The target of rapamycin (TOR) proteins

Rapamycin potently inhibits downstream signaling from the target of rapamycin (TOR) proteins. These evolutionarily conserved protein kinases coordinate the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. The TOR proteins regulate (i) the initiation and elongation phases of translation, (ii) ribosome biosynthesis, (iii) amino acid import, (iv) the transcription of numerous enzymes involved in multiple metabolic pathways, and (v) autophagy. Intriguingly, recent studies have also suggested that TOR signaling plays a critical role in brain development, learning, and memory formation.

[1]  S. Sehgal,et al.  Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. , 1975, The Journal of antibiotics.

[2]  L. Paavola.  The corpus luteum of the guinea pig. III. Cytochemical studies on the Golgi complex and GERL during normal postpartum regression of luteal cells, emphasizing the origin of lysosomes and autophagic vacuoles , 1978, The Journal of cell biology.

[3]  R. Traut,et al.  Phosphorylation of eukaryotic protein synthesis initiation factors. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[4]  E. McConkey,et al.  Evidence for control of protein synthesis in HeLa cells via the elongation rate , 1980, Journal of cellular physiology.

[5]  W. Levy,et al.  Preferential localization of polyribosomes under the base of dendritic spines in granule cells of the dentate gyrus , 1982, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[6]  W. Walden,et al.  Effect of medium hypertonicity on reovirus translation rates. An application of kinetic modeling in vivo. , 1985, Biochemistry.

[7]  J. Hershey,et al.  Regulation of initiation factors during translational repression caused by serum depletion. Covalent modification. , 1985, The Journal of biological chemistry.

[8]  Philip Goelet,et al.  The long and the short of long–term memory—a molecular framework , 1986, Nature.

[9]  W. Walden,et al.  Translational control of gene expression in a normal fibroblast. Characterization of a subclass of mRNAs with unusual kinetic properties. , 1986, Biochemistry.

[10]  J. Lamborghini,et al.  Disappearance of Rohon‐Beard neurons from the spinal cord of larval Xenopus laevis , 1987, The Journal of comparative neurology.

[11]  Nolan H. Sigal,et al.  A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin , 1989, Nature.

[12]  A. Nairn,et al.  Thrombin and histamine stimulate the phosphorylation of elongation factor 2 in human umbilical vein endothelial cells. , 1989, The Journal of biological chemistry.

[13]  S. Morley,et al.  Phorbol esters stimulate phosphorylation of eukaryotic initiation factors 3, 4B, and 4F. , 1989, The Journal of biological chemistry.

[14]  S. Schreiber,et al.  A receptor for the immuno-suppressant FK506 is a cis–trans peptidyl-prolyl isomerase , 1989, Nature.

[15]  N. Sigal,et al.  The cytosolic-binding protein for the immunosuppressant FK-506 is both a ubiquitous and highly conserved peptidyl-prolyl cis-trans isomerase. , 1990, The Journal of biological chemistry.

[16]  S. Morley,et al.  Differential stimulation of phosphorylation of initiation factors eIF-4F, eIF-4B, eIF-3, and ribosomal protein S6 by insulin and phorbol esters. , 1990, The Journal of biological chemistry.

[17]  N. Sonenberg,et al.  Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F , 1990, Molecular and cellular biology.

[18]  J. Heitman,et al.  Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast , 1991, Science.

[19]  G. Scheper,et al.  Eukaryotic initiation factors-4E and -4F stimulate 5' cap-dependent as well as internal initiation of protein synthesis. , 1992, The Journal of biological chemistry.

[20]  O. Steward,et al.  Demonstration of local protein synthesis within dendrites using a new cell culture system that permits the isolation of living axons and dendrites from their cell bodies , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  W. Rychlik,et al.  Amino acid sequence of the human protein synthesis initiation factor eIF-4 gamma. , 1992, The Journal of biological chemistry.

[22]  J. Kunz,et al.  Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression , 1993, Cell.

[23]  M. Mclaughlin,et al.  Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity , 1993, Molecular and cellular biology.

[24]  I. Weiler,et al.  Metabotropic glutamate receptors trigger postsynaptic protein synthesis. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[25]  A. Triller,et al.  Gephyrin antisense oligonucleotides prevent glycine receptor clustering in spinal neurons , 1993, Nature.

[26]  L. Schwartz,et al.  Do all programmed cell deaths occur via apoptosis? , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Stuart L. Schreiber,et al.  A mammalian protein targeted by G1-arresting rapamycin–receptor complex , 1994, Nature.

[28]  A. Gingras,et al.  Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function , 1994, Nature.

[29]  RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Paul Tempst,et al.  RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs , 1994, Cell.

[31]  N. Sonenberg,et al.  PHAS-I as a link between mitogen-activated protein kinase and translation initiation. , 1994, Science.

[32]  K. Nakanishi,et al.  A putative sirolimus (rapamycin) effector protein. , 1994, Biochemical and biophysical research communications.

[33]  J. Kunz,et al.  TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. , 1994, Molecular biology of the cell.

[34]  P. B. Mahajan.  Modulation of transcription of rRNA genes by rapamycin. , 1994, International journal of immunopharmacology.

[35]  R. Abraham,et al.  Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells (*) , 1995, The Journal of Biological Chemistry.

[36]  T. Hunter,et al.  When is a lipid kinase not a lipid kinase? When it is a protein kinase , 1995, Cell.

[37]  The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins. , 1995, Molecular and cellular biology.

[38]  K. Maeda,et al.  Molecular cloning of a cDNA clone encoding a phosphoprotein component related to the Ig receptor-mediated signal transduction. , 1995, Journal of immunology.

[39]  A. Meijer,et al.  Phosphorylation of Ribosomal Protein S6 Is Inhibitory for Autophagy in Isolated Rat Hepatocytes (*) , 1995, The Journal of Biological Chemistry.

[40]  N. Sonenberg,et al.  Translational control of gene expression , 2000 .

[41]  N. Sonenberg,et al.  Repression of cap‐dependent translation by 4E‐binding protein 1: competition with p220 for binding to eukaryotic initiation factor‐4E. , 1995, The EMBO journal.

[42]  S. Schreiber,et al.  PIK-Related Kinases: DNA Repair, Recombination, and Cell Cycle Checkpoints , 1995, Science.

[43]  A. Nairn,et al.  Inhibition of Tumor Necrosis Factor Signal Transduction in Endothelial Cells by Dimethylaminopurine* , 1996, The Journal of Biological Chemistry.

[44]  W. Sossin.  Mechanisms for the generation of synapse specificity in long-term memory: the implications of a requirement for transcription. , 1996, Trends in Neurosciences.

[45]  J. Brosius,et al.  Translational Machinery in Dendrites of Hippocampal Neurons in Culture , 1996, Journal of Neuroscience.

[46]  C. Proud,et al.  Regulation of translation elongation factor‐2 by insulin via a rapamycin‐sensitive signalling pathway. , 1996, The EMBO journal.

[47]  D. Templeton,et al.  Constitutive activation of S6 kinase by deletion of amino-terminal autoinhibitory and rapamycin sensitivity domains , 1996, Molecular and cellular biology.

[48]  G. Thomas,et al.  The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases , 1996, Molecular and cellular biology.

[49]  K. Arndt,et al.  Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. , 1996, Genes & development.

[50]  E. Kandel,et al.  Toward a molecular definition of long-term memory storage. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[51]  A. Simm,et al.  Okadaic acid induces cellular hypertrophy in AKR-2B fibroblasts: involvement of the p70S6 kinase in the onset of protein and rRNA synthesis. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[52]  E. Schuman,et al.  A Requirement for Local Protein Synthesis in Neurotrophin-Induced Hippocampal Synaptic Plasticity , 1996, Science.

[53]  R. Abraham,et al.  Immunopharmacology of rapamycin. , 1996, Annual review of immunology.

[54]  I. Stansfield,et al.  An MBoC Favorite: TOR controls translation initiation and early G1 progression in yeast , 2012, Molecular biology of the cell.

[55]  E. Kandel,et al.  Synapse-Specific, Long-Term Facilitation of Aplysia Sensory to Motor Synapses: A Function for Local Protein Synthesis in Memory Storage , 1997, Cell.

[56]  G. Thomas,et al.  TOR signalling and control of cell growth. , 1997, Current opinion in cell biology.

[57]  David R. Kaplan,et al.  Regulation of Neuronal Survival by the Serine-Threonine Protein Kinase Akt , 1997, Science.

[58]  Jun Wu,et al.  B cell receptor-associated protein α4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A , 1997 .

[59]  A. Nairn,et al.  Glutamate-Dependent Phosphorylation of Elongation Factor-2 and Inhibition of Protein Synthesis in Neurons , 1997, The Journal of Neuroscience.

[60]  M. Hoekstra.  Responses to DNA damage and regulation of cell cycle checkpoints by the ATM protein kinase family. , 1997, Current opinion in genetics & development.

[61]  Expression and chromosomal localization of the human alpha 4/IGBP1 gene, the structure of which is closely related to the yeast TAP42 protein of the rapamycin-sensitive signal transduction pathway. , 1997, Genomics.

[62]  Y. Agid,et al.  Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. , 1997, Histology and histopathology.

[63]  J. Traugh,et al.  Phosphorylation of Elongation Factor 1 and Ribosomal Protein S6 by Multipotential S6 Kinase and Insulin Stimulation of Translational Elongation* , 1997, The Journal of Biological Chemistry.

[64]  Christine C. Hudson,et al.  Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. , 1997, Science.

[65]  A. Nairn,et al.  N-methyl-D-aspartate receptor activation and visual activity induce elongation factor-2 phosphorylation in amphibian tecta: a role for N-methyl-D-aspartate receptors in controlling protein synthesis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[66]  M. Polymenis,et al.  Coupling of cell division to cell growth by translational control of the G1 cyclin CLN3 in yeast. , 1997, Genes & development.

[67]  E. Garí,et al.  The Cln3 cyclin is down‐regulated by translational repression and degradation during the G1 arrest caused by nitrogen deprivation in budding yeast , 1997, The EMBO journal.

[68]  H. Sanjo,et al.  Ig receptor binding protein 1 (alpha4) is associated with a rapamycin-sensitive signal transduction in lymphocytes through direct binding to the catalytic subunit of protein phosphatase 2A. , 1998, Blood.

[69]  C. Proud,et al.  Activation of Microtubule‐Associated Protein Kinase (Erk) and p70 S6 Kinase by D2 Dopamine Receptors , 1998, Journal of neurochemistry.

[70]  Rapamycin Induces the G0 Program of Transcriptional Repression in Yeast by Interfering with the TOR Signaling Pathway , 1998, Molecular and Cellular Biology.

[71]  A. Gingras,et al.  4E-BP3, a New Member of the Eukaryotic Initiation Factor 4E-binding Protein Family* , 1998, The Journal of Biological Chemistry.

[72]  Takeshi Noda,et al.  Tor, a Phosphatidylinositol Kinase Homologue, Controls Autophagy in Yeast* , 1998, The Journal of Biological Chemistry.

[73]  C. Berset,et al.  The TOR (target of rapamycin) signal transduction pathway regulates the stability of translation initiation factor eIF4G in the yeast Saccharomyces cerevisiae. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[74]  C. Proud,et al.  Amino acid availability regulates p70 S6 kinase and multiple translation factors. , 1998, The Biochemical journal.

[75]  U. Frey,et al.  Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation , 1998, Trends in Neurosciences.

[76]  S. Schreiber,et al.  Alpha 4 associates with protein phosphatases 2A, 4, and 6. , 1998, Biochemical and biophysical research communications.

[77]  Bernhard Lüscher,et al.  Postsynaptic clustering of major GABAA receptor subtypes requires the γ2 subunit and gephyrin , 1998, Nature Neuroscience.

[78]  S. Snyder,et al.  RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[79]  N. Sonenberg,et al.  A Novel Functional Human Eukaryotic Translation Initiation Factor 4G , 1998, Molecular and Cellular Biology.

[80]  R. Roth,et al.  Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[81]  A. Gingras,et al.  μ-Opioid Receptor Activates Signaling Pathways Implicated in Cell Survival and Translational Control* , 1998, The Journal of Biological Chemistry.

[82]  D. S. Cowen,et al.  Coupling of Serotonin 5‐HT1B Receptors to Activation of Mitogen‐Activated Protein Kinase (ERK‐2) and p70 S6 Kinase Signaling Systems , 1998, Journal of neurochemistry.

[83]  A. Schmidt,et al.  The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease , 1998, The EMBO journal.

[84]  J. Warner,et al.  The economics of ribosome biosynthesis in yeast. , 1999, Trends in biochemical sciences.

[85]  J. Avruch,et al.  Regulation of Translational Effectors by Amino Acid and Mammalian Target of Rapamycin Signaling Pathways , 1999, The Journal of Biological Chemistry.

[86]  J. Broach,et al.  Tor proteins and protein phosphatase 2A reciprocally regulate Tap42 in controlling cell growth in yeast , 1999, The EMBO journal.

[87]  A. Gingras,et al.  eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. , 1999, Annual review of biochemistry.

[88]  D. Klionsky,et al.  Vacuolar import of proteins and organelles from the cytoplasm. , 1999, Annual review of cell and developmental biology.

[89]  A. Gingras,et al.  Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. , 1999, Molecular cell.

[90]  R. Denton,et al.  Dissociation of the eukaryotic initiation factor‐4E/4E‐BP1 complex involves phosphorylation of 4E‐BP1 by an mTOR‐associated kinase , 1999, FEBS letters.

[91]  H. Trachsel,et al.  CLN3 expression is sufficient to restore G1-to-S-phase progression in Saccharomyces cerevisiae mutants defective in translation initiation factor eIF4E. , 1999, The Biochemical journal.

[92]  J. Heitman,et al.  The TOR signaling cascade regulates gene expression in response to nutrients. , 1999, Genes & development.

[93]  S. Snyder,et al.  Interaction of RAFT1 with gephyrin required for rapamycin-sensitive signaling. , 1999, Science.

[94]  G. Thomas,et al.  Target of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation. , 1999, Current opinion in genetics & development.

[95]  D. Alessi,et al.  Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. , 1999, The Biochemical journal.

[96]  E. Kandel,et al.  A Transient, Neuron-Wide Form of CREB-Mediated Long-Term Facilitation Can Be Stabilized at Specific Synapses by Local Protein Synthesis , 1999, Cell.

[97]  T. Powers,et al.  Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae. , 1999, Molecular biology of the cell.

[98]  S. Rundle,et al.  The Arabidopsis homolog of yeast TAP42 and mammalian alpha4 binds to the catalytic subunit of protein phosphatase 2A and is induced by chilling. , 1999, Plant physiology.

[99]  Michael N. Hall,et al.  The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors , 1999, Nature.

[100]  C. Tokunaga,et al.  Alpha4 protein as a common regulator of type 2A‐related serine/threonine protein phosphatases 1 , 1999, FEBS letters.

[101]  S. Gygi,et al.  Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. , 1999, Genes & development.

[102]  A. Tolkovsky,et al.  Autophagy Is Activated by Apoptotic Signalling in Sympathetic Neurons: An Alternative Mechanism of Death Execution , 1999, Molecular and Cellular Neuroscience.

[103]  S. Schreiber,et al.  Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[104]  Kathryn E. Hentges,et al.  The flat-top gene is required for the expansion and regionalization of the telencephalic primordium. , 1999, Development.

[105]  Y. Uchiyama,et al.  Regulation of a novel pathway for cell death by lysosomal aspartic and cysteine proteinases , 1999, Neuroscience.

[106]  A. Schmidt,et al.  Starvation Induces Vacuolar Targeting and Degradation of the Tryptophan Permease in Yeast , 1999, The Journal of cell biology.

[107]  E. Hafen,et al.  Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. , 2000, Genes & development.

[108]  S. Gygi,et al.  Serum‐stimulated, rapamycin‐sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI , 2000, The EMBO journal.

[109]  Tobias Schmelzle,et al.  TOR, a Central Controller of Cell Growth , 2000, Cell.

[110]  N. Sonenberg,et al.  Eap1p, a Novel Eukaryotic Translation Initiation Factor 4E-Associated Protein in Saccharomyces cerevisiae , 2000, Molecular and Cellular Biology.

[111]  D. Klionsky,et al.  Autophagy, cytoplasm-to-vacuole targeting pathway, and pexophagy in yeast and mammalian cells. , 2000, Annual review of biochemistry.

[112]  Christine C. Hudson,et al.  A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. , 2000, Cancer research.

[113]  A. Bernal,et al.  Drosophila Thor participates in host immune defense and connects a translational regulator with innate immunity. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[114]  J. Chen,et al.  Cytoplasmic-nuclear shuttling of FKBP12-rapamycin-associated protein is involved in rapamycin-sensitive signaling and translation initiation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[115]  Multiple Mechanisms Control Phosphorylation of PHAS-I in Five (S/T)P Sites That Govern Translational Repression , 2000, Molecular and Cellular Biology.

[116]  S. Schreiber,et al.  FKBP12-Rapamycin-associated Protein (FRAP) Autophosphorylates at Serine 2481 under Translationally Repressive Conditions* , 2000, The Journal of Biological Chemistry.

[117]  M. Johnston,et al.  A chemical genomics approach toward understanding the global functions of the target of rapamycin protein (TOR). , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[118]  M. Constantine-Paton,et al.  NMDA receptor-mediated control of protein synthesis at developing synapses , 2000, Nature Neuroscience.

[119]  T. P. Neufeld,et al.  Regulation of cellular growth by the Drosophila target of rapamycin dTOR. , 2000, Genes & development.

[120]  C. Proud,et al.  Activation of mRNA translation in rat cardiac myocytes by insulin involves multiple rapamycin-sensitive steps. , 2000, American journal of physiology. Heart and circulatory physiology.

[121]  S. Emr,et al.  Autophagy as a regulated pathway of cellular degradation. , 2000, Science.

[122]  Stuart L. Schreiber,et al.  Partitioning the transcriptional program induced by rapamycin among the effectors of the Tor proteins , 2000, Current Biology.

[123]  W. Sossin,et al.  Serotonin Activates S6 Kinase in a Rapamycin-Sensitive Manner inAplysia Synaptosomes , 2001, The Journal of Neuroscience.

[124]  M. Choder,et al.  The Fission Yeast TOR Homolog,tor1 +, Is Required for the Response to Starvation and Other Stresses via a Conserved Serine* , 2001, The Journal of Biological Chemistry.