Affinage

RPS6

Small ribosomal subunit protein eS6 · UniProt P62753

Round 2 corrected
Length
249 aa
Mass
28.7 kDa
Annotated
2026-04-28
130 papers in source corpus 61 papers cited in narrative 60 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RPS6 (eS6) is a structural component of the 40S ribosomal subunit whose five conserved C-terminal serine residues (Ser235, Ser236, Ser240, Ser244, Ser247) are phosphorylated by p70 S6K1/S6K2 downstream of the PI3K–mTORC1–PDK1 axis and by p90 RSK, serving as a central signaling node that couples nutrient and growth-factor sensing to translational control (PMID:3257566, PMID:1939282, PMID:9465032). Phosphorylation of rpS6 selectively promotes translation of short-CDS mRNAs through progressive dephosphorylation as ribosomes traverse longer open reading frames, while genome-wide ribosome profiling in yeast demonstrates that rpS6 phosphorylation does not broadly regulate 5′TOP mRNA translation (PMID:34871442, PMID:26582391). Beyond translation, rpS6 phosphorylation drives the ribosome biogenesis transcriptional program, mediates compensatory organ hypertrophy through cyclin D1/E regulation, controls blood–testis barrier dynamics via F-actin reorganization, provides positive feedback to mTORC2/Akt signaling, and defines a wound-healing activation zone in skin (PMID:23318442, PMID:25229342, PMID:22948214, PMID:24557881, PMID:37098351). Somatic activating mutations in RPS6 (e.g., p.R232H) cause hemimegalencephaly-associated cortical dysplasia through increased cell proliferation (PMID:31411685).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1981 Medium

    Early kinetic studies established that rpS6 phosphorylation occurs rapidly after mitogenic stimulation and correlates with mRNA recruitment into polysomes, raising the hypothesis that S6 phosphorylation facilitates translational activation.

    Evidence Polysome profiling and S6 phosphorylation kinetics in serum-stimulated HeLa cells

    PMID:7333277

    Open questions at the time
    • Correlation does not establish causation between S6 phosphorylation and mRNA recruitment
    • No identification of which mRNAs are affected
  2. 1984 Medium

    S6 phosphorylation was shown to induce conformational changes in the 40S subunit, altering accessibility of multiple ribosomal proteins, providing a biophysical mechanism by which S6 phosphorylation could modulate ribosome function.

    Evidence Reductive methylation accessibility assay comparing phosphorylated vs. unphosphorylated ribosomes

    PMID:6693389

    Open questions at the time
    • Single method; no functional translation consequence demonstrated
    • No structural resolution of conformational changes
  3. 1991 High

    Purification and characterization of p70 S6K established that a single mitogen-activated kinase phosphorylates rpS6 on exactly five C-terminal serines (Ser235/236/240/244 plus a fifth site), matching the in vivo pattern, and that the kinase itself is regulated by phosphorylation reversible by PP2A.

    Evidence Biochemical purification from Swiss 3T3 cells, in vitro kinase assay with 40S subunits, tryptic phosphopeptide mapping, PP2A inactivation

    PMID:1939282 PMID:3257566

    Open questions at the time
    • Upstream signaling pathway not yet defined
    • Identity of the fifth low-stoichiometry site uncertain
  4. 1995 High

    The discovery that rapamycin selectively inhibits p70 S6K and that FRAP/mTOR kinase activity is required for p70 S6K activation placed rpS6 phosphorylation downstream of the rapamycin-sensitive mTOR pathway, distinct from the Ras–MAPK cascade.

    Evidence Selective rapamycin inhibition in multiple cell lines; FRAP kinase-dead mutants failing to activate S6K; dominant-negative Ras/Raf not blocking S6K

    PMID:1380182 PMID:7566123 PMID:8090223

    Open questions at the time
    • Direct phosphorylation of S6K by mTOR not yet demonstrated
    • Mechanism of rapamycin resistance in truncation mutants unclear
  5. 1995 High

    Mapping of three nuclear localization signals in the C-terminal half of rpS6 and identification of a distinct nucleolar-targeting domain established that rpS6 traffics through the nucleus/nucleolus, consistent with ribosome biogenesis roles.

    Evidence Deletion mutagenesis of S6–β-galactosidase chimeras in L cells

    PMID:8590812

    Open questions at the time
    • Functional consequence of nuclear localization for rpS6 not tested
    • Whether phosphorylation regulates NLS function unknown
  6. 1998 High

    Direct phosphorylation of S6K1 at Thr389 by mTOR was demonstrated in vitro and shown to be essential for S6K activity, while amino acid withdrawal inactivates S6K through a pathway independent of Akt, establishing amino acid sensing as a distinct input to rpS6 phosphorylation.

    Evidence In vitro kinase assay with immunoprecipitated mTOR, phosphosite mapping; amino acid deprivation in CHO cells with PI3K/mTOR inhibitors

    PMID:9465032 PMID:9693128

    Open questions at the time
    • Amino acid sensing mechanism upstream of mTOR not identified
    • Relative contributions of S6K1 vs. S6K2 to rpS6 phosphorylation unclear
  7. 2003 High

    The TSC1/2–Rheb axis was identified as the critical link between PI3K/Akt and mTOR/S6K: TSC2 acts as a GAP for Rheb, and loss-of-function TSC mutations constitutively hyperphosphorylate rpS6, explaining the elevated S6K activity in tuberous sclerosis.

    Evidence GTPase assays with purified Rheb, genetic epistasis, TSC2 disease-mutant analysis, S6 phosphorylation in TSC2-null cells with tuberin re-expression

    PMID:12045200 PMID:12820960

    Open questions at the time
    • How Rheb directly activates mTOR kinase not resolved
    • Tissue-specific consequences of TSC-driven rpS6 hyperphosphorylation not fully explored
  8. 2005 High

    The mTOR/S6K1/eIF3 dynamic scaffold model revealed how S6K1 basally associates with the eIF3 translation initiation complex and, upon mTOR-mediated phosphorylation, dissociates to phosphorylate eIF4B, providing a mechanistic link between rpS6 kinase activation and translation initiation complex remodeling.

    Evidence Sequential co-immunoprecipitation of mTOR, S6K1, eIF3, and eIF4B with rapamycin treatment

    PMID:16006006 PMID:16286006

    Open questions at the time
    • Whether rpS6 phosphorylation itself contributes to eIF3 complex dynamics unknown
    • Stoichiometry and kinetics of scaffold assembly not defined
  9. 2008 High

    S6K1 knockout mice showed extended lifespan and resistance to age-related pathologies, while hypothalamic S6K manipulation bidirectionally controlled energy homeostasis, establishing the S6K–rpS6 axis as a systemic regulator of aging and metabolism in mammals.

    Evidence S6K1 knockout mouse lifespan and metabolic analysis; bilateral adenoviral injection of S6K variants into rat mediobasal hypothalamus

    PMID:19041762 PMID:19797661

    Open questions at the time
    • Relative contribution of rpS6 phosphorylation vs. other S6K substrates to lifespan extension not resolved
    • Human translatability unknown
  10. 2013 High

    Two independent genetic models—S6K1/S6K2 double-knockout mice and rpS6 non-phosphorylatable knock-in mice—converged on the discovery that rpS6 phosphorylation specifically controls the ribosome biogenesis transcriptional program, establishing a non-translational function for rpS6 phosphorylation.

    Evidence Whole-genome microarray of total and polysomal liver RNA from S6K DKO and rpS6 knock-in mice after feeding

    PMID:23318442

    Open questions at the time
    • Transcription factor mediating rpS6 phosphorylation-dependent RiBi gene induction not identified
    • Whether this operates through a ribosome-free rpS6 pool unclear
  11. 2014 High

    rpS6 phosphorylation was identified as the specific mTORC1-S6K1 effector mediating compensatory renal hypertrophy, acting through cyclin D1/E regulation; additionally, rpS6 was found to provide positive feedback to mTORC2/Akt signaling through direct physical interaction with mTORC2 components.

    Evidence rpS6 phospho-site knock-in mice with uninephrectomy; co-IP of rpS6 with mTORC2 components; bidirectional manipulation of rpS6 affecting Akt-Ser473 phosphorylation

    PMID:24557881 PMID:25229342

    Open questions at the time
    • Structural basis of rpS6–mTORC2 interaction unknown
    • Whether extra-ribosomal rpS6 mediates mTORC2 feedback not tested
  12. 2015 High

    Genome-wide ribosome profiling in yeast with non-phosphorylatable rpS6 definitively showed that rpS6 phosphorylation does not regulate global translation or preferential translation of individual mRNAs, challenging the decades-old model that S6 phosphorylation broadly controls 5′TOP mRNA translation.

    Evidence Ribosome profiling and polysome profiling in yeast rpS6 phospho-mutant cells; identification of Ypk3 as the direct rpS6 kinase via genetic complementation

    PMID:25767889 PMID:26582391

    Open questions at the time
    • Yeast findings may not fully translate to mammals with more complex 5′TOP regulation
    • Non-translational roles of rpS6 phosphorylation in yeast not fully characterized
  13. 2019 High

    The somatic RPS6 p.R232H mutation was shown to be an activating mutation causing hemimegalencephaly-associated cortical dysplasia through increased cell proliferation, establishing RPS6 as a disease gene for brain overgrowth syndromes within the mTORopathy spectrum.

    Evidence Whole-exome sequencing of hemimegalencephaly patient; in utero electroporation of RPS6-R232H in mice with proliferation and migration assays

    PMID:31411685

    Open questions at the time
    • Mechanism by which R232H activates mTOR signaling not defined
    • Frequency of RPS6 mutations in cortical dysplasia cohorts not established
  14. 2021 High

    Selective ribosome footprinting revealed that rpS6 is progressively dephosphorylated as ribosomes translate longer ORFs, providing a length-dependent mechanism whereby rpS6 phosphorylation selectively promotes translation of short-CDS mRNAs rather than acting through 5′TOP elements.

    Evidence Phospho-RPS6 antibody-based selective ribosome profiling in RPS6 phospho-site knock-in cells

    PMID:34871442

    Open questions at the time
    • Phosphatase responsible for elongation-dependent rpS6 dephosphorylation not identified
    • Whether this mechanism operates identically in all mammalian tissues unknown
  15. 2023 High

    In vivo imaging of wounded skin revealed a spatially defined p-rpS6 zone that encompasses proliferation, senescence, and angiogenesis around wound margins; rpS6 non-phosphorylatable knock-in mice showed altered wound healing kinetics, demonstrating a tissue-level organizing role for rpS6 phosphorylation.

    Evidence Immunofluorescence mapping of p-rpS6 in skin wounds; rpS6 knock-in mice wound healing assays

    PMID:37098351

    Open questions at the time
    • Signals initiating wound-edge rpS6 phosphorylation not identified
    • Whether the p-rpS6 zone acts through translation, RiBi, or other mechanisms unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the phosphatase responsible for elongation-coupled rpS6 dephosphorylation, the structural basis of rpS6's interaction with mTORC2, whether extra-ribosomal rpS6 mediates nuclear/signaling functions, and the transcription factor through which rpS6 phosphorylation controls the ribosome biogenesis program.
  • Phosphatase for elongation-dependent rpS6 dephosphorylation unknown
  • Extra-ribosomal rpS6 pool not characterized
  • Transcription factor mediating RiBi program downstream of rpS6 not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005840 ribosome 3 GO:0005634 nucleus 1 GO:0005730 nucleolus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-1640170 Cell Cycle 1 R-HSA-1643685 Disease 1
Partners
ARRB1EIF3AMTORRPL10RPS6KB1RPS6KB2RPTOR
Complex memberships
40S ribosomal subunit80S ribosome

Evidence

Reading pass · 60 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 A mitogen-activated S6 kinase of Mr 70,000 (p70 S6K) was purified to homogeneity from Swiss 3T3 cells stimulated by EGF, serum, or orthovanadate. The purified kinase phosphorylates ribosomal protein S6 of the 40S subunit in vitro, exhibits autophosphorylation activity, and is inactivated by phosphatase 2A treatment, establishing that the kinase itself is regulated by phosphorylation. Biochemical purification (Mono Q/Mono S chromatography), in vitro kinase assay with 40S subunit, phosphatase 2A inactivation Proceedings of the National Academy of Sciences of the United States of America High 3257566
1989 A hepatic 70 kDa S6 kinase purified from cycloheximide-treated rats phosphorylates ribosomal protein S6 and additional substrates including histone H2b, glycogen synthase, and ATP citrate lyase (the latter on the same serine phosphorylated by insulin in intact cells), demonstrating broad substrate specificity beyond S6. 50,000-fold purification using peptide affinity column (C-terminal S6 peptide), in vitro kinase assays with multiple substrates The Journal of biological chemistry High 2760046
1989 An insulin-stimulated S6 kinase purified from rabbit liver has a molecular weight of ~70,000 and its activity is abolished by phosphatase 2A treatment, confirming phosphorylation-dependent activation. The inactivated enzyme can be re-activated ~5-fold by preincubation with partially purified MAP-2 kinase, placing a MAP kinase-like activity upstream. Multi-step chromatographic purification, phosphatase 2A inactivation, reactivation by MAP-2 kinase The Journal of biological chemistry Medium 2553707
1991 The purified 70K S6 kinase phosphorylates S6 exclusively on five sites (Ser235, Ser236, Ser240, Ser244, and a fifth low-stoichiometry site) within a 19-amino acid peptide at the carboxyl terminus of S6, matching the in vivo phosphorylation pattern. Mn²⁺ and Zn²⁺ inhibit the kinase with IC₅₀ ~2 µM for Zn²⁺, and autophosphorylation (~1.2 mol/mol) reduces activity ~25%. In vitro kinase assay with purified 70K S6K and 40S subunit, tryptic phosphopeptide mapping, site identification by sequencing, metal ion inhibition studies The Journal of biological chemistry High 1939282
1981 S6 phosphorylation in HeLa cells peaks rapidly (~30 min) after serum stimulation, preceding the slower increase in translation elongation/initiation rates, and correlates temporally with mRNA recruitment into polysomes, suggesting rpS6 phosphorylation may facilitate mRNA recruitment rather than globally controlling elongation. Polysome profiling, kinetic analysis of S6 phosphorylation vs. protein synthesis rates in suspension culture European journal of biochemistry Medium 7333277
1984 Extensive phosphorylation of ribosomal protein S6 is associated with conformational changes in the 40S ribosomal subunit, specifically altered accessibility of proteins S3, S4, S7, S23/24 (small subunit) and L9, L10, L12, L18, L27, L34, L36 (large subunit) to reductive methylation. Reductive methylation accessibility assay comparing ribosomes with unphosphorylated vs. phosphorylated S6 The Journal of biological chemistry Medium 6693389
1986 Insulin, IGF-1, and TPA activate a cytosolic S6 kinase in rat astrocytes, demonstrating that S6 kinase responds to tyrosine kinase receptors and protein kinase C activation in neural cells. The effect is insensitive to cycloheximide, indicating activation occurs through post-translational modification of a pre-existing kinase. S6 kinase activity assay in cytosolic fractions of cultured astrocytes after hormone treatment; cycloheximide control FEBS letters Medium 3530808
1992 Rapamycin selectively inhibits p70 S6 kinase activity and blocks the appearance of the hyperphosphorylated form of p70 S6K in COS cells, but does not affect p85 Rsk S6 kinase or MAP kinase, demonstrating that a rapamycin-sensitive signaling element is specifically required for p70 S6K activation. Kinase assays with 40S subunits, SDS-PAGE mobility shift, selective inhibitor treatment in hepatoma cells and transfected COS cells Science High 1380182
1994 The p70/p85 S6 kinase signaling pathway is independent of p21ras: dominant-negative p74raf and p21ras block p44MAPK but not p70S6K activation. Furthermore, activation of p70S6K by PDGFR requires autophosphorylation at tyrosine 751 within the kinase-insert domain of the receptor, bifurcating the signaling from the ras-MAPK pathway at the receptor level. Dominant-negative Raf and Ras mutant expression, epitope-tagged kinase assays, PDGFR kinase-insert domain mutants Nature High 8090223
1995 FRAP/mTOR kinase activity is required in vivo for activation of p70 S6K: kinase-dead FRAP variants fail to activate p70S6K, and FRAP autophosphorylates in vitro; autophosphorylation is inhibited by the FKBP12-rapamycin complex. An N-terminal domain of FRAP beyond its kinase domain is also required for p70S6K regulation. FRAP variant overexpression, in vitro autophosphorylation, rapamycin-FKBP12 inhibition of autophosphorylation, kinase-dead mutant analysis Nature High 7566123
1996 S6 kinase contains an autoinhibitory domain (codons 58–77) that overrides mitogen-dependence; deletion of the first 77 amino acids produces a constitutively active, rapamycin-insensitive S6K. A separate N-terminal domain (codons 1–58) is required for mitogen-induced activation and rapamycin sensitivity, defining two functionally distinct N-terminal regulatory regions. Deletion mutagenesis of S6K, expression in Rat1 cells, kinase activity assays, morphological phenotype analysis Molecular and cellular biology High 8524322
1998 RAFT1/mTOR directly phosphorylates p70 S6K on Thr-389 (a rapamycin-sensitive site essential for S6K activity) in vitro and in vivo, and also phosphorylates 4E-BP1 and 4E-BP2. Thr-389 phosphorylation is necessary for S6K activity, and RAFT1 phosphorylates p70S6K much more efficiently than 4E-BP1. In vitro kinase assay with immunoprecipitated RAFT1/mTOR, phospho-specific site mapping, rapamycin treatment, serum stimulation kinetics Proceedings of the National Academy of Sciences of the United States of America High 9465032
1998 Amino acid withdrawal rapidly inactivates p70 S6K and promotes 4E-BP1 dephosphorylation in CHO cells through a pathway sensitive to rapamycin and PI3K inhibitors but independent of protein kinase B (PKB/Akt), demonstrating that amino acids regulate p70 S6K via a distinct upstream pathway from insulin/PKB. Amino acid deprivation/repletion in CHO cells, kinase activity assays, PI3K and mTOR inhibitor treatments, PKB activity measurements The Biochemical journal High 9693128
1999 Drosophila S6 kinase (dS6K) regulates cell size in a cell-autonomous manner: dS6K null flies display extreme developmental delay, severe body size reduction due to smaller cells (not fewer cells), a phenotype distinct from ribosomal protein mutations (Minutes). This genetically establishes S6K as a cell-size regulator. Drosophila dS6K null mutant analysis, cell counting, cell size measurement, mosaic analysis Science High 10497130
1999 Leucine activation of p70S6K in amino acid-depleted cells requires strict structural features: the correct chirality, the four-branched hydrocarbon structure, and a primary amine. The effect is rapamycin-sensitive but less sensitive to wortmannin, indicating that leucine acts via mTOR rather than PI3K to activate p70S6K. p70S6K activity assays with leucine analogues in H4IIE cells, pharmacological inhibition with rapamycin and wortmannin FEBS letters Medium 10214966
1999 Osmotic stress (sorbitol) inactivates p70/p85 S6K and causes dephosphorylation of Thr412 in the COOH-terminus via a calyculin A-sensitive phosphatase, similar to rapamycin. Rapamycin-resistant truncation mutants of S6K are also resistant to osmotic stress-induced inactivation, demonstrating that both rapamycin and osmotic stress converge on a common calyculin A-sensitive phosphatase-dependent mechanism. S6K kinase assays, phospho-specific antibodies, pharmacological inhibitors of phosphatases, rapamycin-resistant S6K truncation mutants The Journal of biological chemistry High 10455142
2000 TGF-β induces association of its receptor with PP2A-Bα subunit, leading to assembly of a PP2A complex (Bα, Aβ, Cα subunits) with p70S6K, dephosphorylation and inactivation of p70S6K, and G1 arrest. This is a second pathway for TGF-β-induced cell cycle arrest parallel to Smad2/3 activation. Co-immunoprecipitation of PP2A subunits with TGF-β receptor and p70S6K, kinase activity assays, G1 arrest rescue experiments Genes & development High 11124802
1999 S6K1 and S6K2 activation requires sequential phosphorylation: PI3K-mediated phosphorylation of C-terminal sites permits PDK1 to phosphorylate the activation loop residue, and mTOR acts as a checkpoint for amino acid availability. At least eight phosphorylation sites mediate S6K1 activation in a hierarchical fashion. Review synthesizing phosphorylation site mutant data, PI3K/mTOR pathway dissection, PDK1 phosphorylation of activation loop Experimental cell research Medium 10579915
2002 S6K2 activation requires mTOR kinase activity, amino acid sufficiency, and phosphatidic acid, similar to S6K1. Manipulation of mTOR nuclear/cytoplasmic distribution (using NLS/NES tags) showed that optimal mTOR shuttling is required for maximal S6K2 activation, with S6K2 being a predominantly nuclear protein. mTOR NLS/NES tagging constructs, kinase activity assays, subcellular fractionation, leptomycin B treatment The Journal of biological chemistry Medium 12087098
2002 Loss of TSC2/tuberin leads to constitutive hyperphosphorylation of ribosomal protein S6 and constitutive activation of p70S6K in LAM patient-derived smooth muscle cells and TSC2-/- cells. Re-introduction of wild-type tuberin abolishes S6 phosphorylation and inhibits p70S6K, demonstrating that TSC2 negatively regulates the p70S6K–rpS6 axis. Immunoblotting of S6 phosphorylation, p70S6K kinase assays, tuberin re-expression in TSC2-null cells, rapamycin treatment The Journal of biological chemistry High 12045200
2003 TSC1/2 acts as a GAP for the small GTPase Rheb, and insulin-activated Rheb (via PI3K) drives S6K1 phosphorylation; loss-of-function TSC1/2 mutations phenocopy Rheb overexpression in activating S6K1. A disease-associated GAP-domain point mutation in TSC2 fails to stimulate Rheb GTPase or block Rheb-induced S6K1 activation. GTPase assay with purified Rheb, epistasis by co-expression, TSC2 disease mutant analysis, S6K1 phosphorylation assays Molecular cell High 12820960
2003 M-CSF, RANKL, and TNFα promote osteoclast survival through convergent mTOR/S6K signaling; rapamycin blocks cytokine-dependent osteoclast survival and induces apoptosis. Inhibitors of PI3K, Akt, ERK, and geranylgeranylation suppress cytokine-induced S6K activation and osteoclast survival, and inhibition of translation by other mechanisms also induces apoptosis, demonstrating that mTOR/S6K-dependent protein synthesis is essential for osteoclast survival. Rapamycin and signaling inhibitor treatment, S6K activity assays, apoptosis assays, in vitro bone resorption Cell death and differentiation Medium 14502240
2004 Apelin (65-77) activates p70 S6K in CHO cells and endothelial cells via dual pathways: a PI3K→Akt pathway (blocked by wortmannin) leading to T389 and T421/S424 phosphorylation, and an ERK pathway (blocked by PD098059) leading to T421/S424 phosphorylation. PTX and atypical PKC inhibitors abrogate both Akt and p70S6K phosphorylation, and apelin-induced p70S6K activation is mitogenic for HUVEC cells. Kinase assays with phospho-specific antibodies, pathway inhibitors, PTX treatment, thymidine incorporation assay FASEB journal Medium 15385434
2005 mTOR/S6K1 and the eIF3 translation initiation complex function as a dynamic scaffold: inactive S6K1 associates with eIF3 basally; cell stimulation recruits mTOR/raptor to eIF3 where it phosphorylates S6K1 at its hydrophobic motif; S6K1 then dissociates, becomes activated, and phosphorylates eIF4B, which is subsequently recruited to the eIF3 complex. Co-immunoprecipitation of mTOR, S6K1, eIF3, and eIF4B; phospho-specific antibodies; rapamycin treatment; sequential IP/kinase assays Cell High 16006006 16286006
2005 hVps34 (Class III PI3K) is required for p70 S6K1 activation in response to insulin and amino acids, acting upstream of mTOR. Inhibitory anti-hVps34 antibodies, FYVE domain sequestration of PI3P, and siRNA knockdown of hVps34 all block S6K1 activation. hVps34 is inhibited by amino acid/glucose starvation and AMPK activation, but not by insulin, placing it on the nutrient-sensing arm to mTOR/S6K1. Microinjection of inhibitory antibodies, FYVE domain overexpression, siRNA knockdown, hVps34 kinase activity assays, insulin stimulation of S6K1 The Journal of biological chemistry High 16049009
2005 p70 S6K directly phosphorylates tau at S262, S214, and T212 in vitro, and co-immunoprecipitation reveals association between activated p-p70S6K (T421/S424) and phospho-tau (S262) in cells. Zinc-induced p70S6K activation selectively upregulates translation of S6 and tau mRNAs but not global protein synthesis. In vitro kinase assay with p70S6K and tau, immunoprecipitation, immunoblotting with phospho-specific antibodies, metabolic labeling FEBS letters Medium 16364302
2006 S6 kinases are ubiquitinated in cells and subject to proteasome-mediated degradation. Ubiquitination sites are located in the kinase domain, and the N- and C-terminal regulatory regions modulate the efficiency of S6K ubiquitination, identifying a second post-translational mechanism (beyond phosphorylation) controlling S6K abundance. Co-transfection with ubiquitin constructs, proteasome inhibitor treatment, immunoprecipitation, ubiquitin site mapping by domain deletion Biochemical and biophysical research communications Medium 18280803
2006 S6K1 and S6K2 interact with receptor tyrosine kinases, specifically PDGFR, via the kinase or kinase extension domain of S6K in a growth-factor-inducible manner. This complex formation leads to tyrosine phosphorylation of S6K via a PDGFR-Src pathway at Y39 (S6K1) and Y45 (S6K2), but these tyrosine phosphorylations do not affect S6K activity or subcellular localization. Co-immunoprecipitation with PDGFR mutants, tyrosine phosphorylation mapping, Src inhibitors (PP1, SU6656), immunofluorescence The FEBS journal Medium 16640565
2006 Ribosomal proteins Rpl10 and Rps6 are potent regulators of yeast replicative lifespan: deletion of RPS6B (but not RPS6A) extends replicative lifespan by 45% in S. cerevisiae, associated with altered free ribosomal subunit stoichiometry and reduced cell size. This establishes an orthologous role for Rps6 gene dosage in aging. Yeast deletion mutants, replicative lifespan assays, ribosome profiling by polysome analysis, cell size measurement Experimental gerontology Medium 17174052
2007 ATG1 (autophagy kinase) inhibits TOR/S6K-dependent cell growth in Drosophila by blocking S6K activation at Thr389 phosphorylation. In mammalian cells, ATG1 overexpression inhibits S6K, and siRNA knockdown of ATG1 induces ectopic S6K activation and S6 phosphorylation, revealing crosstalk between autophagy regulation and the TOR/S6K growth pathway. Drosophila ATG1 mutant and overexpression analysis, mammalian S6K kinase assays, siRNA knockdown, phospho-Thr389 antibody EMBO reports High 17347671
2007 S6K1 deletion in skeletal muscle cells causes increased AMP/ATP and inorganic phosphate/phosphocreatine ratios, triggering AMPK upregulation. AMPK inhibition in S6K-deficient cells restores cell growth and nutrient sensitivity, demonstrating that S6K1 controls cellular energy state and that AMPK activation mediates the cell atrophy caused by S6K1 deletion. S6K1/2 knockout mice, AMPK activity assays, metabolite measurements (AMP, ATP, phosphocreatine), AMPK inhibition rescue Cell metabolism High 17550782
2008 S6K1 deletion in mice leads to increased lifespan and resistance to age-related pathologies (bone, immune, motor dysfunction, insulin sensitivity loss), with gene expression patterns similar to caloric restriction or AMPK activation, demonstrating that S6K1 is a lifespan regulator in mammals. S6K1 knockout mouse model, lifespan analysis, metabolic phenotyping, gene expression profiling Science High 19797661
2008 Mediobasal hypothalamic (MBH) S6K1 bidirectionally controls energy homeostasis: stereotaxic adenoviral activation of MBH S6K alters food intake, body weight, orexigenic neuropeptide expression, and leptin sensitivity; constitutive activation protects against high-fat diet-induced obesity and insulin resistance. Bilateral adenoviral injection of dominant-negative or constitutively active S6K into rat MBH, metabolic phenotyping, neuropeptide measurements Cell metabolism High 19041762
2008 Drosophila S6KII (p90 RSK) cooperates with casein kinase 2 (CK2) in circadian clock neurons to regulate circadian period: S6KII null flies show short-period phenotype rescued by clock-neuron-specific re-expression; S6KII physically interacts with CK2β; genetic interactions show CK2 activity is required for S6KII's clock function. Drosophila null mutant analysis, circadian behavioral assays, cell-type-specific rescue, co-IP of S6KII and CK2β, genetic epistasis with CK2 mutants The Journal of neuroscience Medium 19144847
2009 Resveratrol inhibits mammalian S6K1 (identified in a large-scale in vitro kinase screen) and attenuates autophagy induced by nutrient limitation or rapamycin. Dominant-negative S6K1 mutant or siRNA knockdown of S6K1 recapitulates the autophagy-suppressing effect of resveratrol, and combining resveratrol with S6K1 knockdown is not additive, indicating S6K1 is a key target of resveratrol's autophagy-modulating effect. Large-scale in vitro kinase screen, dominant-negative S6K1 expression, siRNA knockdown, autophagy assays Aging Medium 20157535
2009 mTOR/S6K1 signaling protects astrocytes from ischemia-induced apoptosis: OGD reduces S6K1 mRNA and protein; S6K1/2 double knockout astrocytes show increased apoptosis, reduced BAD phosphorylation, decreased Bcl-2/Bcl-xL, increased ROS, and impaired translation recovery. Rescue with adenoviral S6K1 (but not S6K2) specifically reduces ROS and confers ischemic resistance. S6K1/S6K2 double knockout mouse astrocytes, OGD model, adenoviral isoform-specific rescue, apoptosis assays, ROS measurement, middle cerebral artery occlusion in vivo The Journal of biological chemistry High 19535330
2009 S6 kinase ortholog RSKS-1 in C. elegans inhibits axon regeneration in mechanosensory neurons: rsks-1 loss-of-function accelerates growth cone formation and axon extension after laser axotomy; this enhanced regrowth is partly dependent on DLK-1 MAPK cascade, and a key downstream effector is the metabolic sensor AMP kinase AAK-2. The antidiabetic drug phenformin (AMPK activator) promotes axon regrowth. C. elegans laser axotomy, rsks-1 null mutants, genetic epistasis with DLK-1 and AAK-2, pharmacological AMPK activation The Journal of neuroscience Medium 24431434
2010 AKT-mTORC1-RPS6 signaling promotes de novo lipogenesis in hepatocellular carcinoma via transcriptional and post-transcriptional mechanisms including inhibition of fatty acid synthase ubiquitination by USP2a and disruption of SREBP1/SREBP2 degradation complexes. siRNA knockdown of RPS6 inhibits lipogenesis-related gene activity and reduces HCC cell proliferation and survival. siRNA knockdown of RPS6, inhibitor studies (rapamycin, pathway inhibitors), gene expression analysis, lipogenic enzyme activity assays, USP2a/SREBP pathway analysis in HCC cell lines and mouse models Gastroenterology Medium 21147110
2011 Heat shock activates both pp70 S6K and pp90rsk in quiescent fibroblasts, with a temporal activation pattern reversed from mitogen-stimulated cells. The heat shock-induced pp70 S6K was identified as equivalent to the serum/growth factor-activated enzyme by chromatographic properties, and both kinases drive S6 phosphorylation in heat-shocked cells. Sequential column chromatography purification, immunoprecipitation kinase assay for pp90rsk, S6 phosphorylation measurement in quiescent fibroblasts after heat shock Journal of cellular physiology Medium 1880153
2012 rpS6 regulates blood-testis barrier (BTB) dynamics: rpS6 is spatiotemporally activated at the BTB during the spermatogenic cycle; siRNA-mediated knockdown of rpS6 in vitro and in vivo promotes the Sertoli cell TJ permeability barrier by recruiting claudin-11 and occludin to the BTB. rpS6 activation disrupts the TJ barrier via effects on F-actin organization and adhesion protein recruitment. siRNA and shRNA knockdown of rpS6 in Sertoli cells in vitro and in adult rat testes in vivo, BTB integrity assay, immunofluorescence for F-actin and junctional proteins Endocrinology High 22948214
2013 S6K1 and S6K2 double knockout mouse liver shows a specific defect in the ribosome biogenesis (RiBi) transcriptional program after feeding: over 75% of RiBi factors (Nop56, Nop14, Gar1, etc.) are controlled by S6K. Importantly, this RiBi transcriptional defect is also observed in rpS6 knock-in mice with non-phosphorylatable serine residues, identifying rpS6 phosphorylation as specifically regulating RiBi transcription independently of ribosomal protein synthesis. S6K1/S6K2 double knockout mice, rpS6 phosphorylation-site knock-in mice, whole-genome microarray of total and polysomal liver RNA, feeding paradigm Oncogene High 23318442
2013 Arginine, leucine, and glutamine activate the MTOR-RPS6K-RPS6-EIF4EBP1 pathway in porcine trophectoderm cells to stimulate proliferation; increased nuclear localization of pRPS6K and cytoplasmic pRPS6 were detected. siRNA silencing of MTOR, RPTOR, or RICTOR blocked amino acid-induced proliferation, placing RPS6 downstream of both mTORC1 and mTORC2 in trophectoderm proliferation. Immunofluorescence, immunoblotting of phospho-RPS6K/RPS6/EIF4EBP1, siRNA knockdown of MTOR/RPTOR/RICTOR, proliferation assay in primary porcine trophectoderm cells Biology of reproduction Medium 23486913
2014 Phosphorylation of rpS6 mediates compensatory renal hypertrophy: rpS6 knock-in mice expressing non-phosphorylatable rpS6 show significantly blunted uninephrectomy-induced renal hypertrophy, with attenuated cyclin D1 increase and reduced cyclin E decrease compared to wild-type. mTORC1 is still activated in knock-in mice (4E-BP1 phosphorylation intact), but rapamycin (which prevents rpS6 phosphorylation) cannot prevent residual hypertrophy in knock-in mice, unequivocally demonstrating rpS6 phosphorylation as the downstream mTORC1-S6K1 effector mediating hypertrophic cell cycle regulation. rpS6 phosphorylation-site knock-in mice, uninephrectomy model, rapamycin treatment, immunoblotting for cyclins and phospho-proteins Kidney international High 25229342
2014 RPS6 interacts with components of mTORC2 (co-immunoprecipitation), and siRNA-mediated knockdown of RPS6 attenuates insulin-induced mTORC2 activity and Akt-Ser473 phosphorylation. Conversely, RPS6 overexpression enhances Akt-Ser473 phosphorylation, establishing that RPS6 provides positive feedback to mTORC2/Akt signaling. In mouse hearts, ischemic preconditioning induces RPS6 phosphorylation at Ser235/236 and activates mTORC2. Co-immunoprecipitation of RPS6 with mTORC2 components, siRNA knockdown, RPS6 overexpression, ischemic preconditioning in perfused mouse hearts, neonatal rat ventricular myocyte assays Circulation research High 24557881
2015 In yeast, TORC1 promotes rpS6 phosphorylation on Ser-232/Ser-233 via the AGC kinase Ypk3 (not Sch9 as previously proposed). Ypk3-null cells have completely abolished rpS6 phosphorylation; phosphorylation-deficient mutations in Ypk3 regulatory motifs abrogate rpS6 phosphorylation; and complementation of ypk3Δ cells with human S6 kinase restores rpS6 phosphorylation. Cells expressing non-phosphorylatable rpS6 show reduced growth and 40S biogenesis defects not explained by translation changes. Yeast deletion mutants, phospho-S6-specific antibody, Ypk3 regulatory mutants, human S6K complementation, polysome profiling, ribosome profiling PloS one / Molecular biology of the cell High 25767889 26582391
2015 RPS6 phosphorylation is controlled by both TORC1 (via Ypk3 and PP1/Glc7) and TORC2 (via Ypk1) in S. cerevisiae, with TORC2 specifically regulating the N-terminal phosphosite. Ribosome profiling shows that rpS6 phosphorylation does not regulate global translation or translation of individual mRNAs, challenging the longstanding model that S6 phosphorylation broadly promotes translation of 5'TOP mRNAs. TORC1/TORC2 genetic dissection, ribosome profiling, polysome profiling, non-phosphorylatable rpS6 knock-in cells Molecular biology of the cell High 26582391
2015 RPS6 reviews extensive evidence that rpS6 phosphorylation occurs on five conserved serine residues in response to diverse stimuli; genetic manipulations in yeast and mammals using rpS6 knock-in mice and S6K knockout mice have revealed roles in cell size control, glucose homeostasis, ribosome biogenesis, and DNA damage responses. The physiological role of phosphorylation may include fine-tuning responses by counteracting positive signals from rpS6 kinase. Synthesis of knock-in mouse, S6K KO, and yeast data International review of cell and molecular biology Medium 26614871
2017 S6 kinases phosphorylate the nuclear epigenetic factor ZRF1 (DNAJC2/MIDA1) on Ser47 in cultured cells and in mammalian tissues in vivo (identified by chemical genetic screen). ZRF1 knockdown or expression of a phosphorylation mutant blunts S6K-dependent premature senescence in TSC-mutant fibroblasts, associated with altered p16 levels. This identifies ZRF1 as a novel S6K substrate linking mTORC1-S6K to cellular senescence. Chemical genetic screen for novel S6K substrates, ZRF1 knockdown, phospho-Ser47 antibody, senescence assays (SA-β-gal, p16), TSC-mutant fibroblasts The EMBO journal High 28242756
2017 mTORC1/rpS6 signaling promotes BTB disruption in the adult rat testis in vivo: constitutively active phosphomimetic rpS6 mutant (quadruple phosphomimetic) induces BTB leakiness better than wild-type rpS6, causing spermatid polarity loss and germ cell exfoliation. These effects are mediated through changes in actin- and microtubule-based cytoskeletal organization, specifically spatiotemporal expression of actin- and MT-binding proteins. In vivo transfection of rat testes with rpS6-WT and phosphomimetic rpS6 mutant, BTB integrity assay, immunofluorescence for cytoskeletal proteins, electron microscopy American journal of physiology. Endocrinology and metabolism High 29089336
2018 β-arrestins constitutively assemble a p70S6K/rpS6 complex in HEK293 cells and Sertoli cells; the interaction between β-arrestin 1 and p70S6K is direct (validated by docking). Upon FSH stimulation, G protein (Gαs)-dependent signaling enhances p70S6K activity within the preassembled β-arrestin/p70S6K/rpS6 complex, leading to rpS6 phosphorylation and translation of 5'TOP mRNAs within minutes. Co-immunoprecipitation, computational docking validation, Gαs depletion, FSHR stimulation, 5'TOP mRNA translation assay FASEB journal Medium 29084767
2018 The mTOR effectors S6K1 and S6K2 localize to stress granules in human cells and are required for stress granule assembly and maintenance after mild oxidative stress. S6K1 promotes stress granule formation via regulation of eIF2α phosphorylation, while S6K2 is important for stress granule persistence. In C. elegans, the S6K ortholog RSKS-1 also promotes stress granule assembly and its loss sensitizes to stress-induced death. Immunofluorescence of S6K1/2 in stress granule markers, siRNA knockdown, eIF2α phosphorylation assays, C. elegans rsks-1 loss-of-function, stress-induced death assays Cell death and differentiation High 29523872
2019 Somatic mosaicism for RPS6 p.R232H mutation in a hemimegalencephaly patient increases cell proliferation in animal models, while MTOR p.S2215F causes neuronal migration delay and cytomegaly; double mutants show synergistic effects (increased proliferation + migration defects + cytomegalic cells with eccentric nuclei/binucleation). This establishes RPS6 p.R232H as an activating mutation that drives cortical dysplasia through increased proliferation downstream of the mTOR pathway. Whole-exome sequencing, deep targeted sequencing, in utero electroporation of variant constructs in mice, cell proliferation and migration assays, histological analysis Human molecular genetics High 31411685
2021 RPS6 phosphorylation promotes translation of mRNAs with short coding sequences (CDSs) more strongly than mRNAs with long CDSs. Selective ribosome footprinting reveals that RPS6 becomes progressively dephosphorylated on ribosomes as they translate longer ORFs, so short-CDS mRNAs retain more p-RPS6 ribosomes. However, 5'TOP mRNAs are not preferentially translated despite their short CDSs, suggesting they use a different mechanism. Selective ribosome footprinting with phospho-RPS6 antibody, RPS6 phosphorylation-site knock-in cells, genome-wide translation analysis Nucleic acids research High 34871442
2021 RPS6 inhibition by siRNA decreases NRF2 expression in HER2-amplified gastric cancer, suggesting RPS6 lies upstream of NRF2 in anti-HER2 drug resistance. PI3K/TORC1/TORC2 inhibition suppresses pRPS6 and NRF2 and reduces tumor growth in resistant models in vitro and in vivo. siRNA knockdown of RPS6, PI3K/mTOR inhibitor treatment, cell viability assays, in vivo xenograft models Clinical cancer research Medium 30504425
2021 The lnc-Rps4l-encoded peptide RPS4XL interacts with RPS6 (identified by CoIP and mass spectrometry) and inhibits RPS6 phosphorylation at Ser240/Ser244, thereby inhibiting hypoxia-induced proliferation of pulmonary artery smooth muscle cells. Co-immunoprecipitation, mass spectrometry, immunofluorescence, MTT/BrdU proliferation assays, phospho-RPS6 immunoblotting Molecular therapy Medium 33429084
2023 In mammalian skin wounding, rpS6 is rapidly phosphorylated within minutes of injury, forming a spatially defined 'p-rpS6-zone' surrounding the wound that persists until healing is complete. This zone encompasses proliferation, cellular senescence, angiogenesis, and growth. A mouse model unable to phosphorylate rpS6 shows accelerated initial wound closure but impaired overall healing, demonstrating that p-rpS6 modulates (but does not drive) the healing process. Immunofluorescence for p-rpS6 in skin wounds, rpS6 non-phosphorylatable knock-in mice, wound healing assays, time-course analysis Developmental cell High 37098351
1995 Human ribosomal protein S6 contains three nuclear localization signals (NLSs) in its C-terminal half. Deletion mutagenesis of S6-β-galactosidase chimeras showed that a single NLS is sufficient for nuclear import, removal of all three NLSs abolishes nuclear entry, and chimeras retaining at least one NLS accumulate specifically in the nucleolus via a distinct domain required but not sufficient for nucleolar targeting. Chimeric S6-LacZ construct transfection in L cells, deletion mutagenesis, β-galactosidase activity localization assay Molecular biology of the cell High 8590812
2004 Yeast rpS6 (Rps6p) functionally interacts with the 60S subunit protein rpL10/Grc5p in ribosome subunit joining and differential protein expression; Grc5p also interacts with the nuclear export factor Nmd3p to modulate polysome complement, establishing rpS6 as part of a network of ribosomal proteins governing subunit joining fidelity. Yeast two-hybrid, polysome profiling, genetic interaction analysis in S. cerevisiae FEMS yeast research Medium 15556089
2013 Human 80S ribosome cryo-EM structure at high resolution reveals the position of RPS6 in the 40S subunit, as part of the metazoan-specific structural architecture with additional inner and outer RNA layers, providing structural context for RPS6's role in ribosome function. High-resolution cryo-electron microscopy of human and Drosophila 80S ribosomes Nature High 23636399
2015 Near-atomic (3.6 Å average, 2.9 Å in stable regions) cryo-EM structure of the human 80S ribosome defines the precise atomic positions of ribosomal proteins including RPS6, revealing amino acid side chain contacts, tRNA binding site interactions, and dynamic subunit interface remodeling during rotation. Single-particle cryo-EM, atomic model building Nature High 25901680

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
1998 RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proceedings of the National Academy of Sciences of the United States of America 948 9465032
2005 mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 946 16286006
2009 Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science (New York, N.Y.) 905 19797661
2003 Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Molecular cell 853 12820960
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2002 Directed proteomic analysis of the human nucleolus. Current biology : CB 780 11790298
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
1995 Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature 626 7566123
1999 Drosophila S6 kinase: a regulator of cell size. Science (New York, N.Y.) 614 10497130
1992 Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science (New York, N.Y.) 614 1380182
1999 Ribosomal S6 kinase signaling and the control of translation. Experimental cell research 583 10579915
2007 IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 545 17693255
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2016 G3BP-Caprin1-USP10 complexes mediate stress granule condensation and associate with 40S subunits. The Journal of cell biology 512 27022092
2010 Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology 495 21147110
2013 Structures of the human and Drosophila 80S ribosome. Nature 481 23636399
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. The Journal of biological chemistry 430 16049009
2010 Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. Journal of proteome research 422 20020773
2013 The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. The Journal of biological chemistry 413 23463506
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2004 The molecular mechanics of eukaryotic translation. Annual review of biochemistry 396 15189156
2015 Structure of the human 80S ribosome. Nature 380 25901680
2002 Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). The Journal of biological chemistry 368 12045200
2015 Aerobic glycolysis tunes YAP/TAZ transcriptional activity. The EMBO journal 362 25796446
2007 Functional specialization of beta-arrestin interactions revealed by proteomic analysis. Proceedings of the National Academy of Sciences of the United States of America 360 17620599
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2011 Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Molecular cell 337 21726808
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2003 M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell death and differentiation 294 14502240
1998 Amino acid availability regulates p70 S6 kinase and multiple translation factors. The Biochemical journal 291 9693128
2010 Functions and regulation of the 70kDa ribosomal S6 kinases. The international journal of biochemistry & cell biology 270 20932932
2010 Akt-RSK-S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases. Science signaling 261 20736484
2015 Ribosomal Protein S6 Phosphorylation: Four Decades of Research. International review of cell and molecular biology 236 26614871
2013 Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program. Oncogene 228 23318442
1994 Activation of p70/p85 S6 kinase by a pathway independent of p21ras. Nature 212 8090223
1988 Identification and characterization of a mitogen-activated S6 kinase. Proceedings of the National Academy of Sciences of the United States of America 203 3257566
2000 TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest. Genes & development 192 11124802
2008 Physiological roles of ribosomal protein S6: one of its kind. International review of cell and molecular biology 187 18703402
2004 Apelin (65-77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 172 15385434
2008 Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell metabolism 153 19041762
2007 S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase. Cell metabolism 149 17550782
2009 Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy. Aging 142 20157535
2007 ATG1, an autophagy regulator, inhibits cell growth by negatively regulating S6 kinase. EMBO reports 132 17347671
1991 Mitogen-activated 70K S6 kinase. Identification of in vitro 40 S ribosomal S6 phosphorylation sites. The Journal of biological chemistry 127 1939282
2001 Leucine and insulin activate p70 S6 kinase through different pathways in human skeletal muscle. American journal of physiology. Endocrinology and metabolism 119 11500301
1989 Purification of a hepatic S6 kinase from cycloheximide-treated Rats. The Journal of biological chemistry 111 2760046
2006 Ribosomal proteins Rpl10 and Rps6 are potent regulators of yeast replicative life span. Experimental gerontology 99 17174052
2005 P70 S6 kinase mediates tau phosphorylation and synthesis. FEBS letters 95 16364302
2015 Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway. Endocrine-related cancer 93 26045471
2018 TOR and RPS6 transmit light signals to enhance protein translation in deetiolating Arabidopsis seedlings. Proceedings of the National Academy of Sciences of the United States of America 90 30482859
2013 Arginine, leucine, and glutamine stimulate proliferation of porcine trophectoderm cells through the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway. Biology of reproduction 88 23486913
2009 Resistance to the Pseudomonas syringae effector HopA1 is governed by the TIR-NBS-LRR protein RPS6 and is enhanced by mutations in SRFR1. Plant physiology 86 19525323
2004 Phytohormones participate in an S6 kinase signal transduction pathway in Arabidopsis. Plant physiology 84 15064379
2018 The mTOR-S6 kinase pathway promotes stress granule assembly. Cell death and differentiation 83 29523872
2002 Regulation of ribosomal S6 kinase 2 by mammalian target of rapamycin. The Journal of biological chemistry 81 12087098
2015 TORC1 promotes phosphorylation of ribosomal protein S6 via the AGC kinase Ypk3 in Saccharomyces cerevisiae. PloS one 80 25767889
1999 Structural requirement of leucine for activation of p70 S6 kinase. FEBS letters 79 10214966
2009 mTOR/S6 kinase pathway contributes to astrocyte survival during ischemia. The Journal of biological chemistry 75 19535330
2021 Ribosomal Protein S6: A Potential Therapeutic Target against Cancer? International journal of molecular sciences 74 35008473
2015 TORC1 and TORC2 work together to regulate ribosomal protein S6 phosphorylation in Saccharomyces cerevisiae. Molecular biology of the cell 73 26582391
1999 Osmotic stress inhibits p70/85 S6 kinase through activation of a protein phosphatase. The Journal of biological chemistry 71 10455142
2009 S6 kinase 1 knockout inhibits uninephrectomy- or diabetes-induced renal hypertrophy. American journal of physiology. Renal physiology 70 19474189
1989 An insulin-stimulated ribosomal protein S6 kinase from rabbit liver. The Journal of biological chemistry 70 2553707
2012 rpS6 Regulates blood-testis barrier dynamics by affecting F-actin organization and protein recruitment. Endocrinology 69 22948214
2014 p70 Ribosomal protein S6 kinase (Rps6kb1): an update. Journal of clinical pathology 68 25100792
2008 Resistance exercise decreases eIF2Bepsilon phosphorylation and potentiates the feeding-induced stimulation of p70S6K1 and rpS6 in young men. American journal of physiology. Regulatory, integrative and comparative physiology 63 18565837
2018 NRF2 through RPS6 Activation Is Related to Anti-HER2 Drug Resistance in HER2-Amplified Gastric Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 62 30504425
2008 p70 S6 kinase and tau in Alzheimer's disease. Journal of Alzheimer's disease : JAD 59 18688088
2014 Pivotal role of mTORC2 and involvement of ribosomal protein S6 in cardioprotective signaling. Circulation research 58 24557881
2010 The two Arabidopsis RPS6 genes, encoding for cytoplasmic ribosomal proteins S6, are functionally equivalent. Plant molecular biology 58 20437080
1996 Constitutive activation of S6 kinase by deletion of amino-terminal autoinhibitory and rapamycin sensitivity domains. Molecular and cellular biology 58 8524322
2011 Immunotoxins and other conjugates containing saporin-s6 for cancer therapy. Toxins 56 22069735
2010 Different domains of Phytophthora sojae effector Avr4/6 are recognized by soybean resistance genes Rps4 and Rps6. Molecular plant-microbe interactions : MPMI 55 20192830
2006 Effect of TRB3 on insulin and nutrient-stimulated hepatic p70 S6 kinase activity. The Journal of biological chemistry 55 16887816
1995 Nuclear and nucleolar targeting of human ribosomal protein S6. Molecular biology of the cell 55 8590812
2021 Phosphorylation of ribosomal protein S6 differentially affects mRNA translation based on ORF length. Nucleic acids research 52 34871442
2007 Co-expression of cyclin D1 and phosphorylated ribosomal S6 proteins in hemimegalencephaly. Acta neuropathologica 51 17483958
2004 Simulation, experiment, and evolution: understanding nucleation in protein S6 folding. Proceedings of the National Academy of Sciences of the United States of America 49 15150413
1991 Heat shock induces two distinct S6 protein kinase activities in quiescent mammalian fibroblasts. Journal of cellular physiology 49 1880153
2018 Phosphorylation of Ribosomal Protein RPS6 Integrates Light Signals and Circadian Clock Signals. Frontiers in plant science 47 29403507
2014 Palmatine inhibits growth and invasion in prostate cancer cell: Potential role for rpS6/NFκB/FLIP. Molecular carcinogenesis 47 25043857
2011 S6 kinase 2 promotes breast cancer cell survival via Akt. Cancer research 47 21427355
2022 p70 S6 kinase as a therapeutic target in cancers: More than just an mTOR effector. Cancer letters 46 35176419
2019 Somatic double-hit in MTOR and RPS6 in hemimegalencephaly with intractable epilepsy. Human molecular genetics 46 31411685
2012 Anchored p90 ribosomal S6 kinase 3 is required for cardiac myocyte hypertrophy. Circulation research 46 22997248
1998 Activation of p70(S6) kinase by beta-adrenoceptor agonists on adult cardiomyocytes. Journal of molecular and cellular cardiology 46 9799659
1981 Phosphorylation of ribosomal protein S6. Relationship to protein synthesis in HeLa cells. European journal of biochemistry 45 7333277
2019 Disruption of the MAMP-Induced MEKK1-MKK1/MKK2-MPK4 Pathway Activates the TNL Immune Receptor SMN1/RPS6. Plant & cell physiology 43 30590768
2008 Endothelial p70 S6 kinase 1 in regulating tumor angiogenesis. Cancer research 43 18829578
2017 mTORC1/rpS6 regulates blood-testis barrier dynamics and spermatogenetic function in the testis in vivo. American journal of physiology. Endocrinology and metabolism 41 29089336
2016 Ribosomal protein S6 kinase1 coordinates with TOR-Raptor2 to regulate thylakoid membrane biosynthesis in rice. Biochimica et biophysica acta 41 27102613
2006 An S6 mutation in BK channels reveals beta1 subunit effects on intrinsic and voltage-dependent gating. The Journal of general physiology 39 17130522
2015 IL-3 Maintains Activation of the p90S6K/RPS6 Pathway and Increases Translation in Human Eosinophils. Journal of immunology (Baltimore, Md. : 1950) 38 26276876
2014 Resistance to Selumetinib (AZD6244) in colorectal cancer cell lines is mediated by p70S6K and RPS6 activation. Neoplasia (New York, N.Y.) 38 25379021
2012 Exploiting p70 S6 kinase as a target for ovarian cancer. Expert opinion on therapeutic targets 35 22564017
2003 Insulin resistance and lipodystrophy in mice lacking ribosomal S6 kinase 2. Diabetes 35 12765942
2013 Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin. Laboratory investigation; a journal of technical methods and pathology 34 23938603
2017 ZRF1 is a novel S6 kinase substrate that drives the senescence programme. The EMBO journal 33 28242756
2007 TOR signaling and S6 kinase 1: Yeast catches up. Cell metabolism 33 17618850
2014 Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers. Oncotarget 32 24831086
2021 lnc-Rps4l-encoded peptide RPS4XL regulates RPS6 phosphorylation and inhibits the proliferation of PASMCs caused by hypoxia. Molecular therapy : the journal of the American Society of Gene Therapy 31 33429084
2015 Ribosomal protein S6 phosphorylation is controlled by TOR and modulated by PKA in Candida albicans. Molecular microbiology 31 26173379
2008 Regulation of ribosomal protein S6 kinases by ubiquitination. Biochemical and biophysical research communications 31 18280803
2010 6-Thioguanine and S⁶-methylthioguanine are mutagenic in human cells. ACS chemical biology 30 20806951
2020 p-Coumaric acid prevents obesity via activating thermogenesis in brown adipose tissue mediated by mTORC1-RPS6. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 29 32350925
2011 Divergent functions for eIF4E and S6 kinase by sonic hedgehog mitogenic signaling in the developing cerebellum. Oncogene 29 21339731
2015 Hydroxychloroquine Destabilizes Phospho-S6 in Human Renal Carcinoma Cells. PloS one 28 26134285
1986 Activation of S6 kinase activity in astrocytes by insulin, somatomedin C and TPA. FEBS letters 28 3530808
1984 Ribosome conformational changes associated with protein S6 phosphorylation. The Journal of biological chemistry 28 6693389
2014 S6 kinase inhibits intrinsic axon regeneration capacity via AMP kinase in Caenorhabditis elegans. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 24431434
2009 Ribosomal s6 kinase cooperates with casein kinase 2 to modulate the Drosophila circadian molecular oscillator. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 19144847
2016 Down-Regulation of Ribosomal S6 kinase RPS6KA6 in Acute Myeloid Leukemia Patients. Cell journal 26 27540520
2014 Phosphorylation of ribosomal protein S6 mediates compensatory renal hypertrophy. Kidney international 26 25229342
2004 Functional interaction in establishment of ribosomal integrity between small subunit protein rpS6 and translational regulator rpL10/Grc5p. FEMS yeast research 26 15556089
2018 G protein-dependent signaling triggers a β-arrestin-scaffolded p70S6K/ rpS6 module that controls 5'TOP mRNA translation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 29084767
2016 Isolation and fine mapping of Rps6: an intermediate host resistance gene in barley to wheat stripe rust. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 25 26754419
2015 Drosophila S6 Kinase like inhibits neuromuscular junction growth by downregulating the BMP receptor thickveins. PLoS genetics 25 25748449
2023 The p-rpS6-zone delineates wounding responses and the healing process. Developmental cell 24 37098351
2006 Receptor association and tyrosine phosphorylation of S6 kinases. The FEBS journal 24 16640565
2005 Arabidopsis PDK1: identification of sites important for activity and downstream phosphorylation of S6 kinase. Biochimie 24 16125835