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288

3. The mTOR pathway in Alzheimers syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288

Mutation Research 659 (2008) 284292

A R T I C L E I N F O

Article history:

Received 15 May 2008Received in revised form 29 May 2008

Accepted 3 June 2008

Available online 11 June 2008

Keywords:

PI3K

Akt

TSC

mTOR

Ras

Human genetic disease

Cancer

A B S T R A C T

The signalling components upstream and downstream of the protein kinase mammalian target of

rapamycin (mTOR) are frequently altered in a wide variety of human diseases. Upstream of mTOR keysignalling molecules arethe small GTPaseRas, the lipid kinasePI3K, theAkt kinase, andthe GTPaseRheb,

whichare knownto be deregulated in many humancancers. Mutations in themTOR pathway component

genes TSC1, TSC2, LKB1, PTEN, VHL, NF1 and PKD1 trigger the development of the syndromes tuberous

sclerosis, Peutz-Jeghers syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-

Duclos disease, Proteus syndrome, von Hippel-Lindau disease, Neurofibromatosis type 1, and Polycystic

kidney disease, respectively. In addition, the tuberous sclerosis proteins have been implicated in the

development of several sporadic tumors and in the control of the cyclin-dependent kinase inhibitor p27,

known to be of relevance for several cancers. Recently, it has been recognized that mTOR is regulated by

TNF-a andWnt, both of whichhave been shownto play critical roles in thedevelopmentof many human

neoplasias. In addition to all these human diseases, the role of mTOR in Alzheimers disease, cardiac

hypertrophy, obesity and type 2 diabetes is discussed.

2008 Elsevier B.V. All rights reserved.

* Corresponding author. Tel.: +43 1 40400 7847; fax: +43 1 4040 7848.

E-mail address: [email protected] (M. Hengstschlager).

Abbreviations: 4EBP1, eukaryotic initiationfactor 4E binding protein-1; ADPKD, autosomal dominant polycystickidney disease;AMPK, 50AMP-activated protein kinase; Cdk,

cyclin-dependent kinase; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FGFR, fibroblasts growth factor receptor; FKBP, FK506-binding

protein;GAP, GTPase activating protein;GSK3b, glycogen synthasekinase 3b; HIF,hypoxia-inducibletranscriptionfactor; IGF-1R, insulin-like growth factor 1 receptor; IGF-

1, insulin-like growth factor 1; IKK, inhibitor of kB kinase; IRS1, insulin receptor substrate 1; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of

rapamycin; NF1, neurofibromatosis type 1; p70S6K, ribosomal p70S6 kinase; PC1, polycystin-1; PDGFb, plateled-derived growth factor b; PDGFR, platelet-derived growth

factor receptor; PDK1, phosphoinositide-dependent kinase-1; PI3K, phosphatidylinositol 3-kinase; PIP2, lipid phosphatidylinositol-4,5-biphosphate; PIP3, phosphatidy-

linositol-3,4,5-triphosphate; PML, promyelocytic leukaemia; PRAS40, proline-rich AKT substrate 40 kDa; protor, protein observed with rictor; PTEN, phosphatase and tensin

homolog; raptor, regulatory associated protein of mTOR; Rheb, Ras homolog enriched in brain; rictor, rapamycin-insensitive companion of mTOR; RTK, receptor tyrosine

kinase; siRNA, small interfering RNA; sin1, stress-activated protein kinase-interacting protein; TGF-a, and transforming growth factor a; TNF-a, tumor necrosis factor-a;TSC, tuberous sclerosis complex; TSC1, tuberous sclerosis complex gene 1; TSC2, tuberous sclerosis complex gene 2; VEGF, vascular endothelial growth factor; VEGFR,

vascular endothelial growth factor receptor; VHL, von Hippel-Lindau disease.

Contents lists available at ScienceDirect

Mutation Research/Reviews in Mutation Research

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / r e v i e w s m rC o m m u n i t y a d d r e s s : w w w . e l s e v i e r . c o m / l o c a t e / m u t r e s

1383-5742/$ see front matter 2008 Elsevier B.V. All rights reserved.

doi:10.1016/j.mrrev.2008.06.001
mailto:[email protected]://www.sciencedirect.com/science/journal/13835742http://dx.doi.org/10.1016/j.mrrev.2008.06.001http://dx.doi.org/10.1016/j.mrrev.2008.06.001http://www.sciencedirect.com/science/journal/13835742mailto:[email protected]


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4. The mTOR pathway and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288

4.1. Upstream and downstream of mTOR in tumor development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288

4.2. Ras, mTOR and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

4.3. TNF-a activates mTOR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

4.4. Wnt regulates mTOR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

4.5. mTOR and renal cell carcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

4.6. The TSC proteins in sporadic cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

4.7. The TSC proteins and p27 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

5. The mTOR pathway and cardiac hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2906. The mTOR pathway in obesity and type 2 diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290

7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290

Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290

1. Introduction

1.1. The mTOR pathway

The mammalian target of rapamycin (mTOR) is a member of the

phosphoinositide-3-kinase-related kinase family, which is centrally

involved in growth regulation, proliferation control and cancer cell

metabolism. In mammalian cells, two structurally and functionallydistinct mTOR-containingcomplexes have been identified. mTORC1

contains raptor (regulatory associated protein of mTOR), mLST8

(also known as GbL) and PRAS40 (proline-rich Akt substrate40 kDa). Whereas the functionof mLST8 is not really clarified, raptor

regulates mTORC1 functioning as a scaffold for recruiting TORC1

substrates. PRAS40 is phosphorylated by Akt at T246 releasing its

inhibitory effects on mTORC1. The major substrates of mTORC1

known so far are 4EBP1 (eukaryotic initiation factor 4E binding

protein-1) and p70S6K (ribosomal p70S6 kinase), both regulators of

protein translation. mTORC1 phosphorylates and activates p70S6K

at T389 to activate the ribosomal protein S6 via phosphorylation at

S240/244 (Fig. 1) [15].

mTORC2 also contains the mLST8 protein, but instead of raptor,

mTORC2 contains rictor (rapamycin-insensitive companion ofmTOR) and sin1 (stress-activated protein kinase-interacting pro-

tein) proteins. Rictor and sin1appearto stabilize eachother through

binding, building the structural foundation for mTORC2. The

interaction between rictor and mTOR is not blocked by the drug

rapamycin nor affected by nutrient levels, which are conditions

known to regulate mTORC1. mTORC2 additionally contains protor

(protein observed with rictor), which lacks any obvious functional

domains. The role of protorfor mTORC2 activity(if any)still remains

elusive. mTORC2 phosphorylates the oncogenic kinase Akt (also

known as protein kinase B) at S473, what in conjunction with the

PDK1 (phosphoinositide-dependent kinase-1)-mediated phosphor-

ylation of Akt at T308 drives full activationof Akt(Fig.1) [15]. Over

100 putative Akt substrates have been reported, although many of

those have not been characterized in more detail [6].One important substrate of Akt has been shown to function

upstream of mTORC1: the TSC1/TSC2 protein complex. The TSC1

gene on chromosome 9q34 encodes hamartin, and TSC2 on

chromosome 16p13.3 encodes tuberin [7,8]. Mutations in either

the TSC1 or TSC2 gene causetuberous sclerosis (TSC), a multisystem

autosomal dominant disorder (see below) [9,10]. Activated

receptor tyrosine kinases activate the phosphatidylinositol-3-

kinase (PI3K) through phosphorylation of adaptors, such as the

insulin receptor substrate 1 (IRS1). Phosphorylation of the

membrane lipid phosphatidylinositol-4,5-biphosphate (PIP2) by

PI3K produces the second messenger phosphatidylinositol-3,4,5-

triphosphate (PIP3) in a reaction that can be reversed by the

phosphatase PTEN (phosphatase and tensin homolog) (Figs. 1 and

2). PDK1 and Akt bind to PIP3 at the plasma membrane, and PDK1

phosphorylates Akt at T308. Akt-mediated phosphorylation on

S939 and T1462 downregulates tuberins GTPase activating (GAP)

potential toward Rheb (Ras homolog enriched in brain), which is a

potent regulator of mTOR. It was recently shown that Rheb

regulates mTOR through FKBP38, a member of the FK506-binding

protein (FKBP) family. FKBP38 binds to mTOR and inhibits its

activity and Rheb interacts directly with FKBP38 and prevents its

association with mTOR (Fig. 1) [1,2,4,11].p70S6K has been demonstrated to phosphorylate IRS1 on

multiple inhibitory sites promoting its degradation (Fig. 1) [12].

This finding is one possible explanation for the observation that

loss of TSC1/2 function results in downregulated Akt phosphor-

ylation [13,14]. It has been suggested that tumors in TSC patient

are less aggressive because of this S6K-dependent negative

feedback inhibition. Furthermore, it has recently been reported

that Rheb has a negative effect on mTORC2. This study provides

evidence that Rheb may affect mTORC2 indirectly probably

through this S6K-dependent negative feedback loop [15]. In

addition, recently it was demonstrated that the TSC1TSC2

Fig. 1. mTORC1 and mTORC2 in the insuling signalling pathway. For details see the

text.

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complex can physically associate with mTORC2 but not mTORC1,and that the TSC protein complex positively regulates mTORC2in a

manner independent of its GTPase-activating protein activity

toward Rheb (Fig. 1) [16].

1.2. Localization of mTOR pathway components

IRS1, PI3K, PDK1 and Akt function at the plasma membrane. In

agreement with its role in the regulation of translation, all the

other components of the described pathway including TSC1/2,

Rheb, mTOR andp70S6K have also been localizedto thecytoplasm.

Besides regulation of translation,mTORhas also been implicated in

the regulation of ribosome biogenesis, macro-autophagy or

transcription [17]. Accordingly, it is not surprising that the

proteins involved in the PI3K signalling pathway are also localizedwithin thenucleus. PI3K has been shown to be nuclear [18] PDK1 is

a nucleo-cytoplasmic shuttling protein [19]. Akt translocates also

to the nucleus [2023] and it was reported that IGF-1 (insulin-like

growth factor1) stimulates phosphorylationof AktT308 andof Akt

S473 in the cytoplasm and in the nucleus [24]. It has even recently

been shown that the PML (promyelocytic leukaemia) tumor

suppressor prevents cancer by inactivating Akt in the nucleus [25].

Several recent reports have brought conclusive evidence that the

tumor suppressor PTEN, once considered as a strictly cytoplasmic

protein, also shuttles to the nuclear compartment, where it joins

the components PI3K, PDK1 and Akt [26,27]. Tuberin has been

reported to be cytoplasmic and nuclear [2831]. Furthermore,

mTOR and its substrate p70S6K have been found to be localized to

both the cytoplasm and the nucleus, and cytoplasmic nuclearshuttling of mTOR has been shown to be involved in rapamycin-

sensitive signalling and translation initiation [3236]. The p70S6K

target S6 is dispersed throughout the cytoplasm. Within the

nucleus S6 protein is concentrated to the nucleoli and almost

absent from the nucleoplasm, what is a consequence of the fact

that eukaryotic ribosomes are assembled in the nucleolus before

export to the cytoplasm [37,38].

2. The mTOR pathway and specific human genetic diseases

2.1. Tuberous sclerosis

Hamartin and tuberin are believed to function in the same

complex, because they associate physically in vivo with high

affinity to form heterodimers [39,40]. Until now, over 50 proteinshave been demonstrated to interact with hamartin and/or tuberin

anda wide variety of functionshave been describedfor this protein

complex [41]. However, in addition, evidence for functional

differences of these two proteins comes from knockout studies

and from microarray and proteomicanalyses [4246]. As described

above (Fig. 1), a major function of the hamartin/tuberin (TSC1/

TSC2) protein complex is to antagonize the mTOR pathway. Akt-

mediated phosphorylation on S939 and T1462 downregulates

tuberins GTPase activating (GAP) potential toward Rheb (Figs. 1

and 2). In summary, Akt stimulates mTOR signalling by inhibiting

the function of tuberin [4752]. Via this pathway mTOR controls

the translation rate of RNAs specifically regulated via the

translation initiation factor eIF4E. Cap-dependent translation is

facilitated by mTOR phosphorylation and inactivation of 4E-BPs,which are suppressors of eIF4E. In addition, mTOR regulates the

translation rates of specific messages (mainly from genes involved

in ribosome biogenesis) via its effects on the phosphorylation of

the 40S ribosomal protein S6 by S6K. S6K is considered to be

involved in translation control of a small subset of mRNAs that

contain a 50-terminal oligopyrimidine tract [1,2,53].

The majority of TSC disease-causing mutations occur de novo in

either TSC1 or TSC2. Linkage analysis suggests that about half of

large families are linked to TSC1 and half to TSC2, whereas in the

sporadic TSC population mutations in TSC2 are about five times

more common than mutations in TSC1. Themutation spectra of the

TSC genes are very heterogenous and no hotspots of mutations

have been found. No significant genotypephenotype correlations

have been established. Patients with TSC2 mutations seem to bemore severely affected than patients with mutations in the TSC1

gene, which appears to be due to a higher rate of second hit events.

TSC patients carry a mutant TSC1 or TSC2 gene in each of their

somatic cells and loss of heterozygosity has been documented in a

wide variety of TSC tumors. Tumor development is assumed to be

the result of somatic second hit mutations according to

Knudsons tumor suppressor model. Accordingly, although TSC

is a disease, which is transmitted in an autosomal dominant

fashion, mutations in the TSC genes are believed to be recessive at

the level of the affected cell [710,53]. TSC affects about 1 in 6000

live births and is characterized by the development of tumor-like

growths, named hamartomas, in the kidneys, heart, skin and brain.

Primary diagnostic criteria for TSC include facial angiofibromas,

peringual fibromas, calcified retinal hamartomas, cortical tubers or

Fig.2. Regulatory components upstreamof theTSC1/TSC2 complexThe phosphorylation sites on tuberinor hamartinare shown under thecorresponding enzymes.For details

see the text.

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renal angiomyolipomas. In addition, nearly all patients exhibit skin

signs, such as, e.g. hypomelanotic macules, forehead fibrous

plaques, facial angiofibromas or shagreen patches. In summary, the

major features of TSC include dermatologic manifestations, renalangiomyolipomas, and neurologic manifestations, such as epi-

lepsy, mental retardation, and autism. The severity of TSC and its

impact on the quality of life is extremely variable. Many patients

have minimal signs and symptoms with no neurologic disability.

The greatest source of morbidity is the brain tumors, named

cortical tubers, causing seizures in 8090% of affected individuals,

and behavioural abnormalities (mostly autism) in over half of

affected individuals [9,10,53].

Lymphangiomyomatosis (also known as lymphangioleiomyo-

matosis) is characterized by widespread pulmonary proliferation

of abnormal smooth-muscle cells and cystic changes within the

lung parenchyma manifested by dyspnea or pneumothorax. It

affects women almost exclusively. Among women with TSC the

incidence for lymphangiomyomatosis is 2639% with many ofthese women being asymptomatic [9,53] (Table 1).

The mTORC1 inhibitor sirolimus has already been studied in

clinical trials analysing its effects in TSC and lymphangiomyoma-

tosis therapy justifying the need for larger, well-powered trials to

test whether sirolimus therapy shouldbecome thestandardof care

for such patients [54,55].

2.2. Peutz-Jeghers syndrome

In the recent past, in addition to Akt other enzymes have been

identified to regulate tuberins functions. The LKB1 tumor

suppressor gene is responsible for the hamartomatous Peutz-

Jeghers syndrome and encodes a serine/threonine kinase, which

phosphorylates and activates AMPK (50

AMP-activated proteinkinase). Under energy starvation conditions phosphorylation by

AMPK activates tuberin via phosphorylationat T1227 andS1345, is

required for the regulation of cell size control, and protects cells

from energy deprivation-induced apoptosis [56,57]. Recently, it

was demonstrated that Wnt inhibits the GSK3b (glycogensynthase kinase 3b)-mediated phosphorylation of tuberin. GSK3inhibits the mTOR pathway via phosphorylating tuberin at S1337

and at S1341. This phosphorylation depends on AMPK-priming

phosphorylation of tuberin at S1345 and triggers activation of

tuberins potential to inhibit mTOR. Accordingly, Wnt inhibits the

GSK3-mediated activation of tuberin to block mTOR [58] (Fig. 2).

The Peutz-Jeghers syndrome, caused by mutation in the LKB1

tumor suppressor gene, is characterized by hamartomas primarily

in the intestine, where they grow as polyps, by abnormal

mucocutaneous pigmentation and an increased risk of malignant

tumors in the intestine and elsewhere [59,60].

2.3. Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome,

Proteus syndrome, Lhermitte-Duclos disease

The tumor suppressor gene PTEN encodes a phosphatase that

catalyzes the conversion of PIP3 to PIP2. Loss of PTEN increases Akt

activity, which downregulates tuberins function (Fig. 2). Germline

PTEN mutations trigger a wide variety of different clinical

syndromes, such as Cowden syndrome, Bannayan-Riley-Ruvalcaba

syndrome, Proteus syndrome, and Lhermitte-Duclos disease. Since

these four diseases are all autosomal dominant hamartoma

syndromes it has been suggested that these syndromes should

be grouped together as PTEN-hamartoma tumor syndromes

[59,60]. As described above, LKB1, associated with the hamarto-

matous Peutz-Jeghers syndrome,activates tuberin via AMPK. Since

PTEN, LKB1 and tuberin have been demonstrated to be involved inthe regulation of HIF and VEGF, it has been speculated that

increasedHIF andVEGF levels may be a commonfeature of familial

hamartoma syndromes. It was reported that tuberin regulates the

expression of the vascular endothelial growth factor (VEGF)

through mTOR-dependent and -independent mechanisms. Loss

of functional tuberin triggers the accumulation of the hypoxia-

inducible transcription factor (HIF) and upregulation of the

expression of HIF-responsive genes including VEGF. TSC2-negative

cells, in contrast to normal cells, fail to downregulate HIF in

response to growth factor deprivation. Expression of a disease-

causing mutation of TSC2 fails to normalize HIF in TSC2-deficient

cells, suggesting that HIF regulation plays a role in TSC2 tumor

suppressor function (Table 1; Figs. 2 and 3) [5962].

2.4. von Hippel-Lindau disease

Mutations in the VHL tumor suppressor gene cause von Hippel-

Lindau disease (VHL). This genetic multisystem disorder is

characterized by the abnormal growth of tumors (angiomas) in

certain parts of the body. Hemangioblastomas (tumors of the

central nervous system) can develop in the brain, the retina of the

eyes, and other areas of the nervous system. Other types of tumors

develop in the adrenal glands, the kidneys, or the pancreas.

Patients can have headaches, problems with balance and walking,

dizziness, weakness of the limbs, vision problems, and high blood

pressure. Individuals with VHL also harbor increased risks for

certain types of cancer, especially renal carcinomas. VHL encodes a

protein, which is part of a multiprotein complex involved in

Table 1

mTOR pathway components in specific human genetic diseases

Gene Protein: function Disease: clinical characteristics

TSC1 Hamartin: binding partner for tuber in Tub erou s scleros is: hamartomas , epileps y, mental retardatio n

Lymphangiomyomatosis: lung cysts, dyspnea, pneumothorax

TSC2 Tuberin: Rheb GTPase activation, regulation of mTORC2, p27, etc. Tuberous sclerosis: hamartomas, epilepsy, mental retardation

Lymphangiomyomatosis: lung cysts, dyspnea, pneumothorax

LKB1 LKB1: ser/thr kinase Peutz-Jeghers syndrome: hamartomas in the intestine

PTEN PTEN: phosphatase Cowden syndrome: hamartomas in multiple organs

Bannayan-Riley-Ruvalcaba syndrome: hamartomas in multiple organs

Lhermitte-Duclos disease: hamartomas in brain

Proteus syndrome: hamartomas in multiple organs

VHL VHL: ubiquitination of HIF von Hippel-Lindau disease: angiomas, hemangioblastomas, renal carci nomas

NF1 Neu rofi bro min: Ra s-GTPa se activa ting Neur ofib romatos is type 1: neu rofi bromas , h amar toma s

PKD1 Po lycys tin- 1: interactio n, b lock o f mTOR Polycystic kidney diseas e: cys ts in b oth kidn eys



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ubiquitination and degradation of the transcription factor HIF

leading to the dysregulation of a variety of genes, involved in

growth control. As described above, mTOR is a key upstreamregulator of HIF. However, the interactive roles of mTOR and VHL

for the control of HIF activity is still under investigation (Fig. 3;

Table 1) [59,60,63,64].

2.5. Neurofibromatosis type 1

The familial cancer syndrome neurofibromatosis type 1 (NF1)

affects about 1 in 3500 individuals. It is characterized by the

development of benign (neurofibromas) and malignant peripheral

nerve sheath tumors. Patients can exhibit cognitive deficits, bone

deformations and hamartomatous lesions of the iris. Neurofibro-

matosis type 1 is often grouped clinically with TSC as a common

neurocutaneous syndrome. It is caused by mutations in NF1. NF1

encodes neurofibromin, which functions as a Ras-GTPase-activat-ing protein. Accordingly, Ras is aberrantly activated in NF1-

deficient tumors. Rashas many functionsin thecell, oneof which is

to activate the PI3K-TSC1/TSC2-mTOR cascade. It has been

demonstrated that in NF1-deficient cells mTOR is constitutively

activated. This activation depends on Ras, PI3K and TSC2.

Furthermore, it has been shown that activation of mTOR is

essential for in vivo NF1-associated tumorigenesis (Fig. 2; Table 1)

[65,66].

2.6. Polycystic kidney disease

Renal cysts are the hallmark of the autosomal dominant

polycystic kidney disease (ADPKD) and are also characteristic for

TSC. Mutations in the PKD1 gene, which encodes polycystin-1(PC1), account foralmost 90%of ADPKD. ADPKDis considered to be

one of the most common monogenic inherited diseases. The

growth of thousands of cysts in both kidneys in a progressive

manner during adulthood results in replacement of normal renal

tissue and significant overall growth of the organs. A synergistic

role of tuberin and PC1 is suggested by the fact that patients with

mutations in both, TSC2 and PKD1, have earlier-onset and more

severe polycystic kidney disease than patients harboring only

PKD1 mutations. It has been demonstrated that tuberin is required

for the localization of PC1 to the plasma membrane [67].

Furthermore, the cytoplasmic tail of PC1 can interact, directly or

indirectly, with tuberin and mTOR. This interaction would appear

to normally result in inhibition of mTOR activity. Disruption of PC1

triggers high levels of mTOR activity (Fig. 3) [68]. In addition,

another protein known to be involved in the etiology of polycystic

kidney disease was found to interact with tuberin. Mutations in

NEK1 cause the formation of kidney cysts in mice. Performing a

yeast two-hybrid screen NEK1 has been identified as interacting

partner of tuberin. It will be of great interest for the future to

further investigate the role of this interaction for the formation of

renal cysts (Table 1) [69]. Recent results demonstrate that PC1

regulates mTOR and is involved in mechanotransduction by

primary cilia measuring the degree of luminal fluid flow. It is

currently under discussion whether a critical function of PC1 and

primary cilia in the kidney may be to sense renal injury by

detecting changes in luminal flow [70].

3. The mTOR pathway in Alzheimers syndrome

Hamartin has been demonstrated to interact with neurofila-

ment-light chain and hamartin and tuberin co-localize with

neurofilament-light chain preferentially in the proximal to central

growth cone region of cultured cortical neurons suggesting that

hamartin could function as an integrator of the neuronal

intermediate filament and the actin cytoskeletal network [71].

In TSC the central nervous system lesions, such as cortical tubers,

result in a variety of neurological manifestations, including mentalretardation and seizures. Furthermore, tuberin has been reported

to be involved in the regulation of neuronal differentiation [72].

Alzheimers disease, the most common form of dementia in the

elderly, is a progressive neurodegenerative disorder characterized

by global cognitive decline involving memory, orientation,

judgment, and reasoning. Upon autopsy abundant amounts of

the typical lesions, extracellular deposits of b-amyloid andintracellular deposits of neurofibrillary tangles, are necessary for

a confirmed diagnosis of Alzheimers disease. There is a very high

incidence of Alzheimer-type neuropathology that is observed in

the brains of middle-aged patients with Down syndrome (Trisomy

21). A genetic link between these two diseases has been suggested

since it was shown that the b-amyloid precursor protein gene

mapped to chromosome 21. Beside the b-amyloid precursorprotein gene recentgenetic studies have identifiedalso other genes

associated with inherited risk for Alzheimers disease, such as

presenilin 1, presenilin 2, and apolipoprotein E. However,

Alzheimers disease is a multifactorial illness with both genetic

and non-genetic causes [73]. Tuberin levels have been found to be

decreased in samples of brains positive for b-amyloid plaques and

neurofibrillary tangles of patients with Alzheimers disease or with

Down syndrome [74]. Deregulation of PTEN and Akt [75,76],

alteration of mTOR activity [77,78] and deregulated p70S6K

activity [79] has also already been found to be associated with

Alzheimers disease pathology.

4. The mTOR pathway and cancer

4.1. Upstream and downstream of mTOR in tumor development

The signalling components upstream and downstream of mTOR

are frequently altered in a wide variety of human tumors. As

described above, mutations in the tumor suppressor genes TSC1,

TSC2, LKB1, PTEN, VHL, NF1 and PKD1 trigger the development of the

hamartoma syndromes Tuberous sclerosis, Peutz-Jeghers syn-

drome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome,

Lhermitte-Duclos disease, Proteus syndrome, von Hippel-Lindau

disease, Neurofibromatosis type 1, and Polycystic kidney disease,

respectively (Table 1). PI3K itself can function as protooncogene,

since increased PI3K activity has been shown to induce cell

transformation and progression and has been found in many

human cancers, such as, e.g. ovarian and gastrointestinal cancer.

Fig. 3. The mTOR pathway downstream of the TSC1/TSC2 complex. For details see

the text.



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Mutations in PI3K upstream elements, such as epidermal growth

factor, ErbB2 or insulin-like growth factor 1 receptor trigger

increased PI3K activity in various cancer cell types [1,3,17,80]. The

protooncogene Akt is amplified in different tumors, such as, e.g.

breast and ovarian cancer [1,6,17]. Rheb expression is upregulated

in many human cancers [81] and p70S6K often is amplified or

overexpressed in breast cancers correlating with poor prognosis

[82].

4.2. Ras, mTOR and cancer

Growth factors activate receptor tyrosine kinases (RTKs),

including epidermal growth factor receptor (EGFR), platelet-

derived growth factor receptor (PDGFR), fibroblasts growth factor

receptor (FGFR), insulin-like growth factor 1 receptor (IGF-1R),

interleukin receptors, vascular endothelial growth factor receptor

(VEGFR), interferon receptors, and integrin receptors, which then

activate two key signalling molecules. As described above, one is

the lipid kinase PI3K and the other one is the small GTPase Ras

(Fig. 2). In fact, most human tumors harbor activating mutations in

K-ras, H-ras, N-ras, the p110a PI3K subunit or in RTKs [17,83].Tuberin is also phosphorylated by ERK at S664 (Fig. 2). Mitogenic

stimuli or oncogenic Ras via Raf activate the mitogen-activatedprotein kinase (MAPK)/Erk pathway leading to phosphorylation of

tuberin and inactivation of the TSC protein complex to regulate

p70S6K [84]. Furthermore, the MAPK-activated kinase RSK1

interacts with tuberin and phosphorylates it at S1798 triggering

inactivation of tuberin and increased mTOR signalling to p70S6K

(Fig. 2) [85]. Very recent data provide evidence that the function of

Ras to trigger inactivation of tuberin via the MAPK/Erk pathway

plays a major role in theregulation of cell survival upon mutational

activation of the oncogene Ras [86,87].

4.3. TNF-a activates mTOR

Dysregulation of the tumor necrosis factor-a (TNF-a) signalling

pathway contributes to the development of many human cancersdue to enhanced IKK activity and constitutive activation of the

transcription factor NF-kB. Very recently, this pathway of

transcription control has also been demonstrated to affect the

regulation of translation. TNF-a activates mTOR through phos-phorylation and inactivation of hamartin by the kinase IKKb(Fig. 2) [88].

4.4. Wnt regulates mTOR

Components of the mTOR pathway may also be therapeutic

targets for diseases linked to hyperactive Wnt signalling. The Wnt

protein family regulates a wide range of cellular functions

including cell growth, proliferation, polarity, differentiation and

development. Deregulation of the Wnt/b-catenin pathway is acommon feature in many humanneoplasms [89,90]. Inthe absence

of the secreted factor Wnt, GSK3 phosphorylates b-catenintriggering ubiquitination and degradation of b-catenin. Wntstimulation leads to activation of the protein Dishevelled (Dsh)

to inhibit the ability of GSK3 to phosphorylate b-catenin. Anothercomponent of this degradation complex is the scaffold protein

Axin. Both, hamartin and tuberin, have been reported to co-

immunoprecipitate with GSK3 and Axin [91,92]. As already

described above, Wnt inhibits the GSK3b-mediated phosphoryla-tion of tuberin. GSK3 inhibits the mTOR pathway via phosphor-

ylating tuberin, what depends on AMPK-priming phosphorylation

of tuberin and triggers activation of tuberins potential to inhibit

mTOR. Accordingly, Wnt inhibits the GSK3-mediated activation of

tuberin to block mTOR (Fig. 2) [58].

4.5. mTOR and renal cell carcinoma

In about 60% of renal cell carcinomas the VHL gene is

inactivated [63,64]. As already described, inactivation of VHL

triggers increased activity of the transcription factor HIF leading to

overexpression of vascular endothelial growth factor (VEGF),

plateled-derived growth factor b (PDGFb) and transforminggrowth factor a (TGF-a). A role of mTOR for renal cell carcinoma

development has been suggested because mutations in TSC1 or

TSC2 lead to activation of mTOR, confer a predisposition to renal-

cell carcinoma and are accompanied by upregulated HIF activity.

mTOR is a key upstream regulator of HIF (Fig. 3). Recent data

suggest that inhibition of mTOR results in clinical benefit in renal

cell carcinoma patients with poor prognostic features [5964,93].

4.6. The TSC proteins in sporadic cancer

The finding that the TSC genes are involved in regulation of the

mTOR signalling network already initiated clinical trials for the

treatment with rapamycin, a negative regulator of mTOR, of renal

tumors and lung cysts found in tuberous sclerosis [15,17].

Approaches like that have clear implications for the devastating

disease, tuberous sclerosis, but beyond that to sufferers fromcancers that may also involve the TSC proteins, such as, e.g.

sporadic bladder cancer, ovarian and gall bladder carcinoma, non-

small-cell carcinoma of the lung and breast cancer [94]. Mutations

in TSC1 have been found to be associated with the development of

human bladder carcinoma [9597]. Evidence has been provided

that reduced expression of tuberin might be involved in the

progression of human pancreatic cancer [98]. It was also reported

that tuberin and hamartin are aberrantly expressed and linked to

clinical outcome in human breast cancer. The TSC1 gene promoter

was seen to be methylated in human breast tumor tissues [99].

Human xanthoastrocytomas consistently show low TSC1 transcript

levels [100]. And recently, it was demonstrated that inactivation of

tuberin via loss of expression or phosphorylation occurs frequently

in endometrial carcinoma [101].

4.7. The TSC proteins and p27

A major regulator of mammalian cell cycle control is the cyclin-

dependent kinase (Cdk) inhibitor p27. The transition from G0/G1

to S phase is regulated via Cdk4 and Cdk6 activated by D-type

cyclins andvia Cdk2 activatedby cyclin E andA. Dueto itspotential

to control Cdk activity p27 is a very potent regulator of this

transition [102,103]. Another important cell cycle regulator is

tuberin. Downregulation of endogenous tuberin expression

induces quiescent fibroblasts to enter the cell cycle and TSC2-

negative cells exhibit a shortened G1 phase. Overexpression of

hamartin or tuberin negatively regulates cell cycle progression

accompanied by an increase of G1 cells and of p27 protein levels.Tuberin negatively regulates the activity of Cdk2 [104107]. p27 is

known to be regulated on the level of protein stability and via

subcellular localization. Binding of tuberin to p27 inhibits p27

degradation by sequestering p27 from the Skp2-containing E3

ubiquitin ligase [108]. Tuberin also induces nuclear p27 localiza-

tion by inhibiting its 14-3-3-mediated cytoplasmic retention [109]

(Fig. 3). In bladder tumors TSCgene mutations are correlated with

reduced p27 expression [9597]. Cytoplasmic localization of p27

was found in breast cancer and it was demonstrated that tuberin

andhamartin expression is downregulated in breastcancer. Due to

this connection between tuberin and p27, one could assume that

under certain circumstances p27 or Cdk2 could also be considered

as targets in addition to mTOR for therapeutics of hamartoma

diseases and other tumor diseases [99,110,111].



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5. The mTOR pathway and cardiac hypertrophy

Under energy starvation conditions tuberin is phosphorylated

and thereby activated by AMPK [56,57]. Dependent on AMPK-

priming phosphorylation of tuberin, GSK3b phosphorylatestuberin and triggers activation of its potential to inhibit mTOR

[58] (Fig. 2). AMPKg2, an important regulatory subunit of AMPK, isencoded by the gene PRKAG2. Mutations in PRKAG2 are responsible

for familial cardiac hypertrophy and Wolff-Parkinson-White

syndrome, a distinctive ventricular electrophysiologic abnormality

[112,113]. The knowledge that an important hallmark of cardiac

hypertrophy (a major risk for cardiac morbidity and mortality) is

hyperactivation of the PI3K-mTOR cascade, initiated a discussion

whether inhibition of the mTOR pathway could be beneficial for

therapies of these diseases [17,60,114,115].

6. The mTOR pathway in obesity and type 2 diabetes

p70S6K has been demonstrated to phosphorylate IRS1 on

multiple inhibitory sites promoting its degradation (Fig. 1) [12].

Inhibition of IRS protein function is one means by which cells

become desensitized to insulin. Phosphorylation of IRS1, which is

known to antagonize IRSsignalling, is elevated in animal models ofobesity and in muscle from type 2 diabetic patients. Recent studies

have shown that insulin resistance can be regulated by mTORC1

activation of p70S6K through the negative feedback loop. The

inability to respond to insulin (insulin resistance) is a hallmark of

both, obesity and type 2 diabetes [4,12,17,60,114,115].

7. Summary

The mTOR signalling pathway is activatedduring a wide variety

of cellular responses, which includes T-lymphocyte activation,

neurogenesis, muscle regeneration, insulin signalling and tumor

formation. This has provoked intense interest in the TSC/mTOR

cascade from virtually all major therapeutic areas related to many

human diseases. mTOR plays an important role in Alzheimersdisease, cardiac hypertrophy, obesity and type 2 diabetes. mTOR is

regulated by TNF-a and Wnt, both of which have been shown to

play critical roles in many human cancers. The TSC proteins have

been implicated in the development of several sporadic tumors

and in the control of p27, known to be of relevance for several

cancers. The mTOR upstream regulators Ras, PI3K, Akt and Rheb

are known to be deregulated in a wide variety of human tumors.

Tuberous sclerosis, Peutz-Jeghers syndrome, Cowden syndrome,

Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease,

Proteus syndrome, von Hippel-Lindau disease, Neurofibromatosis

type 1, and Polycystic kidney disease are caused by mutations in

the mTOR pathway component genes TSC1, TSC2, LKB1, PTEN, VHL,

NF1 and PKD1, respectively. Very recent data suggest that

inhibition of mTOR results in clinical benefit in renal cell carcinomapatients with poor prognostic features and in the treatment of

renal tumors and lung cysts found in tuberous sclerosis. It is the

hope of investigators and patients alike that a more detailed

understanding of the mTOR signalling cascade will lead to new

therapies for many different human diseases.

Acknowledgements

Research in our laboratory is supported by the FWF Austrian

Science Fund (P18894-B12), by the Marie Curie Research Network

of the European Community (FP6 036097-2) and by the

Herzfeldersche Familienstiftung. We apologize to those colleagues

whose work is not cited due to space limitations or our inability to

draw connections between elements of the primary literature.

Conflict of interest

None.

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