Elucidating TOR Signaling and Rapamycin Action: Lessons from <i>Saccharomyces cerevisiae</i>
Microbiology and Molecular Biology ReviewsPublished 1 December 2002Open access
José L. Crespo, Michael N. Hall
Citations371
Generate an AI Snapshot to get a quick, structured summary of this paper.
Study Snapshot
ObjectiveStudy objective
MethodsResearch methodology
PopulationPopulation studied
Sample sizeSample sizes
OutcomesStudy outcomes here
ResultsStudy results comes here
LimitationsResearch study limitations comes here
A concise AI-generated summary of the paper will appear here once you click Generate AI Snapshot.
TL;DR
This review discusses the contributions made by S. cerevisiae to understanding rapamycin action and TOR function and concludes that the modes of action of TOR andRapamycin are remarkably conserved from S. Cerevisiae.
Abstract
TOR (target of rapamycin) is a phosphatidylinositol kinase-related protein kinase that controls cell growth in response to nutrients. Rapamycin is an immunosuppressive and anticancer drug that acts by inhibiting TOR. The modes of action of TOR and rapamycin are remarkably conserved from S. cerevisiae to humans. The current understanding of TOR and rapamycin is derived largely from studies with S. cerevisiae. In this review, we discuss the contributions made by S. cerevisiae to understanding rapamycin action and TOR function.
Keywords
Agricultural and Biological SciencesBiochemistry, Genetics and Molecular Biology
The EMBO JournalLC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing
6,545 Citations2000Yukihiro Kabeya, Noboru Mizushima +7 more
It is demonstrated that the rat microtubule‐associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing.
NatureInduction of autophagy and inhibition of tumorigenesis by beclin 1
3,293 Citations1999Xiao Huan Liang, Saadiya Jackson +5 more
It is shown that beclin 1 is a mammalian autophagy gene that can inhibit tumorigenesis and is expressed at decreased levels in human breast carcinoma, suggesting that decreased expression of Autophagy proteins may contribute to the development or progression of breast and other human malignancies.
NatureA mammalian protein targeted by G1-arresting rapamycin–receptor complex
2,057 Citations1994Eric J. Brown, Mark W. Albers +5 more
A mammalian FKBP–rapamycin-associated protein (FRAP) is isolate whose binding to structural variants of rapamycin complexed to FK BP12 correlates with the ability of these ligands to inhibit cell-cycle progression.
ScienceTargets for Cell Cycle Arrest by the Immunosuppressant Rapamycin in Yeast
2,021 Citations1991Joseph Heitman, N. Rao Movva +1 more
Nonallelic noncomplementation between FPR1, TOR1, and TOR2 alleles suggests that the products of these genes may interact as subunits of a protein complex that may mediate nuclear entry of signals required for progression through the cell cycle.
CellMaximal activation of transcription by statl and stat3 requires both tyrosine and serine phosphorylation
1,988 Citations1995Zilong Wen, Zhong Zhong +1 more
It is shown that gene activation by Stat1 and Stat3, which obligatorily require tyrosine phosphorylation to become active, also depends for maximal activation on one or more of the many serine kinases.
Genes & DevelopmentCell cycle checkpoint signaling through the ATM and ATR kinases
1,956 Citations2001Robert T. Abraham
These checkpoints contain, as their most proximal signaling elements, sensor proteins that scan chromatin for partially replicated DNA, DNA strand breaks, or other abnormalities, and translate these DNA-derived stimuli into biochemical signals that modulate the functions of specific downstream target proteins.
Trends in Biochemical SciencesThe economics of ribosome biosynthesis in yeast
1,950 Citations1999Jonathan R. Warner
In a rapidly growing yeast cell, 60% of total transcription is devoted to ribosomal RNA, and 50% of RNA polymerase II transcription and 90% of mRNA splicing are devoted to Ribosomal proteins (RPs).
CellTOR, a Central Controller of Cell Growth
1,917 Citations2000Tobias Schmelzle, Michael N. Hall
Findings reveal that the target of rapamycin TOR controls an unusually abundant and diverse set of readouts all of which are important for cell growth, suggesting that this conserved kinase is such a central regulator.
FEBS LettersIsolation and characterization of autophagy‐defective mutants of <i>Saccharomyces cerevisiae</i>
1,738 Citations1993Miki Tsukada, Yoshinori Ohsumi
The results on the apg mutants suggest that autophagy via autophagic bodies is indispensable for protein degradation in the vacuoles under starvation conditions, and that at least 15 APG genes are involved inAutophagy in yeast.
Nature MedicineRapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor
1,736 Citations2002Markus Guba, Philipp von Breitenbuch +10 more
The use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients and show antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor and to a markedly inhibited response ofascular endothelial cells to stimulation by VEGF.
The Journal of AntibioticsRapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle.
1,656 Citations1975Claude Vézina, ALICIA KUDELSKI +1 more
From its characteristic ultraviolet absorption spectrum rapamycin can be classified as a triene and its activity is compared with that of amphotericin B, candicidin and nystatin.
ScienceChemistry and Biology of the Immunophilins and Their Immunosuppressive Ligands
1,491 Citations1991Stuart L. Schreiber
Defining the biological roles of this emerging family of receptors and their ligands may illuminate the process of protein trafficking in cells and the mechanisms of signal transmission through the cytoplasm.
CellRAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs
1,478 Citations1994David M. Sabatini, Hediye Erdjument‐Bromage +3 more
It is proposed that RAFT1 is the direct target of FKBP12-rapamycin and a mammalian homolog of the TOR proteins, which were originally identified by mutations that confer rapamycin resistance in yeast.
Molecular Biology of the CellRemodeling of Yeast Genome Expression in Response to Environmental Changes
1,389 Citations2001Helen C. Causton, Bing Ren +8 more
The results of expression analysis with MSN2/MSN4 mutants support the model that the Msn2/Msn4 activators induce the common response to environmental change and extend the understanding of the role of activators in effecting this response.
Translational control of gene expression
1,378 Citations2000Nahum Sonenberg, John W.B. Hershey +1 more
Origins and Principles of Translational Control, Genetic Approaches to Translation Initiation in Saccharomyces cerevisiae, and Programmed translational Frameshifting, Hopping, an
Journal of Biological ChemistryAmino Acid Sufficiency and mTOR Regulate p70 S6 Kinase and eIF-4E BP1 through a Common Effector Mechanism
1,363 Citations1998Kenta Hara, Kazuyoshi Yonezawa +4 more
The present study identifies the operation of a signal tranduction pathway in mammalian cells that provides a checkpoint control, linking amino acid sufficiency to the control of peptide chain initiation, indicating that mTOR is required for the response to amino acids.
Genes & DevelopmentRegulation of 4E-BP1 phosphorylation: a novel two-step mechanism
1,320 Citations1999Anne‐Claude Gingras, Steven P. Gygi +6 more
4E-BP1 phosphorylation by FRAP/mTOR on Thr-37 and Thr-46 is a priming event for subsequent phosphorylated of the carboxy-terminal serum-sensitive sites, including those that interact with eIF4E.
Journal of Biological ChemistryTor, a Phosphatidylinositol Kinase Homologue, Controls Autophagy in Yeast
1,302 Citations1998Takeshi Noda, Yoshinori Ohsumi
It is found that Tor, a phosphatidylinositol kinase homologue, is involved in the control of autophagy in the yeast, Saccharomyces cerevisiae, and that a high concentration of cAMP is inhibitory for induction of Autophagy.
The Journal of Cell BiologyAutophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction.
1,247 Citations1992Koichiro Takeshige, M Baba +3 more
Accumulation of autophagic bodies in the vacuoles was induced not only by nitrogen starvation, but also by depletion of nutrients such as carbon and single amino acids that caused cessation of the cell cycle.
NatureInsulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function
1,232 Citations1994Arnim Pause, Graham J. Belsham +5 more
The cloning is described of two related human complementary DNAs encoding polypeptides that interact specifically with the translation initiation factor elF-4E, which binds to the messenger RNA 5'-cap structure, thereby relieving the translational inhibition.
CellRapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases
1,158 Citations1992Jongkyeong Chung, Calvin J. Kuo +2 more
These studies identify a rapamycin-sensitive signaling pathway, argue for a ubiquitous role for FKBPs in signal transduction, indicate that FK506-FKBP-calcineurin complexes do not interfere with pp70S6K signaling, and show that in fibroblasts pp70 S6K, not RSK, is the physiological S6 kinase.
The Journal of Cell BiologyTor-Mediated Induction of Autophagy via an Apg1 Protein Kinase Complex
1,144 Citations2000Yoshiaki Kamada, Tomoko Funakoshi +4 more
It is shown that the protein kinase activity of Apg1 is enhanced by starvation or rapamycin treatment, and it is found that Apg13, which binds to and activates ApG1, is hyperphosphorylated in a Tor-dependent manner, reducing its affinity to Apg 1.
Proceedings of the National Academy of SciencesRAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1
1,141 Citations1998Patrick E. Burnett, Roxanne K. Barrow +3 more
It is shown that RAFT1 directly phosphorylates p70(S6k), 4E-BP1, and 4e-BP2 and that serum stimulates RAFT 1 kinase activity with kinetics similar to those of p70 (S6K) and 4E -BP1 phosphorylation.
SciencePhosphatidic Acid-Mediated Mitogenic Activation of mTOR Signaling
1,053 Citations2001Yimin Fang, Montserrat Vilella-Bach +3 more
The involvement of PA in mTOR signaling reveals an important function of this lipid in signal transduction and protein synthesis, as well as a direct link between mTOR and mitogens, and suggests a potential mechanism for the in vivo actions of the immunosuppressant rapamycin.
ScienceMammalian TOR: A Homeostatic ATP Sensor
967 Citations2001Patrick B. Dennis, Anja Jaeschke +4 more
It is demonstrated that the mTOR pathway is influenced by the intracellular concentration of ATP, independent of the abundance of amino acids, and that mTOR itself is an ATP sensor.
SciencePhosphorylation of the Translational Repressor PHAS-I by the Mammalian Target of Rapamycin
960 Citations1997Gregory J. Brunn, Christine C. Hudson +6 more
A role for mTOR in translational control is defined and further insights into the mechanism whereby rapamycin inhibits G1-phase progression in mammalian cells are offered.
The EMBO JournalRapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k
932 Citations1997Harold B.J. Jefferies, Stefano Fumagalli +4 more
It is demonstrated that an intact polypyrimidine tract is required for rapamycin to elicit an inhibitory effect on the translation of mRNAs encoding ribosomal proteins and elongation factors.
ScienceStructure of the FKBP12-Rapamycin Complex Interacting with Binding Domain of Human FRAP
930 Citations1996Jung‐Won Choi, Jie Chen +2 more
The structure of the FRB domain of FRAP clarifies both rapamycin-independent and -dependent effects observed for mutants ofFRAP and its homologs in the family of proteins related to the ataxia-telangiectasia mutant gene product, and it illustrates how a small cell-permeable molecule can mediate protein dimerization.
NatureThe TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors
926 Citations1999Thomas W. Beck, Michael N. Hall
The rapamycin-sensitive TOR signalling pathway in Saccharomyces cerevisiae activates a cell-growth program in response to nutrients such as nitrogen and carbon and broadly controls nutrient metabolism by sequestering several transcription factors in the cytoplasm.
Biochemical JournalMammalian 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
923 Citations1999B. Nave, D. Margriet Ouwens +3 more
The findings demonstrate that mTOR is a direct target for PKB and support the conclusion that regulation of phosphorylation of Ser(2448) is a point of convergence for the counteracting regulatory effects of growth factors and amino acid levels.
Genes & DevelopmentHierarchical phosphorylation of the translation inhibitor 4E-BP1
884 Citations2001Anne‐Claude Gingras, Brian Raught +8 more
It is shown thatosphorylation of Ser 65 and Thr 70 alone is insufficient to block binding to eIF4E, indicating that a combination of phosphorylation events is necessary to dissociate 4E-BP1 from eIF3E, and a novel combination of two-dimensional isoelectric focusing and Western blotting with phosphospecific antibodies is established.
Journal of Biological ChemistryIsolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells
871 Citations1995Candace J. Sabers, Mary M. Martin +5 more
The results strongly suggest that the FKBP12-rapamycin complex interacts with homologous ligands in yeast and mammalian cells and that the loss of mTOR function is directly related to the inhibitory effect of rapamycin on G1- to S-phase progression in T-lymphocytes and other sensitive cell types.
CellTarget of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression
841 Citations1993Jeannette Kunz, Rubén Henríquez +4 more
The results suggest that 3-phosphorylated phosphoinositides, whose physiological significance has not been determined, are an important signal in cell cycle activation in yeast and may act in a signalTransduction pathway similar to the interleukin-2 signal transduction pathway in T cells.
The EMBO JournalRegulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase
794 Citations2001X. Wang, Wei Li +4 more
PDK1 is required for activation of members of the AGC kinase family; it is shown that two such kinases, p70 S6 kinase (regulated via mTOR) and p90RSK1 (activated by Erk) phosphorylate eEF2k at a conserved serine and inhibit its activity.
Genes & DevelopmentNuclear localization of the C2H2 zinc finger protein Msn2p is regulated by stress and protein kinase A activity
766 Citations1998Wolfram Görner, E. Durchschlag +6 more
Stress and cAMP-regulated intracellular localization of Msn2p is proposed to be a key step in STRE-dependent transcription and in the general stress response.
Molecular Biology of the CellTOR controls translation initiation and early G1 progression in yeast.
735 Citations1996Nik Barbet, Ulrich Schneider +4 more
PubMedA direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells.
716 Citations2000A Sekulić, Christine C. Hudson +5 more
It is demonstrated that interleukin-3 stimulation induces a wortmannin-sensitive increase in mTOR kinase activity in a myeloid progenitor cell line, and that the activation status of the PI3K-AKT pathway in cancer cells may be an important determinant of cellular sensitivity to the cytostatic effect of rapamycin.
NatureControl of p70 S6 kinase by kinase activity of FRAP in vivo
714 Citations1995Eric J. Brown, Peter A. Beal +4 more
FRAP is a rapamycin-sensitive regulator of p70S6k in vivo and that the kinase activity of FRAP is required for this regulation, and it is shown that FRAP autophosphorylates in vitro.
Molecular MicrobiologyNovel sensing mechanisms and targets for the cAMP–protein kinase A pathway in the yeast <i>Saccharomyces cerevisiae</i>
691 Citations1999Johan M. Thevelein, Johannes H. de Winde
A major issue that remains to be resolved is the precise connection between the cAMP–PKA pathway and other nutrient‐regulated components involved in the control of growth and of phenotypic characteristics correlated with growth, such as the Sch9 and Yak1 protein kinases.
Journal of Biological ChemistryPhosphorylation of Ribosomal Protein S6 Is Inhibitory for Autophagy in Isolated Rat Hepatocytes
678 Citations1995Edward F. C. Blommaart, Joost J.F.P. Luiken +3 more
The fluxes through the autophagic and protein synthetic pathways are regulated in an opposite manner by the degree to which S6 is phosphorylated, which concludes that inhibition of autophagy and phosphorylation of S6 are under the same signal transduction pathway.
SciencePHAS-I as a Link Between Mitogen-Activated Protein Kinase and Translation Initiation
676 Citations1994Tai-An Lin, Xianming Kong +5 more
Results obtained with antibodies, immobilized PHAS-I, and a messenger RNA cap affinity resin indicated that PHas-I did not bind eIF-4E when serine-64 was phosphorylated, indicating that PHAs-I may be a key mediator of the stimulation of protein synthesis by the diverse group of agents and stimuli that activate MAP kinase.
The EMBO JournalRapamycin blocks the phosphorylation of 4E‐BP1 and inhibits cap‐dependent initiation of translation.
673 Citations1996Laura Beretta, Anne‐Claude Gingras +3 more
It is shown that rapamycin inhibits cap‐dependent, but not cap‐independent, translation in NIH 3T3 cells, and results suggest that 4E‐BP1 phosphorylation is mediated by the FRAP/TOR signalling pathway.
Annual Review of ImmunologyCyclosporin A, FK-506, and Rapamycin: Pharmacologic Probes of Lymphocyte Signal Transduction
670 Citations1992N H Sigal, Francis J. Dumont
Observed interactions between CsA, FK-506, and rapamycin suggest that complexes formed between the drugs and their major binding proteins may affect the function of other, unidentified, molecules or, alternatively, that minorbinding proteins may play a role in the drugs' action.
ScienceRapamycin-Induced Inhibition of the 70-Kilodalton S6 Protein Kinase
666 Citations1992Daniel J. Price, Jeffrey Grove +3 more
The immunosuppressant rapamycin inhibited proliferation of the H4IIEC hepatoma cell line and inhibited the appearance of the hyperphosphorylated form of p70 S6 kinase concomitant with the inhibition of enzyme activity toward 40S subunits.
Genes & DevelopmentRegulation of cellular growth by the <i>Drosophila</i> target of rapamycin <i>dTOR</i>
626 Citations2000Hongbing Zhang, James P. Stallock +3 more
The results suggest that dTOR regulates growth during animal development by coupling growth factor signaling to nutrient availability and overexpression of p70 S6 kinase in vivo can rescue dTOR mutant animals to viability.
NatureRapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase
600 Citations1992Calvin J. Kuo, Jongkyeong Chung +4 more
The selective blockade of the p70 S6 kinase activation cascade by the rapamycin–FKBP complex implicates this signalling pathway in the regulation of T cell entry into S phase.
Genes & DevelopmentThe TOR signaling cascade regulates gene expression in response to nutrients
587 Citations1999María E. Cárdenas, N. Shane Cutler +3 more
Analysis of gene expression in yeast cells exposed to rapamycin reveals that the TOR cascade plays a prominent role in regulating transcription in response to nutrients in addition to its known roles in regulating translation, ribosome biogenesis, and amino acid permease stability.
OncogeneThe rapamycin-sensitive signal transduction pathway as a target for cancer therapy
585 Citations2000Manuel Hidalgo, Eric K. Rowinsky
CCI-779, an ester analog of rapamycin with improved pharmaceutical properties and aqueous solubility, has demonstrated impressive activity against a broad range of human cancers growing in tissue culture and in human tumor xenograft models, which has supported the development of compounds targetingRapamycin-sensitive signal-transduction pathways.
Proceedings of the National Academy of SciencesIdentification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue.
569 Citations1995Jie Chen, Xiao-Feng Zheng +2 more
It is shown that the FRAP Ser2035-->Ala mutant displays similar binding affinity when compared with the wild-type protein, whereas all other mutations at this site, including mimics of phosphoserine, abolish binding, presumably due to either unfavorable steric interactions or induced conformational changes.
Molecular Biology of the CellGenomic Expression Responses to DNA-damaging Agents and the Regulatory Role of the Yeast ATR Homolog Mec1p
547 Citations2001Audrey P. Gasch, Mingxia Huang +4 more
A comparative analysis of wild-type and mutant cells responding to these DNA-damaging agents is presented, and specific features of the gene expression responses that are dependent on the Mec1 pathway are identified.
Journal of Biological ChemistryTranslational Regulation of Yeast GCN4
531 Citations1997Alan G. Hinnebusch
Disclosed is a pneumatic launch apparatus which employs separable telescoping tubes which automatically close upon separation of the tubes to trap operating gas in the tubes at the moment of separation.
Proceedings of the National Academy of SciencesRapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins
520 Citations1999James S. Hardwick, Finny G. Kuruvilla +3 more
The results suggest that Tor proteins directly modulate the glucose activation and nitrogen discrimination pathways and the pathways that respond to the diauxic shift (including glycolysis and the citric acid cycle).
SciencePIK-Related Kinases: DNA Repair, Recombination, and Cell Cycle Checkpoints
519 Citations1995Curtis T. Keith, Stuart L. Schreiber
The phosphatidylinositol kinase-related (PIK-related) kinases form a new subgroup within the protein kinase family of enzymes and participate in recombination processes, chromosome maintenance, and the cell cycle.
Journal of Biological ChemistryRegulation of eIF-4E BP1 Phosphorylation by mTOR
516 Citations1997Kenta Hara, Kazuyoshi Yonezawa +7 more
It is concluded that mTOR is an upstream regulator of eIF-4E BP1 as well as the p70 S6 kinase; moreover, these two mTOR targets are regulated in a parallel rather than sequential manner.
Genes & DevelopmentNutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases.
500 Citations1996Charles J. Di Como, Kim Arndt
Genetic analysis and defect in translation of the tap42-11 mutant at the nonpermissive temperature suggest that Tap42, Sit4, and PP2A are components of the Tor signaling pathway.
Proceedings of the National Academy of SciencesExpression and disruption of the <i>Arabidopsis TOR</i> (target of rapamycin) gene
495 Citations2002Benoît Menand, Thierry Desnos +5 more
Current Opinion in Cell BiologyControl of the yeast cell cycle by the Cdc28 protein kinase
489 Citations1993Kim Nasmyth
Much of the order and timing of the cell cycle events may involve the progressive activation of Cdc28 kinase activities associated with different cyclins, whose periodicity during the cycle is determined by both transcriptional and post-transcriptional controls.
Proceedings of the National Academy of SciencesProtein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12–rapamycinassociated protein
489 Citations1999Randall T. Peterson, Bimal N. Desai +2 more
Evidence is presented that FRAP controls 4E-BP1 and p70(s6k) phosphorylation indirectly by restraining a phosphatase, consistent with a model in which phosphorylations of PP2A by FRAP prevents the dephosphorylation of 4 eukaryotic initiation factor 4 E-binding protein 1 and p 70(s 6k), whereas amino acid deprivation or rapamycin treatment inhibits FRAP's ability to restrain the phosphatases.
Proceedings of the National Academy of SciencesEvidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway
488 Citations1998Pamela Scott, Gregory J. Brunn +3 more
The findings support the conclusion that insulin activates mTOR by promoting phosphorylation of the protein via a signaling pathway that contains PKB.
The EMBO JournalComparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins.
485 Citations1993Mike Tyers, George Tokiwa +1 more
It is proposed that Cln3 may be an upstream activator of the G1 cyclins which directly catalyze Start, and given the large number of known cyclins, such cyclin cascades may be a common theme in cell cycle control.
Current BiologySerine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR
482 Citations2000Kiyotaka Yokogami, Shinichiro Wakisaka +2 more
The ability of m TOR to contribute to activation of STAT3 extends the function of mTOR in mammalian cells to include transcriptional regulation.
Proceedings of the National Academy of SciencesRAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex.
479 Citations1994M. Isabel Chiu, Howard R. Katz +1 more
GeneApg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae
477 Citations1997Akira Matsuura, Miki Tsukada +2 more
It is shown that the APG1 gene, involved in the autophagic process in yeast, encodes a novel type of Ser/Thr protein kinase, suggesting that homologous molecular mechanisms, conserved from unicellular to multicellular organisms, are involved in dynamic membrane flow.
Current Opinion in Cell BiologyTOR signalling and control of cell growth
458 Citations1997George Thomas, Michael N. Hall
TOR, phosphatidylinositol 3-kinase, p70s6k, and 4E-BP1 have recently emerged as components of a major signalling pathway that is dedicated to protein translation and thus to cell growth.
Annual Review of Cell and Developmental BiologyVacuolar Import of Proteins and Organelles From The Cytoplasm
457 Citations1999Daniel J. Klionsky, Yoshinori Ohsumi
This review focuses on recent progress made in analyzing these delivery processes at a molecular level in the vacuole/lysosome, the main site of protein and organellar turnover within the cell.
Annual Review of Cell and Developmental BiologySIGNALING TO THE ACTIN CYTOSKELETON
444 Citations1998Anja Schmidt, Michael N. Hall
The actin cytoskeleton is a highly dynamic network composed of actin polymers and a large variety of associated proteins that serves to mediate cell motility and cell shape changes during the cell cycle, to organize the cytoplasm, and to generate mechanical forces within the cell.
CellThe Structure of the Protein Phosphatase 2A PR65/A Subunit Reveals the Conformation of Its 15 Tandemly Repeated HEAT Motifs
442 Citations1999Matthew R. Groves, Neil Hanlon +3 more
The crystal structure of the PR65/Aalpha subunit of protein phosphatase 2A reveals the conformation of its 15 tandemly repeated HEAT sequences, degenerate motifs of approximately 39 amino acids present in a variety of proteins, including huntingtin and importin beta.
Genes & DevelopmentGenetic and biochemical characterization of dTOR, the <i>Drosophila</i> homolog of the target of rapamycin
430 Citations2000Sean Oldham, Jacques Montagne +3 more
Genetic and biochemical analyses indicate that dTOR impinges on the insulin signaling pathway by autonomously affecting growth through modulating the activity of dS6K, but partial loss of dTOR function preferentially reduces growth of the endoreplicating tissues.
CellRTG1 and RTG2: Two yeast genes required for a novel path of communication from mitochondria to the nucleus
426 Citations1993Xinsheng Liao, Ronald A. Butow
It is shown that retrograde regulation of the yeast CIT2 gene encoding peroxisomal citrate synthase depends on a new class of upstream activation site element (UASr) and two previously unidentified genes, RTG1 and RTG2, which are pivotal genes in controlling interorganelle communication between mitochondria,peroxisomes, and the nucleus.
The Journal of Cell BiologyCELLULAR DIFFERENTIATION IN THE KIDNEYS OF NEWBORN MICE STUDIED WITH THE ELECTRON MICROSCOPE
405 Citations1957Sam Clark
The structure of the kidney of the Swiss albino mouse changes progressively during the first 2 weeks after birth, cells proliferate to form new nephrons, cells differentiate by acquiring specialized membranous components, and certain cytological features which are present at birth diminish in abundance or disappear.
Molecular and Cellular BiologyThe Immunosuppressant Rapamycin Mimics a Starvation-Like Signal Distinct from Amino Acid and Glucose Deprivation
392 Citations2002Tao Peng, Todd R. Golub +1 more
It is suggested that RAFT1 is an energy and nutrient sensor and that rapamycin mimics a signal generated by the starvation of amino acids but that the signal is unlikely to be the absence of amino amino acids themselves.
Molecular Biology of the CellRegulation of Ribosome Biogenesis by the Rapamycin-sensitive TOR-signaling Pathway in<i>Saccharomyces cerevisiae</i>
388 Citations1999Ted Powers, Peter Walter
Yeast control of ribosome biosynthesis by the TOR pathway is surprisingly complex and it is found that TOR signaling is a prerequisite for the induction of r-protein gene transcription that occurs in response to improved nutrient conditions.
Molecular Biology of the CellTOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast.
381 Citations1994Stephen B. Helliwell, Philipp Wagner +4 more
TOR1 and TOR2 are likely similar but not identical, rapamycin-sensitive PI kinases possibly regulated by phosphorylation, and may be components of a novel signal transduction pathway controlling progression through G1.
ScienceRole of GTP Hydrolysis in Fission of Caveolae Directly from Plasma Membranes
378 Citations1996Jan E. Schnitzer, Phil Oh +1 more
A cell-free system that reconstituted fission of caveolae from lung endothelial plasma membranes was developed using addition of cytosol and the hydrolysis of guanosine triphosphate (GTP) induced caveolar fission.
The EMBO JournalYeast PKA represses Msn2p/Msn4p‐dependent gene expression to regulate growth, stress response and glycogen accumulation
375 Citations1998Adelle Smith, Mary P. Ward +1 more
The results suggest that Msn2p/Msn4p‐dependent gene expression may account for all, or at least most, of the pleiotropic effects of yeast PKA, including growth regulation, response to stress and carbohydrate store accumulation.
ScienceProbing Immunosuppressant Action with a Nonnatural Immunophilin Ligand
356 Citations1990Barbara E. Bierer, Patricia K. Somers +3 more
A nonnatural immunophilin ligand, 506BD, was synthesized and found to be a high-affinity ligand of FKBP and a potent inhibitor of FkBP rotamase activity, resulting in the inhibition of different signaling pathways.
Journal of Biological ChemistryFKBP12-Rapamycin-associated Protein (FRAP) Autophosphorylates at Serine 2481 under Translationally Repressive Conditions
347 Citations2000Randall T. Peterson, Peter A. Beal +2 more
The identification of a FRAP autophosphorylation site, Ser-2481, is reported, and it is demonstrated that the COOH-terminal tail is required for FRAP kinase activity and for signaling to the translational regulator p70s6k (ribosomal subunit S6 kinase).
Journal of Biological ChemistryThe TOR Kinases Link Nutrient Sensing to Cell Growth
345 Citations2001John R. Rohde, Joseph Heitman +1 more
Ongoing clinical studies address new clinical applications for rapamycin as an antiproliferative drug for chemotherapy and invasive cardiology.
The EMBO JournalTor proteins and protein phosphatase 2A reciprocally regulate Tap42 in controlling cell growth in yeast
339 Citations1999Yu Jiang, James R. Broach
It is concluded that Tor phosphorylates Tap42 and that phosphorylated Tap42 effectively competes with Cdc55/Tpd3 for binding to the phosphatase 2A catalytic subunit, which establishes Tap42 as a target of Tor and add further refinement to the Tor signaling pathway.
Proceedings of the National Academy of SciencesThe TOR-controlled transcription activators GLN3, RTG1, and RTG3 are regulated in response to intracellular levels of glutamine
338 Citations2002José L. Crespo, Ted Powers +2 more
It is shown that the glutamine synthetase inhibitor l-methionine sulfoximine (MSX) specifically provokes glutamine depletion in yeast cells, suggesting that the TOR pathway senses glutamine.
Biochemical JournalAmino acid availability regulates p70 S6 kinase and multiple translation factors
337 Citations1998Xuemin Wang, Linda Campbell +2 more
The data show that amino acid supply regulates multiple translation factors in mammalian cells and indicates that protein kinase B may act upstream of p70 S6 kinase through a pathway independent of this enzyme.
Journal of Biological ChemistryImmunopurified Mammalian Target of Rapamycin Phosphorylates and Activates p70 S6 Kinase α in Vitro
333 Citations1999Shuji Isotani, Kenta Hara +4 more
Results indicate that mTOR is likely to function as a direct activator of p70 in vivo, although the relative contribution of mTOR-catalyzed p70 phosphorylation in each of the many circumstances that engender p70 activation remains to be defined.
Journal of Biological ChemistryThe Human Homolog of Saccharomyces cerevisiae Apg7p Is a Protein-activating Enzyme for Multiple Substrates Including Human Apg12p, GATE-16, GABARAP, and MAP-LC3
325 Citations2001Isei Tanida, Emiko Tanida-Miyake +2 more
Results indicate that hApg7p is an authentic protein-activating enzyme for hAPG12p and the three Apg8p homologs and an E1-like enzyme essential for the hA PG12p conjugation system.
CellTOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin
317 Citations1995Xiao-Feng Zheng, David Fiorentino +3 more
FKBP12-rapamycin does not appear to inhibit the kinase activity of TOR proteins in a general way; instead, it may interfere selectively with TOR protein binding to or phosphorylation of G1 effectors.
The EMBO JournalThe TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease
316 Citations1998Anja Schmidt, Thomas W. Beck +3 more
It is shown that the TOR signalling pathway phosphorylates the Ser/Thr kinase NPR1 and thereby inhibits the starvation‐induced turnover of TAT2, which controls growth by inhibiting a stationary phase (G0) programme.
Journal of Biological Chemistry4E-BP3, a New Member of the Eukaryotic Initiation Factor 4E-binding Protein Family
314 Citations1998Francis Poulin, Anne‐Claude Gingras +3 more
4E-BP3 is a heat stable protein that binds to eIF4E in vitro as well as in vivo, and 4E- BP3 overexpression specifically reduces eIF2E-dependent translation, implying that there is redundancy in this translational control mechanism, underscoring its importance.
Trends in Biochemical SciencesFAT: a novel domain in PIK-related kinases
304 Citations2000Roberta Bosotti, Antonella Isacchi +1 more
A new subfamily of the PI-kinase superfamily has emerged, called PIK-related, and this domain is referred to as the PIkinase domain because it has proved difficult to define shared domains in the large N-terminal portions.
CellThe Yeast Phosphatidylinositol Kinase Homolog TOR2 Activates RHO1 and RHO2 via the Exchange Factor ROM2
302 Citations1997Anja Schmidt, Marc Bickle +2 more
The Saccharomyces cerevisiae phosphatidylinositol kinase homolog TOR2 signals to the actin cytoskeleton through a GTPase switch composed of RHO1, RHO2, ROM2, and SAC7, which activates this switch via ROM2.
Proceedings of the National Academy of SciencesFK 506-binding protein proline rotamase is a target for the immunosuppressive agent FK 506 in Saccharomyces cerevisiae.
296 Citations1991Joseph Heitman, N. Rao Movva +2 more
Experiments described here demonstrate genetically that FKBP is a target for FK 506 in vivo, and isolates the gene encoding the FK BP proline rotamase (FPR1) from Saccharomyces cerevisiae, which is highly homologous with bovine and human FkBP and shares no homology with cyclophilin.
Molecular and Cellular Biologyp34 <sup>Cdc28</sup> -Mediated Control of Cln3 Cyclin Degradation
293 Citations1995Julia A. Yaglom, Maarten H.K. Linskens +4 more
It is reported that the breakdown of Cln3 is ubiquitin dependent and involves the Ubiquitin-conjugating enzyme Cdc34 (Ubc3) and the C-terminal tail ofcln3 functions as a transferable signal for degradation.
Genes & DevelopmentCoupling of cell division to cell growth by translational control of the G<sub>1</sub> cyclin <i>CLN3</i> in yeast
288 Citations1997Michael Polymenis, Emmett V. Schmidt
Inactivation of the uORF accelerates the completion of Start and entry into the cell cycle suggesting that translational regulation of CLN3 provides a mechanism coupling cell growth and division.
The Journal of Cell BiologyStarvation Induces Vacuolar Targeting and Degradation of the Tryptophan Permease in Yeast
288 Citations1999Thomas W. Beck, Anja Schmidt +1 more
The results suggest that TAT2 stability and sorting are controlled by the TOR signaling pathway, and regulated inversely to that of GAP1.
Molecular and Cellular BiologyDominant Missense Mutations in a Novel Yeast Protein related to Mammalian Phosphatidylinositol 3-Kinase and VPS34 Abrogate Rapamycin Cytotoxicity
276 Citations1993Robert Cafferkey, Peter R. Young +8 more
Genomic disruption of DRR1 in a mutant haploid strain restored drug sensitivity and demonstrated that the gene encodes a nonessential function, which supports the idea that FKBP12 and rapamycin form a toxic complex that corrupts the function of other cellular proteins.
Current Opinion in Genetics & DevelopmentTarget of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation
274 Citations1999Patrick B. Dennis, Stefano Fumagalli +1 more
Use of the immunosuppressant rapamycin, a bacterial macrolide, has been instructive in identifying potential signaling components downstream of TOR, leading to the observation that both protein synthesis and turnover are under TOR control.
The EMBO JournalCoordinated regulation of gene expression by the cell cycle transcription factor Swi4 and the protein kinase C MAP kinase pathway for yeast cell integrity.
270 Citations1996J. Carlos Igual, Amy L. Johnson +1 more
It is suggested that SBF and the PKC1 MAP kinase pathway act in concert to maintain cell integrity during bud formation.
The EMBO JournalSerum‐stimulated, rapamycin‐sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI
266 Citations2000Brian Raught, Anne‐Claude Gingras +6 more
Two‐dimensional phosphopeptide mapping demonstrates that the phosphorylation state of specific eIF4GI residues is altered by serum and mitogens, and suggests that the accessibility of the C‐terminus to kinases is modulated by this pathway(s).
Proceedings of the National Academy of SciencesTOR2 is required for organization of the actin cytoskeleton in yeast
263 Citations1996Anja Schmidt, Jeannette Kunz +1 more
It is suggested that the unique function of the phosphatidylinositol kinase homolog TOR2 is required for signaling organization of the actin cytoskeleton during the cell cycle and may thus integrate temporal and spatial control of cell growth.
Molecular and Cellular BiologyThe Principal Rapamycin-Sensitive p70<sup>s6k</sup> Phosphorylation Sites, T-229 and T-389, Are Differentially Regulated by Rapamycin-Insensitive Kinase Kinases
256 Citations1996Patrick B. Dennis, Nick Pullen +2 more
These data are consistent with the hypothesis that T-389 is the principal regulatory phosphorylation site, which, in combination with hyperphosphorylation of the autoinhibitory domain S/TP sites, is acutely regulated by external effectors, whereas T-229 phosphorylated is regulated primarily by internal mechanisms.
Cold Spring Harbor Monograph Archive5 Mechanism and Regulation of Initiator Methionyl-tRNA Binding to Ribosomes
247 Citations2000Alan G. Hinnebusch
In its simplest terms, the process of translation initiation in eukaryotic organisms consists of the binding of methionyl-initiator tRNA and mRNA to the 40S ribosomal subunit, pairing of the anticodon of Met-tRNA i Met with the AUG start codon in mRNA, and joining of the 60S ribo subunit to form an 80S initiation complex.
The EMBO JournalGATE‐16, a membrane transport modulator, interacts with NSF and the Golgi v‐SNARE GOS‐28
241 Citations2000Yuval Sagiv, Aster Legesse‐Miller +2 more
It is proposed that GATE‐16 modulates intra‐Golgi transport through coupling between NSF activity and SNAREs activation, and this work cloned a bovine brain cDNA encoding a conserved 117 amino acid polypeptide that functions as a soluble transport factor.
…