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Organic anions and cations (OAs., Dantzler WH. PKC regulation of organic anion secretion., Ganapathy V, Wu X, Hui J, Seth P, Yuen PM, Wanders RJ, Fok TF.
PKC '83 - Berkum 3-0 WHC - SC Genemuiden 1-0. STAND. 1. FOK!sport mag in samenwerking met Uitgeverij Nieuw Amsterdam vijf. Vitamin D and Human Reproduction | InTechOpen. weight infants only among infants that were either homozygous for the FokI major allele or. PK. Vitamin D. The mechanistic target of rapamycin (mTOR). RICTOR: Overexpression leads to metastasis and knockdown inhibits growth factor-induced PKC-phosphorylation.
Mechanistic target of rapamycin - Wikipedia. MTORAvailable structures. PDBOrtholog search: PDBe.
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RCSBList of PDB id codes. JT6, 1. AUE, 1. FAP, 1. NSG, 2. FAP, 2. GAQ, 2.
NPU, 2. RSE, 3. FAP, 4. DRH, 4. DRI, 4. DRJ, 4. FAP, 4. JSN, 4. JSP, 4. JSV, 4. JSX, 4. JT5, 5. FLCIdentifiers. Aliases. MTOR, FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS, mechanistic target of rapamycin, mechanistic target of rapamycin kinase. External IDs. OMIM: 6.
MGI: 1. 92. 83. 94. Homolo. Gene: 3. 63. Gene. Cards: MTOROrthologs. Species. Human. Mouse. Entrez. Ensembl. Uni. Prot. Ref. Seq (m.
Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are.
RNA)Ref. Seq (protein)Location (UCSC)Chr 1: 1. Mb. Chr 1: 1. 48. Mb. Pub. Med search[3][4]Wikidata. The mechanistic target of rapamycin (m. TOR), also known as the mammalian target of rapamycin and FK5. FRAP1), is a kinase that in humans is encoded by the MTORgene.[5][6][7] m.
TOR is a member of the phosphatidylinositol 3- kinase- related kinase family of protein kinases.[8]m. TOR links with other proteins and serves as a core component of two distinct protein complexes, m. TOR complex 1 and m.
TOR complex 2, which regulate different cellular processes.[9] In particular, as a core component of both complexes, m. TOR functions as a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription.[9][1. As a core component of m. TORC2, m. TOR also functions as a tyrosine protein kinase that promotes the activation of insulin receptors and insulin- like growth factor 1 receptors.[1.
TORC2 has also been implicated in the control and maintenance of the actin cytoskeleton.[9][1. Discovery[edit]The discovery of TOR and m. TOR stemmed from independent studies of the natural product rapamycin by Joseph Heitman, Rao Movva, and Michael N. Hall, and by Stuart L. Schreiber, David M.
Sabatini, and Robert T. Abraham.[1. 3][6][7] In 1.
George Livi and Michael N. Hall independently cloned genes that mediate the toxicity of rapamycin in fungi, known as the TOR/DRR genes.[1. However, the molecular target of the FKBP1.
In 1. 99. 4, Stuart L. Schreiber, David M. Sabatini and Robert T.
Abraham independently discovered a protein that directly interacts with FKBP1. TOR due to its homology to the yeast TOR/DRR genes.[5][6][7]Rapamycin arrests fungal activity at the G1 phase of the cell cycle. In mammals, it suppresses the immune system by blocking the G1 to S phase transition in T- lymphocytes.[1.
Thus, it is used as an immunosuppressant following organ transplantation.[1. Interest in rapamycin was renewed following the discovery of the structurally related immunosuppressive natural product FK5. In 1. 98. 9- 9. 0, FK5. T- cell receptor (TCR) and IL- 2 receptor signaling pathways, respectively.[1. The two natural products were used to discover the FK5. FKBP1. 2, and to provide evidence that FKBP1.
FK5. 06 and FKBP1. These investigations included key studies by Francis Dumont and Nolan Sigal at Merck contributing to show that FK5. These studies implicated FKBP1. In 1. 99. 1, calcineurin was identified as the target of FKBP1.
FK5. 06.[2. 4] That of FKBP1. FKBP1. 2 as the target of rapamycin, and implicated TOR1 and TOR2 as the targets of FKBP1. TOR kinase as its direct target in mammalian tissuess.[5][6][1. Sequence analysis of m. TOR revealed similarity to the proteins encoded by the yeast target of rapamycin 1 and 2 (TOR1 and TOR2) genes, which Joseph Heitman, Rao Movva, and Michael N. Hall had identified in August 1. May 1. 99. 3. Independently, George Livi and colleagues later reported the same genes, which they called dominant rapamycin resistance 1 and 2 (DRR1 and DRR2), in studies published in October 1.
The protein now called m. TOR was originally named FRAP by Stuart L.
Schreiber and RAFT1 by David M. Sabatini; [5][6]FRAP1 was used as its official gene symbol in humans. Because of these different names, m. TOR, which had been first used by Robert T. Abraham,[5] was increasingly adopted by the community of scientists working on the m. TOR pathway to refer to the protein and in homage to the original discovery of the TOR protein in yeast that was named TOR, the Target of Rapamycin, by Joe Heitman, Rao Movva, and Mike Hall.
TOR was originally discovered at the Biozentrum and Sandoz Pharmaceuticals in 1. Basel, Switzerland, and the name TOR pays further homage to this discovery, as TOR means doorway or gate in German, and the city of Basel was once ringed by a wall punctuated with gates into the city, including the iconic Spalentor.[2. Similarly, with subsequent discoveries the zebra fish TOR was named z. TOR, the Arabidopsis thaliana TOR was named At. TOR, and the Drosophila TOR was named d. TOR. In 2. 00. 9 the FRAP1 gene name was officially changed by the HUGO Gene Nomenclature Committee (HGNC) to m. TOR, which stands for mechanistic target of rapamycin.
The discovery of TOR and the subsequent identification of m. TOR opened the door to the molecular and physiological study of what is now called the m.
TOR pathway and had a catalytic effect on the growth of the field of chemical biology, where small molecules are used as probes of biology. Function[edit]MTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF- 1 and IGF- 2), and amino acids.[1. TOR also senses cellular nutrient, oxygen, and energy levels.[2. The m. TOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.[2.
Rapamycin inhibits m. TOR by associating with its intracellular receptor FKBP1. The FKBP1. 2- rapamycin complex binds directly to the FKBP1. Rapamycin Binding (FRB) domain of m.
TOR, inhibiting its activity.[3. Complexes[edit]. Schematic components of the m.
TOR complexes, m. TORC1 (left) and m. TORC2 (right). FKBP1. TORC1.[9]MTOR is the catalytic subunit of two structurally distinct complexes: m. TORC1 and m. TORC2.[3.
Both complexes localize to different subcellular compartments, thus affecting their activation and function.[3. TOR Complex 1 (m. TORC1) is composed of MTOR, regulatory- associated protein of MTOR (Raptor), mammalian lethal with SEC1. MLST8) and the non- core components PRAS4. DEPTOR.[3. 4][3. 5] This complex functions as a nutrient/energy/redox sensor and controls protein synthesis.[1. The activity of m. TORC1 is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.
L- leucine and β- hydroxy β- methylbutyric acid), mechanical stimuli, and oxidative stress.[3. TOR Complex 2 (m.
TORC2) is composed of MTOR, rapamycin- insensitive companion of MTOR (RICTOR), MLST8, and mammalian stress- activated protein kinase interacting protein 1 (m. SIN1).[3. 8][3. 9] m. TORC2 has been shown to function as an important regulator of the actin cytoskeleton through its stimulation of F- actin stress fibers, paxillin, Rho. A, Rac. 1, Cdc. 42, and protein kinase C α (PKCα).[3. TORC2 also phosphorylates the serine/threonine protein kinase Akt/PKB on serine residue Ser.
Phosphorylation of Akt's serine residue Ser. TORC2 stimulates Akt phosphorylation on threonine residue Thr. PDK1 and leads to full Akt activation.[4.
In addition, m. TORC2 exhibits tyrosine protein kinase activity and phosphorylates the insulin- like growth factor 1 receptor (IGF- IR) and insulin receptor (Ins. R) on the tyrosine residues Tyr. Tyr. 11. 46/1. 15. IGF- IR and Ins. R.[1. Inhibition by rapamycin[edit]Rapamycin inhibits m.
TORC1, and this appears to provide most of the beneficial effects of the drug (including life- span extension in animal studies). Rapamycin has a more complex effect on m. TORC2, inhibiting it only in certain cell types under prolonged exposure. Disruption of m. TORC2 produces the diabetic- like symptoms of decreased glucose tolerance and insensitivity to insulin.[4. Gene deletion experiments[edit]The m.