Download Gene Section FRAP1 (FK506 binding protein 12-rapamycin associated protein 1)

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
FRAP1 (FK506 binding protein 12-rapamycin
associated protein 1)
Deborah A Altomare, Joseph R Testa
Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA (DAA, JRT)
Published in Atlas Database: June 2008
Online updated version : http://AtlasGeneticsOncology.org/Genes/FRAP1ID40639ch1p36.html
DOI: 10.4267/2042/44468
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: FLJ44809; FRAP; FRAP2; MTOR; RAFT1; RAPT1; mTOR
HGNC (Hugo): MTOR
Location: 1p36.22
Note: EXOSC10 is exosome component 10, ANGPTL7 encodes angiopoietin-like 7, UBIAD1 is UbiA
prenyltransferase domain containing 1, PTCHD2 is patched domain containing 2, LOC100128221 is similar to
hCG2041787, and SRM encodes spermidine synthase.
DNA/RNA
Protein
Note
A map of the genomic organization of the human
FRAP1
gene
can
be
found
at
http://www.ncbi.nlm.nih.gov/projects/sviewer/?id=NC_
000001.9v=11081381..11252951.
Description
The amino terminus of FRAP (alias, mTOR) consists
of several tandem HEAT (Huntingtin, EF2, A subunit
of PP2A, TOR1) repeats) that are implicated in proteinprotein interations (Hay and Sonenberg, 2004; Bhaskar
and Hay, 2007). Each HEAT repeat contains two alpha
helices of approximatively 40 amino acids.
The carboxy-terminal half contains two FAT (FRAP,
ATM, TRAP) domains.
Upstream of the catalytic domain is the FRB (FKBP12rapamycin binding) domain.
The catalytic domain has sequence similarity to the
catalytic domain of phosphatidylinositol kinase (PIK),
which is homologous to a family of other protein
kinases termed PIKK (PIK-related kinase).
Description
The FRAP1 gene encompasses approximatively 156 kb
and contains 58 exons. The gene resides on the minus
strand. Reported location on human chromosome 1 is
between 11,089,179-11,245,151 bases in NCBI36
coordinates and 11,089,180-11,245,176 bases in
ensemble49 coordinates.
Transcription
Transcript length is 8,680 bp.
Pseudogene
No human pseudogene known.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5)
348
FRAP1 (FK506 binding protein 12-rapamycin associated protein 1)
Altomare DA, Testa JR
The amino acid residues corresponding to the FRAP1 (alias mTOR) protein domains are reported in pfam (see below)
Pfam: PF00454: Phosphatidylinositol 3- and 4-kinase (2181-2431)
Pfam: PF02259: FAT domain (1513-1910)
Pfam: PF02260: FATC domain (2517-2549)
Pfam: PF08771: FKBP12 Rapamycin Binding domain (2015-2114)
mTOR also contains a putative negative regulatory
(NR) domain between the catalytic domain and FATC.
The FATC (FRAP, ATM, TRRAP C-terminal) domain
is essential for the kinase activity. The FATC and FAT
domains are thought to interact in a way the exposes
the catalytic domain.
The protein consists of 2549 amino acids, with a
predicted molecular weight of 288,891 Da.
The ternary complex of human FK506-binding protein
(FKBP12), the inhibitor rapamycin, and the FKBP12rapamycin-binding (FRB) domain of human FRAP has
been crystallized at a resolution of 2.7 angstroms (Choi
et al., 1996), and then refined at 2.2 angstroms (Liang
et al., 1999).
Phosphorylation sites of FRAP (alias, mTOR) are
reported in http://www.phosphosite.org .
mTOR protein exists in two functionally distinct
complexes named mTOR complex 1 (mTORC1) and
complex 2 (mTORC2) (see figure under "Implicated
in"). The regulator of mTORC1 signaling and kinase
activity is the ras-like small GTPase Rheb (Ras
homologue enriched in brain), which binds directly to
the mTOR catalytic domain and enables mTORC1 to
attain an active configuration (Avruch et al., 2006).
Insulin/IGF stimulates the accumulation of Rheb-GTP
through activated AKT and subsequent inhibition of the
Rheb-GTPase-activating function of the tuberous
sclerosis (TSC1/TSC2) heterodimer. Energy depletion
decreases Rheb-GTP through the action of adenosine
monophosphate-activated protein kinase (AMPK) to
phosphorylate TSC2 and stimulate its Rheb-GTPase
activating function and also HIFalpha-mediated
transcriptional responses that act upstream of the
TSC1/2 complex. Amino-acid depletion inhibits
mTORC1 by acting predominantly downstream of the
TSC complex, by interfering with the ability of Rheb to
bind to mTOR.
As shown below, mTORC1 contains the core
components mTOR, Raptor (regulatory associated
protein of mTOR), and mLST8/GbetaL (G protein
beta-subunit-like protein). It is the mTORC1 complex
that is characteristically sensitive to inhibition by
rapamycin. mTORC1 is a major regulator of ribosomal
biogenesis and protein synthesis, largely through the
phosphorylation/inactivation of the 4E-BPs (4Ebinding proteins) and the phosphorylation/activation of
S6K (ribosomal S6 kinase). The binding of S6K1 and
4E-BP1 to raptor requires a TOR signaling (TOS)
motif, which contains an essential phenylalanine
followed by four alternating acidic and small
hydrophobic amino acids (Schalm and Blenis, 2002).
Recently, a TOS motif also has been identified in the N
terminus of HIF1alpha, which has been shown to
interact with Raptor (Land and Tee, 2007).
Furthermore, activation of mTOR by Rheb
overexpression enhanced HIF1alpha activity and
VEGF-A secretion under hypoxic conditions, whereas
the mTOR inhibitor rapamycin blocked the pathway.
PRAS40 (proline-rich AKT substrate 40 kDa) is a
novel mTOR binding partner that mediates AKT
signals to mTOR independently of TSC1/TSC2
(Vander Haar et al., 2007). Hence, PRAS40 and Rheb
are postulated to co-regulate mTORC1 (Guertin and
Sabatini, 2007). PRAS40 binds mTORC1 via Raptor,
and is an mTOR phosphorylation substrate (Thedieck
et al., 2007). Moreover, PRAS40 binds the mTOR
Expression
Expressed is found in numerous tissues, with high
levels in testis.
Localisation
Localization is predominantly cytoplasmic, but the
protein is also associated with mitochondrial,
endoplasmic reticulum and Golgi membranes (Guertin
and Sabatini, 2007). A fraction of protein also may
shuttle between the nucleus and cytoplasm.
Function
There are more than 2500 articles specifically referring
to FRAP1 or mTOR in PubMed. mTOR is central to
several key cellular pathways including insulin
signaling, regulation of eIF4e and p70S6 kinase, and
hypoxia induced factor 1alpha (HIF1alpha) stimulation
of vascular endothelial growth factor (VEGF). These
pathways affect several processes including cell growth
(size), protein translation, ribosome biogenesis,
regulation of cell cycle progression, response to
nutrients and cellular stress, angiogenesis, cell polarity
and cytoskeletal reorganization. mTOR also has been
shown to play a role in the regulation of autophagy
(Pattingre et al., 2008), an adaptive cellular response to
nutrient starvation whereby a cytoplasmic vacuole or
autophagosome engulfs cellular macromolecules and
organelles for degradation.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5)
349
FRAP1 (FK506 binding protein 12-rapamycin associated protein 1)
kinase domain and its interaction with mTOR is
induced under conditions that inhibit mTOR signaling,
such as nutrient or serum deprivation or mitochondrial
metabolic inhibition (Vander Haar et al., 2007).
PRAS40 contains a variant TOS motif and competes
with S6K1 and 4E-BP1 by functioning as a direct
inhibitor of substrate binding (Oshiro et al., 2007,
Wang et al., 2007).
mTORC2 contains mTOR, Rictor (rapamycininsensitive companion of mTOR), SIN1 (SAPK
interacting protein) and mLST8/GbetaL. Proline rich
protein 5-like (PRR5) protein also binds specifically to
mTORC2, via Rictor and/or SIN1 (Thedieck et al.,
2007). mTORC2 has been shown to regulate cell-cycledependent polarization of the actin cytoskeleton.
Although not as sensitive to rapamycin as mTOR1,
mTORC2 may be affected by prolonged rapamycin
exposure in some cell types (Sarbassov et al., 2006;
Zeng et al., 2007). However, the regulation of
mTORC2 is largely unknown and does not function
downstream of Rheb (Blaskar and Hay, 2007).
Direct genetic evidence for the importance of various
components of the mTORC1 and/or mTORC2
complexes was provided by targeted disruption studies
in mice (Guertin et al., 2006). Mice null for mTOR, as
well as those lacking Raptor die early in embryonic
development. However, mLST8-null embryos survive
until e10.5 and resemble embryos missing Rictor.
Collectively, mTORC1 function was found to be
essential in early development, mLST8 was required
only for mTORC2 signaling, and mTORC2 was found
to be a necessary component of the AKT-FOXO and
PKCalphaalpha pathways.
Disease
Among the dominantly inherited disorders classified as
phakomatoses are tuberous sclerosis 1 and 2, PeutzJeghers syndrome, Cowden disease, neurofibromatosis
1 and neurofibromatosis 2, and von-Hippel-Lindau
disease (Tucker et al., 2000). These disorders are
characterized by scattered hamartomatous or
adenomatous "two-hit" lesions that have a low
probability of becoming malignant. These particular
disorders are caused by germline mutations of certain
tumor suppressor genes, i.e., TSC2 / TSC1, LKB1,
PTEN, NF1/NF2 and VHL, respectively, encoding
proteins that intersect with the AKT/mTOR signaling
pathway (Altomare and Testa, 2005).
Germline mutations of TSC1 and TSC2 each give rise
to the hereditary disorder known as tuberous sclerosis
complex (TSC) (Astrinidis and Henske, 2005; Jozwiak
et al., 2008). Hamartomas arise in the central nervous
system, kidney, heart, lung, and skin, with occasional
tumors progressing to malignancy (i.e., renal cell
carcinoma). In TSC tumor cells, biallelic inactivation
of TSC2 or TSC1 results in constitutive mTOR
activity, independent of AKT activation status. Aside
from TSC, another rare lung disease known as
pulmonary lymphangioleiomyomatosis (LAM) occurs
from somatic or genetic mutations of TSC1 or TSC2
that lead to the activation of downstream mTOR
(Krymskaya, 2008). These findings have provided
rationale for the first rapamycin clinical trial for LAM
(Goncharova and Krymskaya, 2008).
The LKB1 tumor suppressor/AMPK pathway is an
alternate means of inactivating TSC2 and contributing
to constitutive mTOR activation (Inoki et al., 2005;
Kwiatkowski and Manning, 2005). The kinase
controlling AMPK (AMP-activated protein kinase) has
been identified as LKB1, which is encoded by the gene
inactivated in Peutz-Jeghers syndrome, a disorder
characterized
by
multiple
gastrointestinal
hamartomatous polyps. There is now experimental
evidence that Peutz-Jeghers polyposis could be
suppressed by targeting mTOR (Wei et al., 2008).
Germline PTEN mutations occur in 80% of patients
with Cowden disease, a heritable multiple hamartoma
syndrome with a high risk of breast, thyroid and
endometrial carcinomas (Gustafson, et al., 2007).
Decreased or absent expression of PTEN results in
constitutive activation of the AKT/mTOR pathway.
Loss-of-function mutations in NF1 contributes to the
neurofibromatosis type I familial cancer syndrome,
which is characterized by benign neurofibromas and
occasional malignant peripheral nerve sheath tumors
(MPNSTs), as well as hamartomatous lesions of the
eye,
myeloid
malignancies,
gliomas,
and
pheochromocytomas. The NF1-encoded protein,
neurofibromin, functions as a Ras-GAP, and
deregulation of Ras due to NF1 inactivation is
postulated to contribute to tumor development.
Activated Ras signaling to PI3K results in activation of
Homology
Mouse (Mus musculus): Frap1, 99 % amino acid
smilarity with Human FRAP1.
Rat (Rattus norvegicus): Frap1, 99% amino acid
similarity with Human FRAP1.
Dog (Canis familiaris): FRAP1, 99% amino acid
similarity with Human FRAP1.
Worm (Caenorhabditis elegans): B0261.2b, 51% amino
acid similarity with Human FRAP1.
Fruit fly (Drosophila melanogaster): Tor, 64% amino
acid similarity with Human FRAP1.
Mutations
Note
No mutations are reported to date.
Implicated in
Various cancers and hamartoma
syndromes
Note
Activation of mTOR signaling is associated with
several hamartoma syndromes, as well as in cancer.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5)
Altomare DA, Testa JR
350
FRAP1 (FK506 binding protein 12-rapamycin associated protein 1)
and a concomitant increase in intracellular AMP. Under
conditions of energy depletion, TSC2 is phosphorylated
and activated by AMPK, thereby inhibiting mTORC1
activity. Amino acid starvation also elicits a decrease in
mTORC1 activity through Rheb. Abundant evidence
suggests that a deregulation between signaling
components in the PI3K-AKT-TSC2-Rheb-mTORC1
pathway is a critical step in tumorigenesis. Tumor
suppressor genes involved in predisposition to
hamartomatous lesions are discussed above in the
Implicated Diseases section.
the AKT/mTOR pathway (Johannessen et al., 2005).
The mTOR inhibitor rapamycin has been shown to
suppress the growth of NF1-associated malignancies in
a genetically modified mouse model (Johannessen et
al., 2008). Like NF1, NF2 also can regulate
AKT/mTOR signaling (Scoles, 2008); the NF2encoded protein, merlin, does so by binding to PIKE
(phosphatidylinositol 3-kinase enhancer).
Germline inactivation of the von Hippel-Lindau tumor
suppressor gene (VHL) causes hamartomatous tumors
associated with the von-Hippel-Lindau syndrome.
Moreover, most renal cell carcinomas have biallelic
alterations in the von VHL gene, resulting in the
accumulation of hypoxia-inducible factors 1 and 2 , and
downstream targets including vascular endothelial
growth factor (VEGF) (Cho et al., 2007). The observed
clinical efficacy of mTOR inhibitors in patients with
renal cell carcinoma may be mediated in part by the
dependence of efficient hypoxia-inducible factor
translation.
Hybrid/Mutated gene
A schematic model of mTOR signaling depicts various
environmental and molecular interactions that influence
the pathway. mTOR protein exists in two functionally
distinct complexes named mTORC1 and mTORC2.
Components are described above, under the Protein
Function section. The classical phosphorylation
substrates of mTORC1 are S6 kinases and 4E-BP1,
although HIF1alpha and PRAS40 also have been
shown to have TOR signaling motifs. Because mTOR
is shared by both mTORC1 and mTORC2, there may
be equilibrium between the two complexes, as well as
competition for mTOR (Bhuskar and Hay, 2007).
Insulin and other growth factors activate mTORC1 via
activation of phosphatidylinositol 3-OH kinase (PI3K)
and downstream AKT. Constitutive activation of
mTORC1 can occur in the absence of TSC1 or TSC2.
Once mTORC1 is activated, it is able to elicit a
negative feedback loop to inhibit AKT activity. In
opposition, mTORC2 is an activator of AKT, which
places this pathway under both positive and negative
controls mediated by mTOR. In contrast to growth
factor activation of mTORC1, responses to cellular
stresses such as energy depletion and amino acid
deprivation are mediated by TSC1/2 and/or Rheb (Hay
and Sonenberg, 2004; Guertin and Sabatini, 2007).
AMPK is activated by reduced intracellular ATP levels
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5)
Altomare DA, Testa JR
Human malignant tumors
Note
Activation of mTOR signaling has been reported in
several types of human malignant tumors.
Clinical results have been reported for the mTOR
inhibitors CCI-799 (Wyeth), RAD001 (Novartis) and
AP23573 (Ariad Pharmaceuticals), all rapamycin
analogs (Guertin and Sabatini, 2007). Therapeutic
response is highly variable, suggesting that biomarkers
still are needed for predicting response to rapamycin
therapy. To date, some of the best clinical response
rates to rapamycin have been observed in patients
suffering from Kaposi's sarcoma or mantle-cell
lymphoma. Patients with renal cell carcinomas
exhibiting a nonclear cell histology also appear to
benefit from treatment with mTOR inhibitors (Hanna et
al., 2008). Patients with advanced sarcomas are yet
another subset of individuals that have benefited from
therapeutic mTOR inhibition (Wan and Helman, 2007).
Disease
Collectively, there are a number of mechanisms that
contribute to the deregulation of the AKT/mTOR
pathway in human malignant tumors (Altomare and
Testa, 2005; Wan and Helman, 2007). Phospho-AKT
immunohistochemical staining is frequently associated
with phospho-mTOR staining. mTOR has emerged as a
validated therapeutic target in cancer (Abraham and
Eng, 2008).
Specific to mTOR, mTORC2 activity was found to be
elevated in glioma cell lines and primary tumors as
compared with normal brain tissue (Masri et al., 2007).
Overexpression of Rictor increased mTORC2 activity,
anchorage-independent growth in soft agar, S-phase
cell cycle distribution, motility, and integrin
expression, whereas knockdown of Rictor inhibited
these events.
351
FRAP1 (FK506 binding protein 12-rapamycin associated protein 1)
Xenograft studies also supported a role for increased
mTORC2 activity in tumorigenesis and enhanced
tumor growth. PKCalpha activity was shown to be
dependent of Rictor-expression, consistent with the
known regulation of actin organization by mTORC2
via PKCalpha. Collectively, these data suggest that
mTORC2 is hyperactivated in gliomas and promotes
tumor cell proliferation and invasive potential due to
increased complex formation in the presence of
overexpressed Rictor.
Prognosis
Recent data suggest that inhibition of mTOR results in
clinical benefit in patients with poor prognostic
features, and in preclinical models this therapeutic
effect involves downregulation of HIF1alpha (Hanna et
al., 2008).
Disease
Ravikumar et al. (2004) showed that mTOR is
sequestered in polyglutamine aggregates in cell models,
transgenic mice, and human brains. Sequestration of
mTOR impaired its kinase activity and induced
autophagy, a key mechanism for clearance of mutant
huntingtin fragments to protect against polyglutamine
toxicity. Rapamycin also attenuated huntingtin
accumulation and cell death in cell models, and
inhibited autophagy. Furthermore, rapamycin protected
against neurodegeneration in a fly model, and the
rapamycin analog CCI-779 decreased aggregate
formation in a mouse model of Huntington disease.
References
Choi J, Chen J, Schreiber SL, Clardy J. Structure of the
FKBP12-rapamycin complex interacting with the binding
domain of human FRAP. Science. 1996 Jul 12;273(5272):23942
Huntington disease
Note
mTOR has been implicated in Huntington disease, an
inherited neurodegenerative disorder.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5)
Altomare DA, Testa JR
352
FRAP1 (FK506 binding protein 12-rapamycin associated protein 1)
Liang J, Choi J, Clardy J. Refined structure of the FKBP12rapamycin-FRB ternary complex at 2.2 A resolution. Acta
Crystallogr D Biol Crystallogr. 1999 Apr;55(Pt 4):736-44
growth and cell motility via overexpression of rictor. Cancer
Res. 2007 Dec 15;67(24):11712-20
Oshiro N, Takahashi R, Yoshino K, Tanimura K, Nakashima A,
Eguchi S, Miyamoto T, Hara K, Takehana K, Avruch J,
Kikkawa U, Yonezawa K. The proline-rich Akt substrate of 40
kDa (PRAS40) is a physiological substrate of mammalian
target of rapamycin complex 1. J Biol Chem. 2007 Jul
13;282(28):20329-39
Tucker M, Goldstein A, Dean M, Knudson A. National Cancer
Institute Workshop Report: the phakomatoses revisited. J Natl
Cancer Inst. 2000 Apr 5;92(7):530-3
Schalm SS, Blenis J. Identification of a conserved motif
required for mTOR signaling. Curr Biol. 2002 Apr 16;12(8):6329
Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jenö P,
Arrieumerlou C, Hall MN. PRAS40 and PRR5-like protein are
new mTOR interactors that regulate apoptosis. PLoS One.
2007 Nov 21;2(11):e1217
Hay N, Sonenberg N. Upstream and downstream of mTOR.
Genes Dev. 2004 Aug 15;18(16):1926-45
Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG,
Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC.
Inhibition of mTOR induces autophagy and reduces toxicity of
polyglutamine expansions in fly and mouse models of
Huntington disease. Nat Genet. 2004 Jun;36(6):585-95
Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH.
Insulin signalling to mTOR mediated by the Akt/PKB substrate
PRAS40. Nat Cell Biol. 2007 Mar;9(3):316-23
Wan X, Helman LJ. The biology behind mTOR inhibition in
sarcoma. Oncologist. 2007 Aug;12(8):1007-18
Altomare DA, Testa JR. Perturbations of the AKT signaling
pathway in human cancer. Oncogene. 2005 Nov
14;24(50):7455-64
Wang L, Harris TE, Roth RA, Lawrence JC Jr. PRAS40
regulates mTORC1 kinase activity by functioning as a direct
inhibitor of substrate binding. J Biol Chem. 2007 Jul
6;282(27):20036-44
Astrinidis A, Henske EP. Tuberous sclerosis complex: linking
growth and energy signaling pathways with human disease.
Oncogene. 2005 Nov 14;24(50):7475-81
Zeng Z, Sarbassov dos D, Samudio IJ, Yee KW, Munsell MF,
Ellen Jackson C, Giles FJ, Sabatini DM, Andreeff M,
Konopleva M. Rapamycin derivatives reduce mTORC2
signaling and inhibit AKT activation in AML. Blood. 2007 Apr
15;109(8):3509-12
Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSCmTOR pathway in human disease. Nat Genet. 2005
Jan;37(1):19-24
Johannessen CM, Reczek EE, James MF, Brems H, Legius E,
Cichowski K. The NF1 tumor suppressor critically regulates
TSC2 and mTOR. Proc Natl Acad Sci U S A. 2005 Jun
14;102(24):8573-8
Abraham RT, Eng CH. Mammalian target of rapamycin as a
therapeutic target in oncology. Expert Opin Ther Targets. 2008
Feb;12(2):209-22
Goncharova
EA,
Krymskaya
VP.
Pulmonary
lymphangioleiomyomatosis (LAM): progress and current
challenges. J Cell Biochem. 2008 Feb 1;103(2):369-82
Kwiatkowski DJ, Manning BD. Tuberous sclerosis: a GAP at
the crossroads of multiple signaling pathways. Hum Mol Genet.
2005 Oct 15;14 Spec No. 2:R251-8
Hanna SC, Heathcote SA, Kim WY. mTOR pathway in renal
cell carcinoma. Expert Rev Anticancer Ther. 2008
Feb;8(2):283-92
Avruch J, Hara K, Lin Y, Liu M, Long X, Ortiz-Vega S,
Yonezawa K. Insulin and amino-acid regulation of mTOR
signaling and kinase activity through the Rheb GTPase.
Oncogene. 2006 Oct 16;25(48):6361-72
Johannessen CM, Johnson BW, Williams SM, Chan AW,
Reczek EE, Lynch RC, Rioth MJ, McClatchey A, Ryeom S,
Cichowski K. TORC1 is essential for NF1-associated
malignancies. Curr Biol. 2008 Jan 8;18(1):56-62
Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY,
Moffat J, Brown M, Fitzgerald KJ, Sabatini DM. Ablation in
mice of the mTORC components raptor, rictor, or mLST8
reveals that mTORC2 is required for signaling to Akt-FOXO
and PKCalpha, but not S6K1. Dev Cell. 2006 Dec;11(6):859-71
Jozwiak J, Jozwiak S, Wlodarski P. Possible mechanisms of
disease development in tuberous sclerosis. Lancet Oncol.
2008 Jan;9(1):73-9
Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP,
Bagley AF, Markhard AL, Sabatini DM. Prolonged rapamycin
treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell.
2006 Apr 21;22(2):159-68
Krymskaya VP. Smooth muscle-like cells in pulmonary
lymphangioleiomyomatosis. Proc Am Thorac Soc. 2008 Jan
1;5(1):119-26
Bhaskar PT, Hay N. The two TORCs and Akt. Dev Cell. 2007
Apr;12(4):487-502
Pattingre S, Espert L, Biard-Piechaczyk M, Codogno P.
Regulation of macroautophagy by mTOR and Beclin 1
complexes. Biochimie. 2008 Feb;90(2):313-23
Cho D, Signoretti S, Regan M, Mier JW, Atkins MB. The role of
mammalian target of rapamycin inhibitors in the treatment of
advanced renal cancer. Clin Cancer Res. 2007 Jan 15;13(2 Pt
2):758s-763s
Scoles DR. The merlin interacting proteins reveal multiple
targets for NF2 therapy. Biochim Biophys Acta. 2008
Jan;1785(1):32-54
Guertin DA, Sabatini DM. Defining the role of mTOR in cancer.
Cancer Cell. 2007 Jul;12(1):9-22
Wei C, Amos CI, Zhang N, Wang X, Rashid A, Walker CL,
Behringer RR, Frazier ML. Suppression of Peutz-Jeghers
polyposis by targeting mammalian target of rapamycin
signaling. Clin Cancer Res. 2008 Feb 15;14(4):1167-71
Gustafson S, Zbuk KM, Scacheri C, Eng C. Cowden
syndrome. Semin Oncol. 2007 Oct;34(5):428-34
This article should be referenced as such:
Land SC, Tee AR. Hypoxia-inducible factor 1alpha is regulated
by the mammalian target of rapamycin (mTOR) via an mTOR
signaling motif. J Biol Chem. 2007 Jul 13;282(28):20534-43
Altomare DA, Testa JR. FRAP1 (FK506 binding protein 12rapamycin associated protein 1). Atlas Genet Cytogenet Oncol
Haematol. 2009; 13(5):348-353.
Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A,
Gera J. mTORC2 activity is elevated in gliomas and promotes
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5)
Altomare DA, Testa JR
353