Ribosomal S6 Kinase Signaling and the Control of Translation

Dufner, Almut; Thomas, George

doi:10.1006/excr.1999.4683

Cited by 676PI3K/AKT/mTOR signaling in cancerRNA and protein synthesis mechanismsMetabolism, Diabetes, and Cancer

Ribosomal S6 Kinase Signaling and the Control of Translation

Dufner, Almut, Thomas, George·1999·Experimental Cell Research

DOI 10.1006/excr.1999.4683

Open this paper in CoChat — free account

Abstract

The highly homologous 40S ribosomal protein S6 kinases (S6K1 and S6K2) play a key role in the regulation of cell growth by controlling the biosynthesis of translational components which make up the protein synthetic apparatus, most notably ribosomal proteins. In the case of S6K1, at least eight phosphorylation sites are believed to mediate kinase activation in a hierarchical fashion. Activation is initiated by phosphatidylinositide-3OH kinase (PI3K)-mediated phosphorylation of key residues in the carboxy-terminus of the kinase, allowing phosphorylation of a critical residue residing in the activation loop of the catalytic domain by phosphoinositide-dependent kinase 1 (PDK1). The kinases responsible for phosphorylating the carboxy-terminal sites have yet to be identified. Additionally, S6 kinases are under the control of the PI3K relative, mammalian Target Of Rapamycin (mTOR), which may serve an additional function as a checkpoint for amino acid availability. In this review we set out to discuss the present state of knowledge regarding upstream signaling components which have been implicated in the control of S6K1 activation and the role of the kinase in controlling cell growth through regulating ribosome biogenesis at the translational level.

Integrity signals

Registry

Crossref · 10.1006/excr.1999.4683

Cites

0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

mTOR can phosphorylate eIF4G and ribosomal S6 kinases such as p70S6K, which phosphorylate eIF4B, enhancing its interaction with eIF3 and stimulating protein synthesis.
“mTOR can also phosphorylate eIF4G, the ribosomal S6 kinases (RS6K) such as p70S6K which phosphorylate eIF4B, enhancing its interaction with eIF3 and stimulate protein synthesis [75–77] (Fig. 1).”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [77]

Phosphorylation and Activation of p70 <sup>s6k</sup> by PDK1
Pullen, N., Dennis, P. B., Andjelkovic, M., Dufner, A., Kozma, S. C., Hemmings, B. A., & Thomas, G. (1998) · Science · doi:10.1126/science.279.5351.707 · Cited by 826 · see citing works
Self-citation
Constitutive activation of protein kinase B alpha by membrane targeting promotes glucose and system A amino acid transport, protein synthesis, and inactivation of glycogen synthase kinase 3 in L6 muscle cells.
Hajduch, E., Alessi, D. R., Hemmings, B. A., & Hundal, H. S. (1998) · Diabetes · doi:10.2337/diabetes.47.7.1006 · Cited by 335 · see citing works

Flagged first, then by citations

Sorted by citations

Oncogenic kinase signalling.
Blume-Jensen, P., & Hunter, T. (2001) · Nature · doi:10.1038/35077225 · Cited by 3,738 · see citing works
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083 · see citing works
“S6K activity is activated by phosphorylation on several residues, including Thr 389, Thr 421 and Ser 424 (ref”
Background
Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex
Brugarolas, J., Lei, K., Hurley, R. L., Manning, B. D., Reiling, J. H., Hafen, E., Witters, L. A., Ellisen, L. W., & Kaelin, W. G. (2004) · Genes & Development · doi:10.1101/gad.1256804 · Cited by 1,384 · see citing works
“Thr 389 is the major rapamycin-sensitive site and can be phosphorylated by mTOR in vitro, suggesting that it is a direct mTOR target (Dufner and Thomas 1999).”
BackgroundInfluential
p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling
Budanov, A. V., & Karin, M. (2008) · Cell · doi:10.1016/j.cell.2008.06.028 · Cited by 1,326 · see citing works
“p70S6K activation can in turn be determined by phosphorylation of ribosomal S6 protein at S235/236 (Dufner and Thomas, 1999; Pende et al., 2004).”
Synthesis and Function of 3-Phosphorylated Inositol Lipids
Vanhaesebroeck, B., Leevers, S. J., Ahmadi, K., Timms, J., Katso, R., Driscoll, P. C., Woscholski, R., Parker, P. J., & Waterfield, M. D. (2001) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.70.1.535 · Cited by 1,535 · see citing works
HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression
Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C., & Semenza, G. L. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.12.3995-4004.2001 · Cited by 1,256 · see citing works
“S6 kinases have been shown to control the translation of mRNAs that containing polypyrimidine tracts within their 59-UTR (8).”
Background
The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins
Harrington, L. S., Findlay, G. M., Gray, A., Толкачева, Т. А., Wigfield, S., Rebholz, H., Barnett, J., Leslie, N. R., Cheng, S., Shepherd, P. R., et al. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200403069 · Cited by 1,123 · see citing works
“The insulin–PI3K pathway controls cell number (through promoting cell cycle progression and survival via PKB/AKT; Lawlor and Alessi, 2001) and cell growth (via activation of the S6Ks; Dufner and Thomas, 1999).”
Background
Guidelines for the use of flow cytometry and cell sorting in immunological studies *
Cossarizza, A., Chang, H., Radbruch, A., Akdiş, M., Andrä, I., Annunziato, F., Bächer, P., Barnaba, V., Battistini, L., Bauer, W. M., et al. (2017) · European Journal of Immunology · doi:10.1002/eji.201646632 · Cited by 572 · see citing works
Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E
Fingar, D. C., Salama, S., Tsou, C., Harlow, E., & Blenis, J. (2002) · Genes & Development · doi:10.1101/gad.995802 · Cited by 1,093 · see citing works
“In mammals, mTOR cooperates with PI3K-dependent effectors to phosphorylate S6K1 and 4EBP1 (Dufner and Thomas 1999; Gingras et al. 2001).”
Background
Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2.Preprint
Peng, X.-D., Xu, P.-Z., Chen, M.-L., Hahn-Windgassen, A., Skeen, J. E., Jacobs, J., Sundararajan, D., Chen, W. S., Crawford, S., Coleman, K., et al. (2003) · Genes & Development · doi:10.1101/gad.1089403 · Cited by 889 · see citing works
“The ability of mTOR to regulate cell size may be dependent on its downstream effectors, the 4E-binding protein (4E-BP1) and p70S6 kinase (S6K1), that regulate protein synthesis (Dufner and Thomas 1999; Gingras et al. 2001).”
Background
Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic
Kang, S., Bader, A. G., & Vogt, P. K. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408864102 · Cited by 827 · see citing works
Akt regulates growth by directly phosphorylating Tsc2
Potter, C. J., Pedraza, L. G., & Xu, T. (2002) · Nature Cell Biology · doi:10.1038/ncb840 · Cited by 959 · see citing works
“A possible mediator of Tsc1–Tsc2 signalling is TOR, a protein that directly phosphorylates S6K in vitro”
Background
Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control.
Oldham, S., & Hafen, E. (2003) · Trends in Cell Biology · doi:10.1016/s0962-8924(02)00042-9 · Cited by 574 · see citing works
hVps34 Is a Nutrient-regulated Lipid Kinase Required for Activation of p70 S6 Kinase
Byfield, M. P., Murray, J. T., & Backer, J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507201200 · Cited by 526 · see citing works
Synthesis of the translational apparatus is regulated at the translational level.
Meyuhas, O. (2000) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2000.01719.x · Cited by 570 · see citing works
“Once phosphorylated, these two phosphothreonine residues act cooperatively to promote maximal activation of S6K1 [58].”
Background
p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD
Harada, H., Andersen, J., Mann, M., Terada, N., & Korsmeyer, S. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.171301998 · Cited by 563 · see citing works
Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression
Hou, L., & Klann, E. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.0995-04.2004 · Cited by 527 · see citing works
“S6K then phosphorylates ribosomal protein S6 (Fumagalli and Thomas, 2000), which can result in enhanced translation of 5ЈTOP mRNAs that encode numerous components of the translation machinery.”
Influential
E2F1 Regulates Cellular Growth by mTORC1 Signaling
Real, S., Meo-Evoli, N., Espada, L., & Tauler, A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016163 · Cited by 816 · see citing works
“Activation of the kinase activity of mTORC1 drives phosphorylation and inactivation of the eukaryotic translation initiation factor 4E-binding protein 4E-BP, a repressor of translation initiation, and phosphorylation and activation of ribosomal protein S6 kinase 1 (S6K1) [8,9].”
Background
The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease
Oudit, G. Y. (2004) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2004.05.015 · Cited by 467 · see citing works
“S6K1 and S6K2 are key regulators of cell growth through control of protein translation particularly for mRNA transcripts containing polypyrimidine sequences at the transcriptional start site by phosphorylating the S6 protein of the 40S ribosomal subunit [142,143].”
Background
Identification of a conserved motif required for mTOR signaling.
Schalm, S., & Blenis, J. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00762-5 · Cited by 507 · see citing works
Biochemical mechanisms for translational regulation in synaptic plasticity
Klann, E., & Dever, T. E. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1557 · Cited by 422 · see citing works
“S6K is also activated through the PI3K, phosphoinositide-dependent kinase 1 (PDK1) and ERK pathway”
Background
Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation
Goncharova, E., Goncharov, D. A., Eszterhas, A., Hunter, D., Glassberg, M., Yeung, R. S., Walker, C., Noonan, D., Kwiatkowski, D., Chou, M. M., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202678200 · Cited by 433 · see citing works
TSC2: filling the GAP in the mTOR signaling pathway
Li, Y. (2003) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.11.007 · Cited by 418 · see citing works
Targeting mammalian target of rapamycin (mTOR) for health and diseases
Tsang, C. K., Qi, H., Liu, L. F., & Zheng, X. (2006) · Drug Discovery Today · doi:10.1016/j.drudis.2006.12.008 · Cited by 403 · see citing works
Regulation of mTOR and Cell Growth in Response to Energy Stress by REDD1
Sofer, A., Lei, K., Johannessen, C. M., & Ellisen, L. W. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.14.5834-5845.2005 · Cited by 449 · see citing works
“We also examined phosphorylation of the S6K substrate ribosomal protein S6 at S235/S236, the major sites phosphorylated in a rapamycin-sensitive manner by activated S6K (11).”
Background
Mechanisms of liver fibrosis
Tsukada, S., Parsons, C. J., & Rippe, R. A. (2005) · Clinica Chimica Acta · doi:10.1016/j.cca.2005.06.014 · Cited by 353 · see citing works
Amino acid transporters: roles in amino acid sensing and signalling in animal cells
Hyde, R., Taylor, P. M., & Hundal, H. S. (2003) · Biochemical Journal · doi:10.1042/bj20030405 · Cited by 370 · see citing works
RAS and RHO GTPases in G1-phase cell-cycle regulation
Coleman, M. L., Marshall, C. J., & Olson, M. F. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1365 · Cited by 354 · see citing works
“S6K1 and S6K2 phosphorylate the S6 protein of the 40S ribosomal complex, which stimulates the translation of mRNAs with 5′ terminal oligopyrimidine (TOP) TRACTS that code for the components of the protein synthesis apparatus (reviewed in Ref”
Method
Induction of Hypoxia-inducible Factor-1α by Transcriptional and Translational Mechanisms
Pagé, E. L., Robitaille, G., Pouysségur, J., & Richard, D. E. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m209114200 · Cited by 385 · see citing works
Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner
Castro, A. F., Rebhun, J. F., Clark, G. J., & Quilliam, L. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300226200 · Cited by 381 · see citing works
The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB
Biondi, R. M., Kieloch, A., Currie, R. A., Deak, M., & Alessi, D. R. (2001) · The EMBO Journal · doi:10.1093/emboj/20.16.4380 · Cited by 377 · see citing works
Oral leucine administration stimulates protein synthesis in rat skeletal muscle
Crozier, S. J., Kimball, S. R., Emmert, S. W., Anthony, J. C., & Jefferson, L. S. (2005) · The Journal of Nutrition · doi:10.1093/jn/135.3.376 · Cited by 371 · see citing works
IGF-I receptor signalling in transformation and differentiation
Valentinis, B., & Baserga, R. (2001) · Molecular Pathology · doi:10.1136/mp.54.3.133 · Cited by 364 · see citing works
Protein kinases as mediators of phosphoinositide 3-kinase signaling.
Toker, A. (2000) · Molecular Pharmacology · doi:10.1124/mol.57.4.652 · Cited by 359 · see citing works
“This elaborate sequence of events in p70S6K activation by at least three pathways (MAPK, PI3K, and TOR) is further complicated by other mechanisms of regulation, which include the small GTPases Rac and Cdc42, Akt/PKB, and amino acids, all of which have been shown to activate p70S6K in vivo (Dufner and Thomas, 1999).”
M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase
Glantschnig, H., Fisher, J. E., Wesolowski, G., Rodan, G. A., & Reszka, A. A. (2003) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401285 · Cited by 350 · see citing works
PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR
Bernardi, R., Guernah, I., Jin, D. K., Grisendi, S., Alimonti, A., Teruya‐Feldstein, J., Cordon‐Cardo, C., Simon, M. C., Rafii, S., & Pandolfi, P. P. (2006) · Nature · doi:10.1038/nature05029 · Cited by 379 · see citing works
Arabidopsis TARGET OF RAPAMYCIN Interacts with RAPTOR, Which Regulates the Activity of S6 Kinase in Response to Osmotic Stress Signals
Mahfouz, M. M., Kim, S., Delauney, A., & Verma, D. P. (2005) · The Plant Cell Online · doi:10.1105/tpc.105.035931 · Cited by 345 · see citing works
“In animals, a closely related isoform, p85S6K, is a product of the same gene using an alternative translational start site and contains an N-terminal nuclear targeting signal (Dufner and Thomas, 1999).”
Background
Antitumor Efficacy of Intermittent Treatment Schedules with the Rapamycin Derivative RAD001 Correlates with Prolonged Inactivation of Ribosomal Protein S6 Kinase 1 in Peripheral Blood Mononuclear Cells
Boulay, A., Zumstein-Mecker, S., Stephan, C., Beuvink, I., Zilbermann, F., Haller, R., Tobler, S., Heusser, C., O’Reilly, T., Stolz, B., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-3554-2 · Cited by 319 · see citing works
“In the presence of mitogens and sufficient nutrients, mTOR relays a signal to translational regulators, specifically enhancing the translation of mRNAs encoding proteins essential for cell growth (12) and progression through the G1 to S transition (13, 14).”
BackgroundSelf-citation
Molecular mechanisms of hepatic fibrogenesis
Parsons, C. J., Takashima, M., & Rippe, R. (2007) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2006.04659.x · Cited by 323 · see citing works
A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt
Aoki, M., Blazek, E., & Vogt, P. K. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.1.136 · Cited by 306 · see citing works
Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease
An, W.-L., Cowburn, R. F., Li, L., Braak, H., Alafuzoff, I., Iqbal, K., Iqbal, I.-G., Winblad, B., & Pei, J.-J. (2003) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63687-5 · Cited by 312 · see citing works
“Activation of ribosomal S6 kinase 1 depends on its level of phosphorylation state at eight sites: Thr (T) 229, Ser (S) 371, T389, S404, S411, S418, T421, and S424.(13) Of these, S411, S418, T421, and S424 are located in the autoinhibitory domain and S371, T389, and S404 lie in the linker domain.”
BackgroundInfluential
Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
Cossarizza, A., Chang, H., Radbruch, A., Acs, A., Adam, D., Adam‐Klages, S., Agace, W. W., Aghaeepour, N., Akdiş, M., Allez, M., et al. (2019) · European Journal of Immunology · doi:10.1002/eji.201970107 · Cited by 982 · see citing works
Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K
Kozma, S. C., & Thomas, G. (2002) · Bioessays · doi:10.1002/bies.10031 · Cited by 308 · see citing works
Self-citation
Phosphorylation of the Protein Kinase Mutated in Peutz-Jeghers Cancer Syndrome, LKB1/STK11, at Ser431 by p90RSK and cAMP-dependent Protein Kinase, but Not Its Farnesylation at Cys433, Is Essential for LKB1 to Suppress Cell Growth*
Sapkota, G. P., Kieloch, A., Lizcano, J., Laín, S., Arthur, J. S., Williams, M. R., Morrice, N., Deák, M., & Alessi, D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009953200 · Cited by 308 · see citing works
Mitogen-Activated Protein Kinase Activation in UV-Induced Signal Transduction
Bode, A. M., & Dong, Z. (2003) · Science s STKE · doi:10.1126/stke.2003.167.re2 · Cited by 295 · see citing works
“The phosphorylation is believed to occur in a hierarchical fashion initiated by signaling through phosphatidylinositol 3kinase (PI3K) (118).”
BackgroundMethod
4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle
Shah, O. J., Anthony, J. C., Kimball, S. R., & Jefferson, L. S. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.4.e715 · Cited by 286 · see citing works
Insulin in the Brain: Sources, Localization and Functions
Ghasemi, R., Haeri, A., Dargahi, L., Mohamed, Z., & Ahmadiani, A. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8339-9 · Cited by 291 · see citing works
“Biosynthesis of translational components of cells, such as ribosomal proteins, is controlled by ribosomal protein S6 kinases, playing a pivotal role in the regulation of cell growth [255].”
Background
The PI‐3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3
Kane, L., & Weiss, A. (2003) · Immunological Reviews · doi:10.1034/j.1600-065x.2003.00008.x · Cited by 260 · see citing works
B cell receptor and CD40 Signaling are Rewired for Synergistic induction of the c-Myc transcription factor in Germinal Center B cells
Luo, W., Weisel, F. J., & Shlomchik, M. (2018) · Immunity · doi:10.1016/j.immuni.2018.01.008 · Cited by 289 · see citing works
“In addition to c-Myc, p-S6 is also critical for regulating cell growth and protein synthesis (Dang, 1999; Dufner and Thomas, 1999; van Riggelen et al., 2010).”
Epstein-Barr Virus LMP2A Transforms Epithelial Cells, Inhibits Cell Differentiation, and Activates Akt
Scholle, F., Bendt, K. M., & Raab‐Traub, N. (2000) · Journal of Virology · doi:10.1128/jvi.74.22.10681-10689.2000 · Cited by 276 · see citing works
“3-Phosphoinositide-dependent protein kinase 1 also activates the ribosomal protein S6 kinase, a key regulator of the biosynthesis of components of the protein translation machinery (1, 3, 18).”
Background
Branched-chain amino acids increase p70<sup>S6k</sup> phosphorylation in human skeletal muscle after resistance exercise
Karlsson, H. K. R., Nilsson, P.-A., Nilsson, J., Chibalin, A. V., Zierath, J. R., & Blomstrand, E. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00430.2003 · Cited by 282 · see citing works
“Phosphorylation of four residues (Ser(411), Ser(418), Thr(421), and Ser(424)) in the COOH-terminal autoinhibitory domain is required for altering the conformation of p70 and making Thr(389) and Ser(404) in the linker domain and Thr(229) in the catalytic domain available for phosphorylation, thereby activating p70 (6,…”
Background
Mechanisms through which sulfur amino acids control protein metabolism and oxidative status
Métayer, S., Seiliez, I., Collin, A., Duchêne, S., Mercier, Y., Geraert, P., & Tesseraud, S. (2007) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2007.05.006 · Cited by 260 · see citing works
Follicle-stimulating Hormone Activation of Hypoxia-inducible Factor-1 by the Phosphatidylinositol 3-Kinase/AKT/Ras Homolog Enriched in Brain (Rheb)/Mammalian Target of Rapamycin (mTOR) Pathway Is Necessary for Induction of Select Protein Markers of Follicular Differentiation
Alam, H., Maizels, E. T., Park, Y., Ghaey, S., Feiger, Z. J., Chandel, N. S., & Hunzicker-Dunn, M. E. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401235200 · Cited by 267 · see citing works
Cardiac regulation by phosphoinositide 3-kinases and PTEN
Oudit, G. Y., & Penninger, J. M. (2008) · Cardiovascular Research · doi:10.1093/cvr/cvp014 · Cited by 243 · see citing works
Homer Interactions Are Necessary for Metabotropic Glutamate Receptor-Induced Long-Term Depression and Translational Activation
Ronesi, J. A., & Huber, K. M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5019-07.2008 · Cited by 244 · see citing works
“2A) (Dufner and Thomas, 1999).”
Cellular Senescence: Molecular Mechanisms, In Vivo Significance, and Redox Considerations
Müller, M. K. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2104 · Cited by 237 · see citing works
“Increased cell size is dependent on de novo protein synthesis and requires activated p70 S6 kinase to phosphorylate 40S ribosomal S6 kinase, a key component in the transcription of mRNAs (105).”
Human Cytomegalovirus Up-Regulates the Phosphatidylinositol 3-Kinase (PI3-K) Pathway: Inhibition of PI3-K Activity Inhibits Viral Replication and Virus-Induced Signaling
Johnson, R. A., Wang, X., Ma, X.-C., Huong, S., & Huang, E.-S. (2001) · Journal of Virology · doi:10.1128/jvi.75.13.6022-6032.2001 · Cited by 246 · see citing works
“To test this hypothesis, the small molecule rapamycin, which inhibits p70S6K activation or phosphorylation without affecting PI3-K activity, was utilized in a titer reduction assay (13, 17, 20 , 26, 71).”
Method
Tansley Review No. 120: Pathways to abscisic acid-regulated gene expression.
Rock, C. (2000) · New Phytologist · doi:10.1046/j.1469-8137.2000.00769.x · Cited by 245 · see citing works
Metabotropic Glutamate Receptor-Mediated Long-Term Depression: Molecular Mechanisms
Gladding, C. M., Fitzjohn, S. M., & Molnár, E. (2009) · Pharmacological Reviews · doi:10.1124/pr.109.001735 · Cited by 233 · see citing works
“For example, the PI3K-Akt-mTOR pathway mediates direct regulation of S6K but also modulates cap-dependent translation by 4E-BP (Banko et al., 2006).”
BackgroundInfluential
Up-regulation of Acetyl-CoA Carboxylase α and Fatty Acid Synthase by Human Epidermal Growth Factor Receptor 2 at the Translational Level in Breast Cancer Cells
Yoon, S., Lee, M.-Y., Park, S. W., Moon, J., Koh, Y.-K., Ahn, Y., Park, B., & Kim, K. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702854200 · Cited by 225 · see citing works
Cellular and molecular responses to increased skeletal muscle loading after irradiation.
Adams, G., Caiozzo, V., Haddad, F., & Baldwin, K. (2002) · American Journal of Physiology - Cell Physiology · doi:10.1152/ajpcell.00173.2002 · Cited by 227 · see citing works
“Increases in the phosphorylation of S6K1 and 4E-BP1 have been reported to be associated with an increase in translation and are known to occur in response to 1) increased muscle loading and/or 2) IGF-I receptor ligation (10, 11, 13, 23, 34, 62).”
Background
Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model
Ricciardi, S., Boggio, E. M., Grosso, S., Lonetti, G., Forlani, G., Stefanelli, G., Calcagno, E., Morello, N., Landsberger, N., Biffo, S., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddq563 · Cited by 223 · see citing works
“Activation of the p70 S6K depends on multiple phosphorylation events occurring in a hierarchical manner within the C-terminal autoinhibitory domain (40).”
Background
Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Δ716 Cdx2+/− compound mutant mice
Aoki, K., Tamai, Y., Horiike, S., Oshima, M., & Taketo, M. M. (2003) · Nature Genetics · doi:10.1038/ng1265 · Cited by 225 · see citing works
L-leucine availability regulates phosphatidylinositol 3-kinase, p70 S6 kinase and glycogen synthase kinase-3 activity in L6 muscle cells: evidence for the involvement of the mammalian target of rapamycin (mTOR) pathway in the L-leucine-induced up-regulation of system A amino acid transport.
Peyrollier, K., Hajduch, E., Blair, A., Hyde, R., & Hundal, H. (2000) · Biochemical Journal · doi:10.1042/bj3500361 · Cited by 221 · see citing works
Mammalian Target of Rapamycin: Discovery of Rapamycin Reveals a Signaling Pathway Important for Normal and Cancer Cell Growth
Gibbons, J. J., Abraham, R. T., & Yu, K. (2009) · Seminars in Oncology · doi:10.1053/j.seminoncol.2009.10.011 · Cited by 209 · see citing works
Novel Small Molecule Inhibitors of 3-Phosphoinositide-dependent Kinase-1*
Feldman, R., Wu, J. M., Polokoff, M., Kochanny, M., Dinter, H., Zhu, D.-G., Biroc, S., Alicke, B., Bryant, J., Yuan, S., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501367200 · Cited by 218 · see citing works
How Protein Kinase C Activation Protects Nerve Cells from Oxidative Stress-Induced Cell Death
Maher, P. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-09-02929.2001 · Cited by 218 · see citing works
PIK3CA mutations in human solid tumors: Role in sensitivity to various therapeutic approaches
Ligresti, G., Militello, L., Steelman, L. S., Cavallaro, A., Basile, F., Nicoletti, F., Stivala, F., McCubrey, J. A., & Libra, M. (2009) · Cell Cycle · doi:10.4161/cc.8.9.8255 · Cited by 214 · see citing works
S6K1 Phosphorylates and Regulates Fragile X Mental Retardation Protein (FMRP) with the Neuronal Protein Synthesis-dependent Mammalian Target of Rapamycin (mTOR) Signaling Cascade
Narayanan, U., Nalavadi, V., Nakamoto, M., Thomas, G., Ceman, S., Bassell, G. J., & Warren, S. T. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.c800055200 · Cited by 216 · see citing works
Self-citation
Coordinate regulation of translation by the PI 3-kinase and mTOR pathways
Martin, K. A., & Blenis, J. (2002) · Advances in cancer research · doi:10.1016/s0065-230x(02)86001-8 · Cited by 199 · see citing works
Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma
Rathmell, J. C., Elstrom, R., Cinalli, R. M., & Thompson, C. B. (2003) · European Journal of Immunology · doi:10.1002/eji.200324048 · Cited by 197 · see citing works
Sexual polyploidization in plants – cytological mechanisms and molecular regulation
Storme, N. D., & Geelen, D. (2013) · New Phytologist · doi:10.1111/nph.12184 · Cited by 223 · see citing works
MAD1 and c‐MYC regulate UBF and rDNA transcription during granulocyte differentiation
Poortinga, G., Hannan, K., Snelling, H., Walkley, C. R., Jenkins, A., Sharkey, K., Wall, M., Brandenburger, Y., Palatsides, M., Pearson, R., et al. (2004) · EMBO Journal · doi:10.1038/sj.emboj.7600335 · Cited by 198 · see citing works
“Finally, post-translational mechanisms, such as phosphorylation of the ribosomal subunit protein S6 by S6 kinase, also regulate the function of the ribosome (Dufner and Thomas, 1999).”
Background
Increase in S6K1 phosphorylation in human skeletal muscle following resistance exercise occurs mainly in type II muscle fibers
Koopman, R., Zorenc, A. H. G., Gransier, R. J. J., Cameron-Smith, D., & van Loon, L. J. C. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00530.2005 · Cited by 196 · see citing works
“The kinase activity of S6K1 is controlled by a series of phosphorylation steps at several Ser/Thr residues (12, 40).”
Background
A Continuous Molecular Roadmap to iPSC Reprogramming through Progression Analysis of Single-Cell Mass Cytometry
Zunder, E. R., Lujan, E., Goltsev, Y., Wernig, M., & Nolan, G. P. (2015) · Cell stem cell · doi:10.1016/j.stem.2015.01.015 · Cited by 177 · see citing works
Insulin Stimulates Postsynaptic Density-95 Protein Translation via the Phosphoinositide 3-Kinase-Akt-Mammalian Target of Rapamycin Signaling Pathway
Lee, C.-C., Huang, C., Wu, M.-Y., & Hsu, K. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414112200 · Cited by 199 · see citing works
The Insulin-like Growth Factor-Phosphatidylinositol 3-Kinase-Akt Signaling Pathway Regulates Myogenin Expression in Normal Myogenic Cells but Not in Rhabdomyosarcoma-derived RD Cells*
Xu, Q., & Wu, Z.-G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005030200 · Cited by 194 · see citing works
mTOR inhibitors: An overview
Neuhaus, P., Klupp, J., & Langrehr, J. (2001) · Liver transplantation · doi:10.1053/jlts.2001.24645 · Cited by 191 · see citing works
mTOR Signaling in Protein Translation Regulation: Implications in Cancer Genesis and Therapeutic Interventions
Showkat, M., Beigh, M. A., & Andrabi, K. I. (2014) · Molecular Biology International · doi:10.1155/2014/686984 · Cited by 191 · see citing works
“The phosphorylation of four serine/threonine-proline sites in the autoinhibitory domain opens the kinase domain and relieves autoinhibition, which then allows subsequent phosphorylations of critical sites in the kinase domain [55].”
Background
mTOR/p70S6k signalling alteration by Aβ exposure as well as in APP‐PS1 transgenic models and in patients with Alzheimer's disease
Lafay‐Chebassier, C., Paccalin, M., Page, G., Barc‐Pain, S., Perault‐Pochat, M. C., Gil, R., Pradier, L., & Hugon, J. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03187.x · Cited by 211 · see citing works
“mTOR can also phosphorylate kinase p70S6k that stimulates protein synthesis (Dufner and Thomas 1999).”
Background
Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer
Albert, J. M., Kim, K. W., Cao, C., & Lu, J. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0400 · Cited by 173 · see citing works
Effect of Branched-Chain Amino Acids on Muscle Atrophy in Cancer Cachexia
Eley, H. L., Russell, S. T., & Tisdale, M. J. (2007) · Biochemical Journal · doi:10.1042/bj20070651 · Cited by 184 · see citing works
IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK.
Starkman, B. G., Cravero, J., Delcarlo, M., & Loeser, R. (2005) · Biochemical Journal · doi:10.1042/bj20041636 · Cited by 184 · see citing works
Atrophy responses to muscle inactivity. I. Cellular markers of protein deficits.
Haddad, F., Roy, R. R., Zhong, H., Edgerton, V., & Baldwin, K. (2003) · Journal of applied physiology · doi:10.1152/japplphysiol.00317.2003 · Cited by 184 · see citing works
“The phosphorylation of p70S6k and of 4EBP1 has been reported to be associated with an increase in translation of mRNAs encoded for specific components of the translation machinery and for proteins in general, respectively ( 17 ).”
Background
Autophagy genes and ageing
Vellai, T. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.126 · Cited by 169 · see citing works
Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue.
Lynch, C., Patson, B., Anthony, J. C., Vaval, A., Jefferson, L., & Vary, T. (2002) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00084.2002 · Cited by 181 · see citing works
Amino Acids as Regulators and Components of Nonproteinogenic Pathways
Meijer, A. J. (2003) · Journal of Nutrition · doi:10.1093/jn/133.6.2057s · Cited by 188 · see citing works
Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin
Decker, T. W., Hipp, S., Ringshausen, I., Bogner, C., Oelsner, M., Schneller, F., & Peschel, C. (2002) · Blood · doi:10.1182/blood-2002-01-0189 · Cited by 157 · see citing works
Dendritic mRNAs encode diversified functionalities in hippocampal pyramidal neurons
Zhong, J. W., Zhang, T., & Bloch, L. M. (2006) · BMC Neuroscience · doi:10.1186/1471-2202-7-17 · Cited by 162 · see citing works
“Finally, we have an mRNA encoding S6 kinase, which could also be appropriately assigned to the next functional group of RNA translational regulators [28].”
Multiple Gq-Coupled Receptors Converge on a Common Protein Synthesis-Dependent Long-Term Depression That Is Affected in Fragile X Syndrome Mental Retardation
Volk, L. J., Pfeiffer, B. E., Gibson, J. R., & Huber, K. M. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2266-07.2007 · Cited by 164 · see citing works
“Feig and Lipton (1993) demonstrated that activation of mAChRs with CCh induced H leucine incorporation in CA1 dendrites.”
BackgroundInfluential
Regulation of cardiac and skeletal muscle protein synthesis by individual branched-chain amino acids in neonatal pigs
Escobar, J., Frank, J. W., Suryawan, A., Nguyen, H. V., Kimball, S. R., Jefferson, L. S., & Davis, T. A. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00402.2005 · Cited by 167 · see citing works
“mRNAs encode proteins involved in the protein synthetic machinery (17).”
Background
PGC-1α, a Key Modulator of p53, Promotes Cell Survival upon Metabolic Stress
Sen, N., Satija, Y. K., & Das, S. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.08.044 · Cited by 164 · see citing works
“We used p70S6K phosphorylation at Thr389 as a readout of mTOR activity (Brown et al., 1995). p70S6K activity can in turn be determined by phosphorylation of ribosomal S6 protein at Ser235/236 (Dufner and Thomas, 1999).”
PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia
Ola, R., Dubrac, A., Han, J., Zhang, F., Fang, J. S., Larrivée, B., Lee, M. M., Angulo‐Urarte, A., Kraehling, J. R., Genet, G., et al. (2016) · Nature Communications · doi:10.1038/ncomms13650 · Cited by 174 · see citing works
mTOR Controls FLIPS Translation and TRAIL Sensitivity in Glioblastoma Multiforme Cells
Panner, A., James, C. D., Berger, M. S., & Pieper, R. O. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.20.8809-8823.2005 · Cited by 154 · see citing works
“mTOR-dependent signaling is regulated by a variety of means including the PI3K/ Akt pathway (14, 24), amino acids (26), and ATP (12).”
Background
Control of p70 ribosomal protein S6 kinase and acetyl-CoA carboxylase by AMP-activated protein kinase and protein phosphatases in isolated hepatocytes.
Krause, U., Bertrand, L., & Hue, L. (2002) · European Journal of Biochemistry · doi:10.1046/j.1432-1033.2002.03074.x · Cited by 169 · see citing works
Protein kinases and transcription factors activation in response to UV-radiation of skin: implications for carcinogenesis
López-Camarillo, C., Aréchaga Ocampo, E., López Casamichana, M., Pérez-Plasencia, C., Álvarez-Sánchez, E., & Marchat, L. A. (2011) · International Journal of Molecular Sciences · doi:10.3390/ijms13010142 · Cited by 165 · see citing works
“UV-A-induced signal transduction leads to the activation of a complex network of downstream effector molecules, including RSK p70 and p90, also known as MAPKAP-K1, which in turn phosphorylate the 40S ribosomal protein S6, resulting in an increase of the translational machinery component [57].”
Background
Regulation of the pentose phosphate pathway by an androgen receptor–mTOR-mediated mechanism and its role in prostate cancer cell growth
Tsouko, E., Khan, A., White, M. A., Han, J., Shi, Y., Merchant, F. A., Sharpe, M. A., Xin, L., & Frigo, D. E. (2014) · Oncogenesis · doi:10.1038/oncsis.2014.18 · Cited by 158 · see citing works
FGF‐2 protects small cell lung cancer cells from apoptosis through a complex involving PKCε, B‐Raf and S6K2
Pardo, O., Wellbrock, C., Khanzada, U. K., Aubert, M., Arozarena, I., Davidson, S., Bowen, F., Parker, P., Filonenko, V., Gout, I., et al. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601198 · Cited by 158 · see citing works
“Ribosomal S6 kinases S6K1 and S6K2, also known as S6Ka and S6Kb (Gout et al, 1998; Shima et al, 1998; Lee-Frumen et al, 1999), both regulate the translational machinery (Dufner and Thomas, 1999).”
Background
The 17q23 Amplicon and Breast Cancer
Sinclair, C. S., Rowley, M., Naderi, A., & Couch, F. J. (2003) · Breast Cancer Research and Treatment · doi:10.1023/a:1023081624133 · Cited by 138 · see citing works
“RPS6KB1 has three known functions: (1) Protein synthesis by inducing selective translation of mRNAs that encode components of the translation apparatus and are essential for cell growth and proliferation [36].”
Background
The complexes of mammalian target of rapamycin
Zhou, H., & Huang, S.-L. (2010) · Current protein and peptide science · doi:10.2174/138920310791824093 · Cited by 156 · see citing works

Authors: Dufner, A., & Thomas, G.
Affiliations: Friedrich Miescher Institute (CH)
Corresponding author: Thomas, George
ORCID: Dufner, Almut
Venue: Experimental Cell Research
Publisher: Elsevier BV
Published: 1999-11
Volume: 253
Issue: 1
Pages: 100-109
ISSN: 0014-4827 (ISSN-L)
DOI: 10.1006/excr.1999.4683
OpenAlex: W1963723155
Cited by: 676
References: 0
Citations by year: 2026: 3 · 2025: 8 · 2024: 7 · 2023: 8 · 2022: 11 · 2021: 20 · 2020: 9 · 2019: 9 · 2018: 13 · 2017: 22 · 2016: 20 · 2015: 24 · 2014: 21 · 2013: 20 · 2012: 28
FWCI: 14.81
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Experimental Cell Research (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: RSK, S6K1, S6K2, translational regulation, PI3K signaling, PDK1, mTOR, kinase activation, activation loop, ribosome biogenesis, cell growth regulation, amino acid availability
MeSH terms: Cell Division, Enzyme Activation, Isoenzymes, Protein Kinase C, Protein Biosynthesis, Signal Transduction, Ribosomal Protein S6 Kinases, Sirolimus, Cell Size

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Ribosomal S6 Kinase Signaling and the Control of Translation

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Record

About these checks