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RAS/ERK Signaling Promotes Site-specific Ribosomal Protein S6 Phosphorylation Via RSK And Stimulates Cap-dependent Translation*

Philippe P Roux, D. Shahbazian, H. Vu, M. Holz, M. Cohen, J. Taunton, N. Sonenberg, J. Blenis
Published 2007 · Biology, Medicine

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Converging signals from the mammalian target of rapamycin (mTOR) and phosphoinositide 3-kinase (PI3K) pathways are well established to modulate translation initiation. Less is known regarding the molecular basis of protein synthesis regulated by other inputs, such as agonists of the Ras/extracellular signal-regulated kinase (ERK) signaling cascade. Ribosomal protein (rp) S6 is a component of the 40S ribosomal subunit that becomes phosphorylated at several serine residues upon mitogen stimulation, but the exact molecular mechanisms regulating its phosphorylation and the function of phosphorylated rpS6 is poorly understood. Here, we provide evidence that activation of the p90 ribosomal S6 kinases (RSKs) by serum, growth factors, tumor promoting phorbol esters, and oncogenic Ras is required for rpS6 phosphorylation downstream of the Ras/ERK signaling cascade. We demonstrate that while ribosomal S6 kinase 1 (S6K1) phosphorylates rpS6 at all sites, RSK exclusively phosphorylates rpS6 at Ser235/236 in vitro and in vivo using an mTOR-independent mechanism. Mutation of rpS6 at Ser235/236 reveals that phosphorylation of these sites promotes its recruitment to the 7-methylguanosine cap complex, suggesting that Ras/ERK signaling regulates assembly of the translation preinitiation complex. These data demonstrate that RSK provides an mTOR-independent pathway linking the Ras/ERK signaling cascade to the translational machinery.
This paper references
Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases
J. Chung (1992)
Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes.
V. Rajasekhar (2003)
Characterization of Regulatory Events Associated with Membrane Targeting of p90 Ribosomal S6 Kinase 1
S. A. Richards (2001)
Translational Regulatory Mechanisms in Persistent Forms of Synaptic Plasticity
R. J. Kelleher (2004)
Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression
D. Fingar (2004)
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)
MAP2 kinase and 70K S6 kinase lie on distinct signalling pathways
L. Ballou (1991)
Distinct mechanisms for the activation of the RSK kinases/MAP2 kinase/pp90rsk and pp70-S6 kinase signaling systems are indicated by inhibition of protein synthesis.
J. Blenis (1991)
mTOR signaling to translation.
A. Gingras (2004)
Structural Bioinformatics-Based Design of Selective, Irreversible Kinase Inhibitors
M. Cohen (2005)
A protein kinase from Xenopus eggs specific for ribosomal protein S6.
E. Erikson (1985)
Phosphorylation of p90 Ribosomal S6 Kinase (RSK) Regulates Extracellular Signal-Regulated Kinase Docking and RSK Activity
Philippe P Roux (2003)
PI3-kinase and TOR: PIKTORing cell growth.
C. Richardson (2004)
mTOR and S6K1 Mediate Assembly of the Translation Preinitiation Complex through Dynamic Protein Interchange and Ordered Phosphorylation Events
M. Holz (2005)
Identification of the 40 S ribosomal protein S6 phosphorylation sites induced by cycloheximide.
J. Krieg (1988)
The Tumor Suppressor DAP Kinase Is a Target of RSK-Mediated Survival Signaling
R. Anjum (2005)
Gene-Specific Regulation by General Translation Factors
T. E. Dever (2002)
Tuberous Sclerosis Complex Gene Products, Tuberin and Hamartin, Control mTOR Signaling by Acting as a GTPase-Activating Protein Complex toward Rheb
A. Tee (2003)
Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase.
Philippe P Roux (2004)
Upstream and downstream of mTOR.
N. Hay (2004)
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 (2004)
Kinetic determination of the effects of ADP-ribosylation on the interaction of eukaryotic elongation factor 2 with ribosomes.
O. Nygård (1990)
ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions
Philippe P Roux (2004)
The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity
D. Shahbazian (2006)
Proliferation, but not growth, blocked by conditional deletion of 40S ribosomal protein S6.
S. Volarević (2000)
Phosphorylation and Functional Inactivation of TSC2 by Erk Implications for Tuberous Sclerosisand Cancer Pathogenesis
L. Ma (2005)
Characterization of S6K2, a novel kinase homologous to S6K1
K. K. Lee-Fruman (1999)
When translation meets transformation: the mTOR story
J. Averous (2006)
Changes in ribosome function by cAMP-dependent and cAMP-independent phosphorylation of ribosomal protein S6.
S. J. Burkhard (1983)
Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis.
Igor Ruvinsky (2005)
Identification of 40 S ribosomal protein S6 phosphorylation sites in Swiss mouse 3T3 fibroblasts stimulated with serum.
H. Bandi (1993)
Ribosomal protein S6 phosphorylation: from protein synthesis to cell size.
Igor Ruvinsky (2006)
p70 S6 Kinase Is Regulated by Protein Kinase Cζ and Participates in a Phosphoinositide 3-Kinase-Regulated Signalling Complex
A. Romanelli (1999)
Targets and mechanisms for the regulation of translation in malignant transformation
M. Clemens (2004)
Multiple phosphorylation of ribosomal protein S6 during transition of quiescent 3T3 cells into early G1, and cellular compartmentalization of the phosphate donor.
G. Thomas (1979)
RSK and MSK in MAP kinase signalling
C. Hauge (2006)
Involvement of Proteasome α-Subunit PSMA7 in Hepatitis C Virus Internal Ribosome Entry Site-Mediated Translation
M. Krueger (2001)
Regulation of cap-dependent translation by eIF4E inhibitory proteins
J. Richter (2005)
The phosphorylation of liver ribosomal proteins in vivo. Evidence that only a single small subunit protein (S6) is phosphorylated.
A. Gressner (1974)

This paper is referenced by
Mechanisms of Drug Resistance in Cancer Therapy
M. Mandala (2018)
mTOR signaling for biological control and cancer
A. Alayev (2013)
Downstream Targets of mTORC1
Bruno D. Fonseca (2009)
GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine
R. Ferro (2018)
Insulin signaling in primary adipocytes in insulin sensitive and insulin resistant states
Siri Fagerholm (2013)
Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles
D. Adhikari (2010)
Identification of novel signaling pathways in T cells mediated by protein kinase C, Carma1, MALT1 and Bcl10
K. Hamilton (2014)
Analyses of improved long term memory in SHARP1 and SHARP2 double knockout mice
A. Shahmoradi (2014)
Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer
Hayley J. Donnella (2017)
Synthetic lethality screen identifies RPS6KA2 as modifier of epidermal growth factor receptor activity in pancreatic cancer.
N. Milošević (2013)
Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex
A. Shahmoradi (2015)
TGF‐β inhibits prolactin‐induced expression of β‐casein by a Smad3‐dependent mechanism
Wen-jun Wu (2008)
S6 inhibition contributes to isoflurane neurotoxicity in the developing brain.
Guohui Li (2015)
Quantitative phosphoproteomics reveals novel phosphorylation events in insulin signaling regulated by protein phosphatase 1 regulatory subunit 12A.
X. Zhang (2014)
TAp73 contributes to the oxidative stress response by regulating protein synthesis
A. Marini (2018)
Tris (dibenzylideneacetone) dipalladium: a small-molecule palladium complex is effective in inducing apoptosis in chronic lymphocytic leukemia B-cells
N. Kay (2016)
Nucleolar Signaling Determines Cell Fate: The RP-Mdm2-p53 Axis Fine-Tunes Cellular Homeostasis
Y. Liu (2014)
Protein abundance of AKT and ERK pathway components governs cell type‐specific regulation of proliferation
Lorenz Adlung (2017)
Extra-Ribosome Functions of Ribosomal Proteins
D. Franklin (2016)
p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis.
N. Theodosakis (2017)
Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling.
M. Drummond (2009)
The oncoprotein H-RasV12 increases mitochondrial metabolism
S. Telang (2007)
Transient and rapid activation of Akt/GSK‐3β and mTORC1 signaling by D3 dopamine receptor stimulation in dorsal striatum and nucleus accumbens
Marie-Josèphe Salles (2013)
Activity in T Cells Responding to IL-2 S-Phase Entry and Maintains S 6 Kinase Protein / Caspase-8-Signaling Axis Promotes A Fas-Associated Death Domain
A. Arechiga (2007)
Proteogenomic analysis of human chromosome 9-encoded genes from human samples and lung cancer tissues.
Jung-Mo Ahn (2014)
Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKA- and EP1/Ca2+-mediated mechanism in the human pancreatic carcinoma cell line PANC-1.
Hui-Hua Chang (2015)
Rationale for a Combination Therapy Consisting of MCL1- and MEK-Inhibitors in Acute Myeloid Leukemia
K. Seipel (2019)
mTORC1 Signaling Is Palmitoylation-Dependent in Hippocampal Neurons and Non-neuronal Cells and Involves Dynamic Palmitoylation of LAMTOR1 and mTOR
S. Sanders (2019)
Translational control by oncogenic signaling pathways.
Beichen Gao (2015)
Protein Phosphorylation as a Key Mechanism of mTORC1/2 Signaling Pathways
E. Tchevkina (2012)
Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization.
Benjamin A. Mooso (2012)
A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits
David M. Feliciano (2013)
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