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S6K1−/−/S6K2−/− Mice Exhibit Perinatal Lethality And Rapamycin-Sensitive 5′-Terminal Oligopyrimidine MRNA Translation And Reveal A Mitogen-Activated Protein Kinase-Dependent S6 Kinase Pathway

M. Pende, S. H. Um, V. Mieulet, Melanie Sticker, V. L. Goss, Jurgen Mestan, M. Müller, S. Fumagalli, S. Kozma, G. Thomas
Published 2004 · Biology, Medicine

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ABSTRACT Activation of 40S ribosomal protein S6 kinases (S6Ks) is mediated by anabolic signals triggered by hormones, growth factors, and nutrients. Stimulation by any of these agents is inhibited by the bacterial macrolide rapamycin, which binds to and inactivates the mammalian target of rapamycin, an S6K kinase. In mammals, two genes encoding homologous S6Ks, S6K1 and S6K2, have been identified. Here we show that mice deficient for S6K1 or S6K2 are born at the expected Mendelian ratio. Compared to wild-type mice, S6K1−/− mice are significantly smaller, whereas S6K2 −/− mice tend to be slightly larger. However, mice lacking both genes showed a sharp reduction in viability due to perinatal lethality. Analysis of S6 phosphorylation in the cytoplasm and nucleoli of cells derived from the distinct S6K genotypes suggests that both kinases are required for full S6 phosphorylation but that S6K2 may be more prevalent in contributing to this response. Despite the impairment of S6 phosphorylation in cells from S6K1 −/−/S6K2 −/− mice, cell cycle progression and the translation of 5′-terminal oligopyrimidine mRNAs were still modulated by mitogens in a rapamycin-dependent manner. Thus, the absence of S6K1 and S6K2 profoundly impairs animal viability but does not seem to affect the proliferative responses of these cell types. Unexpectedly, in S6K1 −/−/S6K2 −/− cells, S6 phosphorylation persisted at serines 235 and 236, the first two sites phosphorylated in response to mitogens. In these cells, as well as in rapamycin-treated wild-type, S6K1 −/−, and S6K2 −/− cells, this step was catalyzed by a mitogen-activated protein kinase (MAPK)-dependent kinase, most likely p90rsk. These data reveal a redundancy between the S6K and the MAPK pathways in mediating early S6 phosphorylation in response to mitogens.
This paper references
10.1093/emboj/16.12.3693
Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k
H. B. Jefferies (1997)
10.1101/087969458.30.389
14 Ribosomal Protein S6 Phosphorylation and Signal Transduction
H. B. Jefferies (1996)
10.1038/35050135
Hypoinsulinaemia, glucose intolerance and diminished β-cell size in S6K1-deficient mice
M. Pende (2000)
10.1073/PNAS.95.4.1432
RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1.
P. E. Burnett (1998)
10.1038/35010581
An encore for ribosome biogenesis in the control of cell proliferation
G. Thomas (2000)
10.1074/jbc.274.48.34493
Immunopurified Mammalian Target of Rapamycin Phosphorylates and Activates p70 S6 Kinase α in Vitro *
S. Isotani (1999)
10.1073/PNAS.85.13.4720
Differential regulation of S6 phosphorylation by insulin and epidermal growth factor in Swiss mouse 3T3 cells: insulin activation of type 1 phosphatase.
A. Olivier (1988)
10.1128/MCB.17.9.5426
The insulin-induced signalling pathway leading to S6 and initiation factor 4E binding protein 1 phosphorylation bifurcates at a rapamycin-sensitive point immediately upstream of p70s6k.
S. R. von Manteuffel (1997)
10.1128/MCB.22.23.8101-8113.2002
Transduction of Growth or Mitogenic Signals into Translational Activation of TOP mRNAs Is Fully Reliant on the Phosphatidylinositol 3-Kinase-Mediated Pathway but Requires neither S6K1 nor rpS6 Phosphorylation
M. Stolovich (2002)
10.1126/SCIENCE.285.5436.2126
Drosophila S6 kinase: a regulator of cell size.
J. Montagne (1999)
10.1073/PNAS.80.4.926
Ordered phosphorylation of 40S ribosomal protein S6 after serum stimulation of quiescent 3T3 cells.
J. Martín-Pérez (1983)
10.1073/PNAS.95.9.5033
Targeted disruption of p70(s6k) defines its role in protein synthesis and rapamycin sensitivity.
H. Kawasome (1998)
10.1038/334715a0
Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II
T. Sturgill (1988)
10.1016/S0303-7207(99)00061-1
Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction
M. Frödin (1999)
10.1074/jbc.M006969200
Regulation of Ribosomal S6 Kinase 2 by Effectors of the Phosphoinositide 3-Kinase Pathway*
K. Martin (2001)
10.1016/S0960-9822(02)01091-6
TOR Deficiency in C. elegans Causes Developmental Arrest and Intestinal Atrophy by Inhibition of mRNA Translation
Xiaomeng Long (2002)
10.1128/MCB.19.4.2485
p70S6K Controls Selective mRNA Translation during Oocyte Maturation and Early Embryogenesis inXenopus laevis
M. S. Schwab (1999)
10.1093/emboj/20.16.4370
Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase
X. Wang (2001)
10.1006/BBRC.1998.9784
Cloning and Characterization of p70S6KβDefines a Novel Family of p70 S6 Kinases
Masao Saitoh (1998)
10.1016/s0021-9258(18)80057-6
In vivo phosphorylation and activation of ribosomal protein S6 kinases during Xenopus oocyte maturation.
E. Erikson (1989)
10.1073/PNAS.95.14.8351
Neurabin is a synaptic protein linking p70 S6 kinase and the neuronal cytoskeleton.
P. E. Burnett (1998)
10.1016/S0959-437X(99)80007-0
Target of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation.
P. Dennis (1999)
10.1016/S0091-679X(08)61797-5
Preparation of isolated rat liver cells.
P. Seglen (1976)
10.1126/SCIENCE.1075762
The Protein Kinase Complement of the Human Genome
G. Manning (2002)
10.1016/s0021-9258(18)53642-5
Identification of 40 S ribosomal protein S6 phosphorylation sites in Swiss mouse 3T3 fibroblasts stimulated with serum.
H. Bandi (1993)
10.1016/s0021-9258(19)50382-9
Ordered multisite phosphorylation of Xenopus ribosomal protein S6 by S6 kinase II.
R. Wettenhall (1992)
10.1016/S0092-8674(02)01009-7
Identification of TOR Signaling Complexes More TORC for the Cell Growth Engine
R. Abraham (2002)
10.1016/S0092-8674(00)00117-3
TOR, a Central Controller of Cell Growth
T. Schmelzle (2000)
10.1016/0014-5793(95)01170-J
Comparison of the specificities of p70 S6 kinase and MAPKAP kinase‐1 identifies a relatively specific substrate for p70 S6 kinase: the N‐terminal kinase domain of MAPKAP kinase‐1 is essential for peptide phosphorylation
Ian A. Leighton (1995)
10.1101/GAD.887201
Regulation of translation initiation by FRAP/mTOR.
A. Gingras (2001)
10.1101/087969458.30.363
13 Translational Control of Ribosomal Protein mRNAs in Eukaryotes
O. Meyuhas (1996)
10.1016/0076-6879(86)21017-4
High efficiency fusion procedure for producing monoclonal antibodies against weak immunogens.
R. Lane (1986)
10.1016/s0021-9258(18)37981-x
Identification of the 40 S ribosomal protein S6 phosphorylation sites induced by cycloheximide.
J. Krieg (1988)
10.1128/MCB.23.3.852-863.2003
Protein Kinase C Phosphorylates Ribosomal Protein S6 Kinase βII and Regulates Its Subcellular Localization
Taras Valovka (2003)
10.1016/S0014-5793(01)02651-5
Effects of MAP kinase cascade inhibitors on the MKK5/ERK5 pathway
N. Mody (2001)
10.1073/PNAS.91.10.4441
Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family.
H. B. Jefferies (1994)
10.1016/s0021-9258(17)41789-3
Elongation factor-1 alpha mRNA is selectively translated following mitogenic stimulation.
H. B. Jefferies (1994)
10.1126/SCIENCE.1063518
Mammalian TOR: A Homeostatic ATP Sensor
P. Dennis (2001)
10.1038/sj.onc.1202895
Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); A novel nuclear target of Akt
Hyongjong Koh (1999)
10.1002/j.1460-2075.1990.tb08095.x
Oncogenic activation of the human trk proto‐oncogene by recombination with the ribosomal large subunit protein L7a.
A. Ziemiecki (1990)
10.1038/358070A0
Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase
C. Kuo (1992)
10.1038/sj.onc.1202894
Characterization of S6K2, a novel kinase homologous to S6K1
K. K. Lee-Fruman (1999)
10.1101/GAD.1089403
Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2.
X. Peng (2003)
10.1016/S0092-8674(00)81878-4
MLP-Deficient Mice Exhibit a Disruption of Cardiac Cytoarchitectural Organization, Dilated Cardiomyopathy, and Heart Failure
S. Arber (1997)
10.1074/JBC.M111782200
Nerve Growth Factor Specifically Stimulates Translation of Eukaryotic Elongation Factor 1A-1 (eEF1A-1) mRNA by Recruitment to Polyribosomes in PC12 Cells*
E. Petroulakis (2002)
10.1101/GAD.995802
Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E.
D. Fingar (2002)
10.1002/j.1460-2075.1992.tb05226.x
Identification and early activation of a Xenopus laevis p70s6k following progesterone‐induced meiotic maturation.
H. Lane (1992)
10.1073/PNAS.91.24.11477
Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins.
N. Terada (1994)
10.1093/emboj/17.22.6649
Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase
H. Shima (1998)
10.1007/978-1-4612-4826-2_13
"Single-shot" intrasplenic immunization for the production of monoclonal antibodies.
M. Spitz (1986)
10.1126/SCIENCE.279.5351.707
Phosphorylation and activation of p70s6k by PDK1.
N. Pullen (1998)
10.1074/jbc.273.46.30061
Molecular Cloning and Characterization of a Novel p70 S6 Kinase, p70 S6 Kinase β Containing a Proline-rich Region*
I. Gout (1998)
10.1126/SCIENCE.2660260
Altering the genome by homologous recombination.
M. Capecchi (1989)
10.1002/(SICI)1098-2795(199703)46:3<383::AID-MRD18>3.0.CO;2-#
Ribosomal S6 kinase p90rsk and mRNA cap‐binding protein eIF4E phosphorylations correlate with MAP kinase activation during meiotic reinitiation of mouse oocytes
Anne-Claude Gavin (1997)
10.1073/PNAS.88.10.4171
Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily.
P. F. Jones (1991)
10.1093/emboj/19.12.2924
A phosphoserine‐regulated docking site in the protein kinase RSK2 that recruits and activates PDK1
M. Frödin (2000)
10.1016/0076-6879(86)21006-X
Single-shot" intrasplenic immunization for the production of monoclonal antibodies.
M. Spitz (1986)
Translational control of gene expression
N. Sonenberg (2000)
10.1074/JBC.C200665200
The Mammalian Target of Rapamycin (mTOR) Partner, Raptor, Binds the mTOR Substrates p70 S6 Kinase and 4E-BP1 through Their TOR Signaling (TOS) Motif*
H. Nojima (2003)
10.1016/S0079-6603(00)65003-1
Role of S6 phosphorylation and S6 kinase in cell growth.
S. Volarević (2001)
10.1002/j.1460-2075.1994.tb06418.x
Nuclear localization of p85s6k: functional requirement for entry into S phase.
C. Reinhard (1994)
10.1016/s0021-9258(18)54634-2
Mitogen-activated 70K S6 kinase. Identification of in vitro 40 S ribosomal S6 phosphorylation sites.
S. Ferrari (1991)



This paper is referenced by
Application of the [-32 P ] ATP kinase assay to study anabolic signaling in human skeletal muscle
C. McGlory (2014)
10.1042/BST0390495
Regulation of the SREBP transcription factors by mTORC1.
C. Lewis (2011)
10.1038/cgt.2011.55
SV40 T/t-common polypeptide inhibits angiogenesis and growth of HER2-overexpressing human ovarian cancer
S-P Hsueh (2011)
10.1002/jcb.25458
Aggregation of Ribosomal Protein S6 at Nucleolus Is Cell Cycle‐Controlled and Its Function in Pre‐rRNA Processing Is Phosphorylation Dependent
Duo Zhang (2016)
10.1038/sj.emboj.7601166
The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity
D. Shahbazian (2006)
10.1074/jbc.M109.071142
Ribosomal Protein S6 Kinase Is a Critical Downstream Effector of the Target of Rapamycin Complex 1 for Long-term Facilitation in Aplysia*
Daniel B. Weatherill (2010)
10.4161/cc.7.21.6965
Aging: ROS or TOR
M. V. Blagosklonny (2008)
10.2165/00063030-200721020-00003
Targeting the Phosphatidylinositol 3-Kinase Pathway in Airway Smooth Muscle
Vera P Krymskaya (2012)
Hormonal and Nutrient Signalling to Protein Kinase B and Mammalian Target of Rapamycin in Pancreatic Beta-Cells
Norhan Mostafa (2012)
10.1523/JNEUROSCI.2866-14.2015
Dynamics of Elongation Factor 2 Kinase Regulation in Cortical Neurons in Response to Synaptic Activity
Justin W. Kenney (2015)
10.1128/MCB.01079-13
Control of Paip1-Eukayrotic Translation Initiation Factor 3 Interaction by Amino Acids through S6 Kinase
Y. Martineau (2014)
10.1042/BST20110682
Roles of the mammalian target of rapamycin, mTOR, in controlling ribosome biogenesis and protein synthesis.
V. Iadevaia (2012)
10.1074/jbc.M112.427351
Mammalian Target of Rapamycin Complex 1 (mTORC1) Plays a Role in Pasteurella multocida Toxin (PMT)-induced Protein Synthesis and Proliferation in Swiss 3T3 Cells*
H. Oubrahim (2012)
10.1371/journal.pone.0005618
Mice Deficient in Ribosomal Protein S6 Phosphorylation Suffer from Muscle Weakness that Reflects a Growth Defect and Energy Deficit
Igor Ruvinsky (2009)
Molecular mechanisms of ovarian follicular development and early embryogenesis
G. Nagaraju (2014)
10.1134/S1607672910050017
Time course of ribosomal kinase activity during hindlimb unloading
E. Lysenko (2010)
10.1017/S1461145709991192
Effects of neonatal MK-801 treatment on p70S6K-S6/eIF4B signal pathways and protein translation in the frontal cortex of the developing rat brain.
S. Kim (2010)
10.1016/j.febslet.2007.07.047
Identification of S6K2 as a centrosome‐located kinase
R. Rossi (2007)
10.1074/jbc.M607836200
Regulation of S6 Kinase 1 Activation by Phosphorylation at Ser-411*
Z. Hou (2007)
10.1016/j.celrep.2012.11.020
S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1.
Vered Ben-Hur (2013)
10.1016/j.immuni.2012.02.020
Regulation of actin dynamics by protein kinase R control of gelsolin enforces basal innate immune defense.
Aaron T Irving (2012)
10.1242/jeb.066225
Regulation of the mTOR signaling network in hibernating thirteen-lined ground squirrels
C. Wu (2012)
10.1038/sj.onc.1209888
mTOR, translation initiation and cancer
Y. Mamane (2006)
10.1016/j.drup.2008.03.001
Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment.
B. Jiang (2008)
10.1016/j.cellsig.2015.04.004
Two widely used RSK inhibitors, BI-D1870 and SL0101, alter mTORC1 signaling in a RSK-independent manner.
M. Roffé (2015)
10.1172/JCI77361
Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity.
Shihyin Tsai (2015)
10.1128/MCB.01537-08
Interferon-Dependent Engagement of Eukaryotic Initiation Factor 4B via S6 Kinase (S6K)- and Ribosomal Protein S6K-Mediated Signals
B. Kroczynska (2009)
10.1007/s00726-012-1445-1
Phosphorylation of nuclear and cytoplasmic pools of ribosomal protein S6 during cell cycle progression
M. Rosner (2012)
10.1158/0008-5472.CAN-10-3253
S6 kinase 2 promotes breast cancer cell survival via Akt.
S. Sridharan (2011)
regulatory inputs from oncogenic and anabolic pathways
X. Wang (2014)
regulation of protein turnover proper target phosphorylation in muscle cells maintaining S6 kinase inactivation impairs growth and translational
V. Oorschot (2016)
10.1210/me.2010-0087
cAMP-dependent activation of mammalian target of rapamycin (mTOR) in thyroid cells. Implication in mitogenesis and activation of CDK4.
Sara Blancquaert (2010)
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