Atlas of Genetics and Cytogenetics in Oncology and Haematology


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MTOR (FK506 binding protein 12-rapamycin associated protein 1)

Identity

Other namesFRAP1
FLJ44809
FRAP
FRAP2
MTOR
RAFT1
RAPT1
mTOR
HGNC (Hugo) MTOR
LocusID (NCBI) 2475
Location 1p36.22
Location_base_pair Starts at 11166588 and ends at 11322608 bp from pter ( according to hg19-Feb_2009)
 
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

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_000001.9&v=11081381..11252951
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.

Protein

 
  The amino acid residues corresponding to the FRAP1 (alias mTOR) protein domains are reported in pfam (see below: external links)
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)
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 protein-protein 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 (FKBP12-rapamycin 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).
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 FKBP12-rapamycin-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 .
 
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.
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 (4E-binding 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 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 (rapamycin-insensitive 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-cycle-dependent 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.
Homology mouse (Mus musculus): Frap1, 99 % Amino Acid Similarity 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

Entity Various cancers and hamartoma syndromes
Note Activation of mTOR signaling is associated with several hamartoma syndromes, as well as in cancer.
Disease Among the dominantly inherited disorders classified as phakomatoses are tuberous sclerosis 1 and 2, Peutz-Jeghers 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 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 NF2-encoded 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 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.
  
Entity 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. 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).
  
Entity Huntington disease
Note mTOR has been implicated in Huntington disease, an inherited neurodegenerative disorder.
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.
  

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors ProstateOverviewID5041 ProstateOverviewID5041 ProstateOverviewID5041 ProstateOverviewID5041

External links

Nomenclature
HGNC (Hugo)MTOR   3942
Cards
AtlasFRAP1ID40639ch1p36
Entrez_Gene (NCBI)MTOR  2475  mechanistic target of rapamycin (serine/threonine kinase)
GeneCards (Weizmann)MTOR
Ensembl (Hinxton)ENSG00000198793 [Gene_View]  chr1:11166588-11322608 [Contig_View]  MTOR [Vega]
ICGC DataPortalENSG00000198793
cBioPortalMTOR
AceView (NCBI)MTOR
Genatlas (Paris)MTOR
WikiGenes2475
SOURCE (Princeton)NM_004958
Genomic and cartography
GoldenPath (UCSC)MTOR  -  1p36.22   chr1:11166588-11322608 -  1p36   [Description]    (hg19-Feb_2009)
EnsemblMTOR - 1p36 [CytoView]
Mapping of homologs : NCBIMTOR [Mapview]
OMIM601231   
Gene and transcription
Genbank (Entrez)AA725390 AB209995 AK126762 AK302863 AK304273
RefSeq transcript (Entrez)NM_004958
RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NG_033239 NT_032977 NW_001838534 NW_004929289
Consensus coding sequences : CCDS (NCBI)MTOR
Cluster EST : UnigeneHs.338207 [ NCBI ]
CGAP (NCI)Hs.338207
Alternative Splicing : Fast-db (Paris)GSHG0001749
Alternative Splicing GalleryENSG00000198793
Gene ExpressionMTOR [ NCBI-GEO ]     MTOR [ SEEK ]   MTOR [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP42345 (Uniprot)
NextProtP42345  [Medical]
With graphics : InterProP42345
Splice isoforms : SwissVarP42345 (Swissvar)
Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)FAT (PS51189)    FATC (PS51190)    PI3_4_KINASE_1 (PS00915)    PI3_4_KINASE_2 (PS00916)    PI3_4_KINASE_3 (PS50290)   
Domains : Interpro (EBI)ARM-like [organisation]   ARM-type_fold [organisation]   DUF3385_TOR [organisation]   FATC [organisation]   Kinase-like_dom [organisation]   PI3/4_kinase_cat_dom [organisation]   PI3/4_kinase_CS [organisation]   PIK-rel_kinase_FAT [organisation]   PIK_FAT [organisation]   Rapamycin-bd_dom [organisation]   TPR-like_helical [organisation]  
Related proteins : CluSTrP42345
Domain families : Pfam (Sanger)DUF3385 (PF11865)    FAT (PF02259)    FATC (PF02260)    PI3_PI4_kinase (PF00454)    Rapamycin_bind (PF08771)   
Domain families : Pfam (NCBI)pfam11865    pfam02259    pfam02260    pfam00454    pfam08771   
Domain families : Smart (EMBL)PI3Kc (SM00146)  
DMDM Disease mutations2475
Blocks (Seattle)P42345
PDB (SRS)1AUE    1FAP    1NSG    2FAP    2GAQ    2NPU    2RSE    3FAP    4DRH    4DRI    4DRJ    4FAP    4JSN    4JSP    4JSV    4JSX    4JT5    4JT6   
PDB (PDBSum)1AUE    1FAP    1NSG    2FAP    2GAQ    2NPU    2RSE    3FAP    4DRH    4DRI    4DRJ    4FAP    4JSN    4JSP    4JSV    4JSX    4JT5    4JT6   
PDB (IMB)1AUE    1FAP    1NSG    2FAP    2GAQ    2NPU    2RSE    3FAP    4DRH    4DRI    4DRJ    4FAP    4JSN    4JSP    4JSV    4JSX    4JT5    4JT6   
PDB (RSDB)1AUE    1FAP    1NSG    2FAP    2GAQ    2NPU    2RSE    3FAP    4DRH    4DRI    4DRJ    4FAP    4JSN    4JSP    4JSV    4JSX    4JT5    4JT6   
Human Protein AtlasENSG00000198793 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP42345
HPRD03134
IPIIPI00031410   IPI01015128   IPI00643451   IPI00642946   
Protein Interaction databases
DIP (DOE-UCLA)P42345
IntAct (EBI)P42345
FunCoupENSG00000198793
BioGRIDMTOR
InParanoidP42345
Interologous Interaction database P42345
IntegromeDBMTOR
STRING (EMBL)MTOR
Ontologies - Pathways
Ontology : AmiGOGolgi membrane  RNA polymerase III type 1 promoter DNA binding  RNA polymerase III type 2 promoter DNA binding  RNA polymerase III type 3 promoter DNA binding  TFIIIC-class transcription factor binding  positive regulation of protein phosphorylation  positive regulation of endothelial cell proliferation  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  cytoplasm  mitochondrial outer membrane  lysosome  lysosomal membrane  endoplasmic reticulum membrane  cytosol  phosphatidylinositol 3-kinase complex  regulation of glycogen biosynthetic process  protein phosphorylation  protein phosphorylation  response to stress  signal transduction  epidermal growth factor receptor signaling pathway  germ cell development  response to nutrient  drug binding  insulin receptor signaling pathway  fibroblast growth factor receptor signaling pathway  negative regulation of autophagy  positive regulation of lamellipodium assembly  positive regulation of gene expression  positive regulation of myotube differentiation  endomembrane system  membrane  cell growth  cell growth  negative regulation of macroautophagy  kinase activity  kinase activity  phosphorylation  PML body  peptidyl-serine phosphorylation  peptidyl-threonine phosphorylation  protein domain specific binding  protein catabolic process  positive regulation of actin filament polymerization  T cell costimulation  ruffle organization  cellular response to nutrient levels  TOR signaling  TORC1 complex  TORC1 complex  TORC2 complex  regulation of fatty acid beta-oxidation  regulation of response to food  regulation of Rac GTPase activity  regulation of actin cytoskeleton organization  Fc-epsilon receptor signaling pathway  growth  ribosome binding  response to amino acid  regulation of carbohydrate utilization  innate immune response  positive regulation of translation  negative regulation of cell size  regulation of protein kinase activity  positive regulation of transcription from RNA polymerase III promoter  protein autophosphorylation  positive regulation of lipid biosynthetic process  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  positive regulation of peptidyl-tyrosine phosphorylation  phosphoprotein binding  positive regulation of stress fiber assembly  negative regulation of NFAT protein import into nucleus  positive regulation of protein kinase B signaling  mTOR-FKBP12-rapamycin complex  cellular response to hypoxia  
Ontology : EGO-EBIGolgi membrane  RNA polymerase III type 1 promoter DNA binding  RNA polymerase III type 2 promoter DNA binding  RNA polymerase III type 3 promoter DNA binding  TFIIIC-class transcription factor binding  positive regulation of protein phosphorylation  positive regulation of endothelial cell proliferation  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  cytoplasm  mitochondrial outer membrane  lysosome  lysosomal membrane  endoplasmic reticulum membrane  cytosol  phosphatidylinositol 3-kinase complex  regulation of glycogen biosynthetic process  protein phosphorylation  protein phosphorylation  response to stress  signal transduction  epidermal growth factor receptor signaling pathway  germ cell development  response to nutrient  drug binding  insulin receptor signaling pathway  fibroblast growth factor receptor signaling pathway  negative regulation of autophagy  positive regulation of lamellipodium assembly  positive regulation of gene expression  positive regulation of myotube differentiation  endomembrane system  membrane  cell growth  cell growth  negative regulation of macroautophagy  kinase activity  kinase activity  phosphorylation  PML body  peptidyl-serine phosphorylation  peptidyl-threonine phosphorylation  protein domain specific binding  protein catabolic process  positive regulation of actin filament polymerization  T cell costimulation  ruffle organization  cellular response to nutrient levels  TOR signaling  TORC1 complex  TORC1 complex  TORC2 complex  regulation of fatty acid beta-oxidation  regulation of response to food  regulation of Rac GTPase activity  regulation of actin cytoskeleton organization  Fc-epsilon receptor signaling pathway  growth  ribosome binding  response to amino acid  regulation of carbohydrate utilization  innate immune response  positive regulation of translation  negative regulation of cell size  regulation of protein kinase activity  positive regulation of transcription from RNA polymerase III promoter  protein autophosphorylation  positive regulation of lipid biosynthetic process  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  positive regulation of peptidyl-tyrosine phosphorylation  phosphoprotein binding  positive regulation of stress fiber assembly  negative regulation of NFAT protein import into nucleus  positive regulation of protein kinase B signaling  mTOR-FKBP12-rapamycin complex  cellular response to hypoxia  
Pathways : BIOCARTACTCF: First Multivalent Nuclear Factor [Genes]    Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway [Genes]    mTOR Signaling Pathway [Genes]    B Cell Survival Pathway [Genes]    Regulation of eIF4e and p70 S6 Kinase [Genes]    Stat3 Signaling Pathway [Genes]   
Pathways : KEGGErbB signaling pathway    HIF-1 signaling pathway    mTOR signaling pathway    PI3K-Akt signaling pathway    Insulin signaling pathway    Thyroid hormone signaling pathway    Adipocytokine signaling pathway    Type II diabetes mellitus    Pathways in cancer    Proteoglycans in cancer    MicroRNAs in cancer    Glioma    Prostate cancer    Acute myeloid leukemia   
Protein Interaction DatabaseMTOR
Wikipedia pathwaysMTOR
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)MTOR
snp3D : Map Gene to Disease2475
SNP (GeneSNP Utah)MTOR
SNP : HGBaseMTOR
Genetic variants : HAPMAPMTOR
Exome VariantMTOR
1000_GenomesMTOR 
ICGC programENSG00000198793 
Somatic Mutations in Cancer : COSMICMTOR 
CONAN: Copy Number AnalysisMTOR 
Mutations and Diseases : HGMDMTOR
Genomic VariantsMTOR  MTOR [DGVbeta]
dbVarMTOR
ClinVarMTOR
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM601231   
MedgenMTOR
GENETestsMTOR
Disease Genetic AssociationMTOR
Huge Navigator MTOR [HugePedia]  MTOR [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneMTOR
Homology/Alignments : Family Browser (UCSC)MTOR
Phylogenetic Trees/Animal Genes : TreeFamMTOR
Chemical/Protein Interactions : CTD2475
Chemical/Pharm GKB GenePA28360
Clinical trialMTOR
Cancer Resource (Charite)ENSG00000198793
Other databases
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=MTOR
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
CoreMineMTOR
iHOPMTOR
OncoSearchMTOR

Bibliography

Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP.
Choi J, Chen J, Schreiber SL, Clardy J.
Science. 1996; 273(5272):239-242.
PMID 8662507
 
Refined structure of the FKBP12-rapamycin-FRB ternary complex at 2.2 A resolution.
Liang J, Choi J, Clardy J.
Acta Crystallogr D Biol Crystallogr. 1999; 55(Pt 4):736-744.
PMID 10089303
 
National Cancer Institute Workshop Report: the phakomatoses revisited.
Tucker M, Goldstein A, Dean M, Knudson A.
J Natl Cancer Inst. 2000; 92(7):530-533.
PMID 10749907
 
Identification of a conserved motif required for mTOR signaling.
Shalm SS, Blenis J.
Curr Biol. 2002; 12(8):632-639.
PMID 11967149
 
Upstream and downstream of mTOR.
Hay N, Sonenberg N.
Genes Dev. 2004; 18(16):1926-1945. (Review)
PMID 15314020
 
Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease.
Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC.
Nature Genet. 2004; 36:585-596.
PMID 15146184
 
Perturbations of the AKT signaling pathway in human cancer.
Altomare DA, Testa JR.
Oncogene. 2005; 24(50):7455-7464. (Review)
PMID 16288292
 
Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease.
Astrinidis A, Henske EP.
Oncogene. 2005; 24(50):7475-7481. (Review)
PMID 16288294
 
Dysregulation of the TSC-mTOR pathway in human disease.
Inoki K, Corradetti MN, Guan KL.
Nat Genet. 2005; 37(1):19-24. (Review)
PMID 15624019
 
The NF1 tumor suppressor critically regulates TSC2 and mTOR.
Johannessen CM, Reczek EE, James MF, Brems H, Legius E, Cichowski K.
Proc Natl Acad Sci U S A. 2005; 102(24):8573-8578. (Review)
PMID 15937108
 
Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways.
Kwiatkowski DJ, Manning BD.
Hum Mol Genet. 2005; 14 Spec No. 2:R251-R258. (Review)
PMID 16244323
 
Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase.
Avruch J, Hara K, Lin Y, Liu M, Long X, Ortiz-Vega S, Yonezawa K.
Oncogene. 2006; 25(48):6361-6372. (Review)
PMID 17041622
 
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.
Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM.
Dev Cell. 2006; 11(6):859-871.
PMID 17141160
 
Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB.
Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM.
Mol Cell. 2006; 22(2):159-168.
PMID 16603397
 
The two TORCs and Akt.
Bhaskar PT, Hay N.
Dev Cell. 2007; 12(4):487-502. (Review)
PMID 17419990
 
The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer.
Cho D, Signoretti S, Regan M, Mier JW, Atkins MB.
Clin Cancer Res. 2007; 13(2 Pt 2):758s-763s. (Review)
PMID 17255306
 
Defining the role of mTOR in cancer.
Guertin DA, Sabatini DM.
Cancer Cell. 2007; 12(1):9-22. (Review)
PMID 17613433
 
The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1.
Oshiro N, Takahashi R, Yoshino K, Tanimura K, Nakashima A, Eguchi S, Miyamoto T, Hara K, Takehana K, Avruch J, Kikkawa U, Yonezawa K.
J Biol Chem. 2007; 282(28): 20329-20339.
PMID 17517883
 
Cowden syndrome.
Gustafson S, Zbuk KM, Scacheri C, Eng C.
Semin Oncol. 2007; 34(5):428-434. (Review)
PMID 17920899
 
Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif.
Land SC, Tee AR.
J Biol Chem. 2007: 282(28):20534-20543.
PMID 17502379
 
MTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor.
Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A, Gera J.
Cancer Res. 2007; 67(24):11712-11720.
PMID 18089801
 
PRAS40 and PRR5-Like Protein Are New mTOR Interactors that Regulate Apoptosis.
Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jenö P, Arrieumerlou C, Hall MN.
PLoS ONE. 2007; 2(11):e1217.
PMID 18030348
 
Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40.
Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH.
Nat Cell Biol. 2007; 9(3):316-323.
PMID 17277771
 
The biology behind mTOR inhibition in sarcoma.
Wan X, Helman LJ.
Oncologist. 2007; 12(8):1007-1018.
PMID 17766661
 
PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding.
Wang L, Harris TE, Roth RA, Lawrence JC Jr.
J Biol Chem. 2007; 282(27):20036-20044.
PMID 17510057
 
Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML.
Zeng Z, Sarbassov dos D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, Giles FJ, Sabatini DM, Andreeff M, Konopleva M.
Blood. 2007; 109(8):3509-3512.
PMID 17179228
 
Mammalian target of rapamycin as a therapeutic target in oncology.
Abraham RT, Eng CH.
Expert Opin Ther Targets. 2008; 12(2):209-222. (Review)
PMID 18208369
 
Pulmonary lymphangioleiomyomatosis (LAM): progress and current challenges.
Goncharova EA, Krymskaya VP.
J Cell Biochem. 2008; 102(2):369-382. (Review)
PMID 17541983
 
mTOR pathway in renal cell carcinoma.
Hanna SC, Heathcote SA, Kim WY.
Expert Rev Anticancer Ther. 2008; 8(2):283-92. (Review)
PMID 18279068
 
TORC1 is essential for NF1-associated malignancies.
Johannessen CM, Johnson BW, Williams SM, Chan AW, Reczek EE, Lynch RC, Rioth MJ, McClatchey A, Ryeom S, Cichowski K.
Curr Biol. 2008; 18(1):56-62. (Review)
PMID 18164202
 
Possible mechanisms of disease development in tuberous sclerosis.
Jozwiak J, Jozwiak S, Wlodarski P.
Lancet Oncol. 2008; 9(1):73-79. (Review)
PMID 18177819
 
Smooth muscle-like cells in pulmonary lymphangioleiomyomatosis.
Krymskaya VP.
Proc Am Thorac Soc. 2008; 5(1):119-126. (Review)
PMID 18094094
 
Regulation of macroautophagy by mTOR and Beclin 1 complexes.
Pattingre S, Espert L, Biard-Piechaczyk M, Codogno P.
Biochimie. 2008; 90(2):313-323. (Review)
PMID 17928127
 
The merlin interacting proteins reveal multiple targets for NF2 therapy.
Scoles DR.
Biochim Biophys Acta. 2008; 1785(1):32-54. (Review)
PMID 17980164
 
Suppression of Peutz-Jeghers polyposis by targeting mammalian target of rapamycin signaling.
Wei C, Amos CI, Zhang N, Wang X, Rashid A, Walker CL, Behringer RR, Frazier ML.
Clin Cancer Res. 2008; 14(4):1167-1171.
PMID 18281551
 
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Written06-2008Deborah A Altomare, Joseph R Testa
Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA

Citation

This paper should be referenced as such :
Altomare, DA ; Testa, JR
FRAP1 (FK506 binding protein 12-rapamycin associated protein 1)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(5):348-353.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/FRAP1ID40639ch1p36.html

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