Affinage

RPS6KB1

Ribosomal protein S6 kinase beta-1 · UniProt P23443

Length
525 aa
Mass
59.1 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RPS6KB1 (p70 S6K1) is a serine/threonine kinase that operates downstream of mTOR to couple nutrient and growth-factor signaling to ribosome biogenesis, mRNA translation, and cell/organism growth (PMID:8887654, PMID:9560223, PMID:11752451). Its activation is built on an ordered, intrasteric mechanism: phosphorylation of the C-terminal autoinhibitory S/TP sites relieves an amino-terminal constraint and cooperates with rapamycin-sensitive phosphorylation of the T389 hydrophobic-motif site, which in turn creates a docking interaction with the PIF-binding pocket of PDK1 to permit T229 activation-loop phosphorylation (PMID:8887654, PMID:9614086, PMID:11500365). Inputs upstream of this cascade include amino-acid/tRNA-aminoacylation status acting through mTOR (PMID:9873056), distinct PDK1-dependent leucine versus insulin routes (PMID:20051528), and H2O2/Ca2+-mediated activation (PMID:10551813); the kinase is reset by direct dephosphorylation through the PP2A-B'/PPP2R5C holoenzyme (PMID:20444422). Genetically, S6K1 specifically controls ribosomal protein (5'TOP) mRNA translation and S6 phosphorylation, with loss buffered by the homolog S6K2 (PMID:9822608, PMID:9560223). Active S6K1 phosphorylates eIF4B at Ser422 to enhance translation initiation (PMID:19289497) and drives degradation of the translational repressor PDCD4 to relieve eIF4A inhibition (PMID:33027666), while phosphorylating IRS1/2 to impose negative feedback that attenuates insulin/IGF-1–PI3K-Akt signaling—a circuit that links mTOR hyperactivation to insulin resistance and β-cell dysfunction (PMID:15380067, PMID:20622167, PMID:21906027). Beyond translation, S6K1 phosphorylates RNF168 at Ser60 to suppress its E3 ligase activity and dampen the DNA-damage response (PMID:29403037), forms a cGAS/TBK1-dependent S6K1–STING–TBK1 complex required for IRF3-driven antiviral gene expression (PMID:27043414), associates with the F-actin cytoskeleton at the leading-edge actin arc to support migration (PMID:15149849), and—via Syntaxin 13—regulates lysosome morphology and NF-κB–mediated inflammaging (PMID:38413780). Amplification of RPS6KB1 at 17q23 drives its overexpression in breast cancer (PMID:10197603).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1996 High

    Established the regulatory architecture of S6K activation by defining T389 as the principal rapamycin-sensitive site that governs activation-loop T229 phosphorylation through an intrasteric mechanism gated by the C-terminal autoinhibitory domain.

    Evidence Truncation and point mutagenesis with kinase assays and multiple inhibitors (rapamycin, wortmannin)

    PMID:8887654

    Open questions at the time
    • Did not identify the physiological kinases acting on T389 or T229
    • Intrasteric model inferred from mutants rather than structure
  2. 1998 High

    Resolved the order of activation by showing C-terminal S/TP phosphorylation relieves N-terminal autoinhibition and, with T389, converts S6K into a competent PDK1 substrate at the activation loop.

    Evidence Acidic-substitution mutants and in vitro PDK1 phosphorylation/kinase assays

    PMID:9614086

    Open questions at the time
    • In vitro reconstitution; cellular kinetics of site phosphorylation not resolved
  3. 1998 High

    Demonstrated in vivo that S6K1 specifically controls ribosomal S6 phosphorylation and 5'TOP mRNA translation, dissecting this branch from rapamycin's effects on 4E-BP1 and general translation, and revealed compensation by the S6K2 homolog.

    Evidence Gene knockout in mice and ES cells with polysome profiling and S6 phosphorylation assays

    PMID:9560223 PMID:9822608

    Open questions at the time
    • Redundancy with S6K2 obscures full loss-of-function phenotype
    • Direct S6 phosphorylation by S6K1 inferred from genetic readout
  4. 1999 Medium

    Connected S6K activity to developmental and physiological translational programs, showing it both promotes 5'TOP and suppresses non-5'TOP mRNA translation and correlates with muscle hypertrophy.

    Evidence Xenopus oocyte injection of constitutively active mutant with reporters; rat resistance-exercise model with kinase and polysome assays

    PMID:10082514 PMID:9886927

    Open questions at the time
    • Muscle data correlative
    • Mechanism of selective non-5'TOP repression unresolved
  5. 1999 Medium

    Identified upstream inputs to S6K beyond classical growth factors: amino-acid/tRNA aminoacylation status through mTOR and H2O2/Ca2+-dependent activation upstream of PI3K and mTOR.

    Evidence tRNA-synthetase mutant and aminoacylation inhibitors with rapamycin-resistant mTOR; glucose oxidase/catalase and Ca2+ chelation with kinase assays

    PMID:10551813 PMID:9873056

    Open questions at the time
    • Molecular sensor linking deacylated tRNA or ROS to mTOR not identified
    • ROS pathway placement inferred from inhibitor hierarchy
  6. 2001 High

    Defined the PDK1 PIF-binding pocket as the structural determinant required for S6K (and SGK1) but not Akt activation, mechanistically linking T389 docking to T-loop phosphorylation.

    Evidence PDK1 pocket mutants, co-IP, and comparative in vitro kinase assays across substrates

    PMID:11500365

    Open questions at the time
    • Structural detail of the docking interaction not obtained in this study
  7. 2001 High

    Confirmed in vivo that PDK1 routes insulin/growth signaling to organismal growth through two parallel branches, Akt and S6K.

    Evidence Drosophila genetic epistasis with dPDK1 loss/gain of function and substrate activity measurements

    PMID:11752451

    Open questions at the time
    • Branch-specific contributions to growth not quantitatively separated
  8. 2004 High

    Established S6K-mediated negative feedback on IRS1/2 as the mechanism linking mTOR hyperactivation to insulin resistance, decoupling Akt from IRS-dependent growth-factor inputs.

    Evidence TSC1/TSC2 deletion and Rheb overexpression with IRS1/2 and Akt phosphorylation assays

    PMID:15380067

    Open questions at the time
    • Direct IRS phosphorylation sites by S6K not mapped in this study
  9. 2004 Medium

    Extended S6K function beyond catalysis to localization and non-substrate partnerships, placing S6K at the actin arc with mTOR/Akt/PDK1 in migration and identifying CoA synthase and the PDK1-PILSAP complex as physical associations.

    Evidence F-actin cosedimentation and immunocytochemistry with rapamycin; reciprocal co-IP/BIAcore; dominant-negative PILSAP with in vivo angiogenesis

    PMID:15149849 PMID:15187024 PMID:15589845

    Open questions at the time
    • Functional consequence of CoA synthase binding unclear
    • Actin-localization study from a single lab
    • How PILSAP-processed PDK1 selects S6K not fully resolved
  10. 2009 High

    Identified eIF4B Ser422 as a direct S6K1 substrate that enhances eIF3A association and ATPase activity, defining a translation-initiation effector required for interferon-dependent protein expression.

    Evidence S6k1/S6k2 double-KO MEFs, eIF4B phosphorylation, eIF3A co-IP, and ATPase assays

    PMID:19289497

    Open questions at the time
    • Relative contribution of S6K1 vs S6K2 to eIF4B phosphorylation not isolated
  11. 2010 High

    Defined the off-switch for S6K by identifying the PP2A-B'/PPP2R5C holoenzyme as a conserved direct phosphatase counteracting S6K phosphorylation.

    Evidence PP2A-B' knockout Drosophila, co-IP, and PPP2R5C knockdown in human cells

    PMID:20444422

    Open questions at the time
    • Specific S6K residues dephosphorylated by PP2A-B' not mapped
  12. 2010 Medium

    Demonstrated that S6K hyperactivation, not basal activity, is detrimental across stem-cell and tissue contexts, linking S6K-driven translation to loss of pluripotency, β-cell dysfunction, and stem-cell loss.

    Evidence Constitutively active S6K in hESCs; transgenic active-S6K β-cells; Drosophila TSC1/2-S6K intestinal stem-cell epistasis

    PMID:20622167 PMID:20698768 PMID:23843608

    Open questions at the time
    • β-cell phenotype tied to IRS/Akt feedback but direct targets not all defined
    • hESC study single lab
  13. 2012 High

    Showed therapeutically that relieving S6K-imposed feedback on the PDK1-Akt axis underlies cardioprotection by S6K inhibition.

    Evidence Rapamycin/PF-4708671 in MI model with cardiomyocyte-specific PDK1 and Akt1/3 knockouts

    PMID:21906027

    Open questions at the time
    • Whether feedback operates via IRS or other adaptors in heart not specified
  14. 2013 High

    Established cell-autonomous S6K control of stem-cell fate, with S6K promoting germline progenitor proliferation in parallel to Notch and insulin/IGF pathways via a conserved TOR phosphorylation site.

    Evidence C. elegans rsks-1 genetic epistasis with germline-autonomous rescue

    PMID:22278922

    Open questions at the time
    • Downstream translational targets driving GSC fate not identified
  15. 2015 Medium

    Revealed an inter-tissue role: hepatic amino-acid/mTORC1/S6K signaling controls systemic lipid metabolism through afferent vagal and efferent sympathetic neuronal relays.

    Evidence Hepatic active/dominant-negative S6K viral expression with surgical denervation, deafferentation, and β-blockers

    PMID:26268630

    Open questions at the time
    • Molecular signal from liver to nerve not identified
    • Single lab
  16. 2016 Medium

    Identified creatine kinase (ARGK-1) as a longevity effector downstream of S6K loss, linking reduced S6K to AMPK activation and extended lifespan.

    Evidence C. elegans rsks-1 proteomics, ARGK-1 overexpression lifespan/AMPK epistasis, and S6K1-KO mouse brain measurement

    PMID:26923601

    Open questions at the time
    • How S6K loss elevates ARGK-1 not mechanistically defined
    • Lifespan link extrapolated from invertebrate to mouse only at protein-level
  17. 2016 High

    Expanded S6K into innate immunity by showing its kinase domain (not activity) scaffolds a cGAS/TBK1-dependent S6K1-STING-TBK1 complex required for IRF3 activation and antiviral responses.

    Evidence Reciprocal co-IP, kinase-dead and domain mutants, cGAS-deficient cells, TBK1 depletion, and in vivo antiviral assays

    PMID:27043414

    Open questions at the time
    • Structural basis of S6K1-STING contact not resolved
  18. 2018 High

    Connected S6K to genome maintenance by identifying RNF168 Ser60 as a direct substrate whose phosphorylation inhibits ligase activity and promotes proteolysis, impairing the DNA-damage response.

    Evidence Phosphosite mapping, ligase and stability assays, and phospho-deficient RNF168-S60A rescue in Lkb1-null tumors

    PMID:29403037

    Open questions at the time
    • Generality of this DDR effect across tissues beyond LKB1-loss context not established
  19. 2020 High

    Showed mitotic suppression of mTORC1-S6K stabilizes PDCD4 to repress eIF4A, defining an S6K/PDCD4/eIF4A axis that governs cell fate during mitotic arrest and chemosensitivity.

    Evidence Non-phosphorylatable raptor mutant, PDCD4 stability assays, eIF4A inhibition, and Taxol-sensitivity readouts

    PMID:33027666

    Open questions at the time
    • Direct S6K phosphorylation site on PDCD4 not mapped here
  20. 2024 Medium

    Linked TORC1-S6K to organelle homeostasis and aging, identifying Syntaxin 13 as the mediator of S6K-dependent lysosome morphology and NF-κB-mediated inflammaging.

    Evidence Drosophila fat-body S6K epistasis with Syntaxin 13 and lysosome/IMD readouts; conservation via mouse liver rapamycin and NF-κB measurement

    PMID:38413780

    Open questions at the time
    • Whether S6K directly phosphorylates Syntaxin 13 unknown
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How S6K1 substrate selection is spatially partitioned among translation, DNA-damage, innate-immune, cytoskeletal, and organelle pathways—and which scaffolds or localizations direct each output—remains unresolved.
  • No unifying model of how one kinase coordinates distinct effector branches
  • Structural basis for non-catalytic scaffolding (e.g. STING) not determined
  • Direct phosphosites on several effectors (IRS, PDCD4, Syntaxin 13) not all mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0045182 translation regulator activity 3 GO:0140657 ATP-dependent activity 1
Localization
GO:0005856 cytoskeleton 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-73894 DNA Repair 1
Partners
EIF3AEIF4BPDK1PPP2R5CRNF168STING1STX12TBK1
Complex memberships
PDK1-PILSAP complexS6K1-STING-TBK1 complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 The principal rapamycin-sensitive phosphorylation sites on p70(S6K) are T-389 (in the linker/hydrophobic motif region) and T-229 (in the activation loop). T-389 is the principal regulatory site whose phosphorylation, together with hyperphosphorylation of the carboxyl-terminal autoinhibitory domain S/TP sites, controls T-229 phosphorylation through an intrasteric mechanism. Mutation of T-389 to an acidic residue confers resistance to rapamycin, wortmannin, and SQ20006, while T-229 phosphorylation is regulated by internal mechanisms and is differentially sensitive to inhibitors. Truncation and point mutants of p70(S6K), phosphorylation site mapping, kinase activity assays with inhibitors (rapamycin, wortmannin, SQ20006) Molecular and cellular biology High 8887654
1998 Phosphorylation of the carboxyl-terminal autoinhibitory domain S/TP sites mimics the effect of carboxyl-terminal deletion and rescues kinase activation caused by amino-terminal truncation. Phosphorylation of T-389 in cooperation with the S/TP site phosphorylations controls T-229 (activation loop) phosphorylation through an intrasteric mechanism. A mutant harboring acidic substitutions at both S/TP sites and T-389 is an excellent in vitro substrate for PDK1 (the T-229 kinase), whereas single-substitution variants are poor PDK1 substrates. Point mutagenesis of p70(S6K) S/TP autoinhibitory sites to acidic residues, in vitro PDK1 phosphorylation assays, kinase activity measurements The Journal of biological chemistry High 9614086
2001 PDK1 activates S6K1 at the T-loop (T229) via interaction with the PIF-binding pocket in PDK1's kinase domain. Prior phosphorylation of S6K1 at its hydrophobic motif (T389) promotes interaction with the PIF-binding pocket of PDK1 and subsequent T-loop phosphorylation. This pocket is required for S6K1 and SGK1 activation but not for PKB/Akt phosphorylation by PDK1. PIF-binding pocket mutants of PDK1, in vitro kinase assays, co-immunoprecipitation, functional activation studies with S6K1, SGK1, and PKB The EMBO journal High 11500365
1998 Genetic disruption of the p70(S6K)/p85(S6K) gene in mice results in a small growth phenotype (particularly during embryogenesis) but not lethality or infertility. Despite loss of p70/p85-S6K, S6 phosphorylation and 5'TOP mRNA translational up-regulation proceed normally in response to mitogens and remain rapamycin-sensitive, due to compensatory up-regulation of a novel homolog S6K2. Gene knockout in mice, polysome profiling, S6 phosphorylation Western blot, rapamycin sensitivity assays in mouse embryo fibroblasts The EMBO journal High 9822608
1998 Targeted disruption of p70(S6K) in murine embryonic stem cells eliminates ribosomal S6 phosphorylation and abolishes serum-induced translational up-regulation of ribosomal protein mRNAs (5'TOP mRNAs), establishing that p70(S6K) specifically controls ribosomal biogenesis by regulating ribosomal protein synthesis at the level of mRNA translation. Rapamycin inhibition of 4E-BP1 phosphorylation, general mRNA translation, and overall protein synthesis proceeds independently of p70(S6K). Gene targeting in ES cells, ribosomal S6 phosphorylation assay, selective mRNA translation assays, rapamycin treatment Proceedings of the National Academy of Sciences of the United States of America High 9560223
1999 p70(S6K) activity is high in resting Xenopus oocytes and decreases upon progesterone-induced maturation, with three peaks during embryogenesis. Rapamycin-sensitive p70(S6K) activity suppresses translation of non-5'TOP mRNAs (mos, Cdc25A) while promoting 5'TOP mRNA translation; a rapamycin-insensitive constitutively active p70(S6K) mutant reverses rapamycin effects on oocyte maturation timing. Xenopus oocyte injection of rapamycin-insensitive constitutively active p70(S6K) mutant, translation assays with 5'TOP and non-5'TOP reporter constructs, kinase activity measurements during development Molecular and cellular biology High 10082514
1999 Amino acid-dependent activation of p70(S6K) requires mTOR and involves tRNA aminoacylation: amino acid alcohols (inhibitors of tRNA aminoacylation), cycloheximide/puromycin (which block use of aminoacylated tRNA), and a temperature-sensitive histidyl-tRNA synthetase mutant each suppress p70(S6K) activity, indicating that deacylated tRNA is a negative regulator of p70(S6K). Amino acid alcohol treatment, cycloheximide/puromycin treatment, temperature-sensitive tRNA synthetase mutant cells, rapamycin and wortmannin inhibition, mTOR rapamycin-resistant mutant (S2035I) The Journal of biological chemistry High 9873056
2004 Constitutive activation of the Rheb/mTOR/S6K pathway (by TSC1 or TSC2 deletion or ectopic Rheb expression) induces insulin resistance through downregulation of IRS1 and IRS2, making Akt completely refractory to IRS-dependent growth factor activation (insulin/IGF-I) but not to IRS-independent pathways (PDGF). This establishes S6K-mediated negative feedback on IRS1/2 as the mechanism linking mTOR hyperactivation to insulin resistance. Genetic deletion of TSC1 or TSC2, ectopic Rheb expression, IRS1/2 Western blot, Akt phosphorylation assays, growth factor stimulation with insulin/IGF-I vs PDGF Current biology : CB High 15380067
2010 The Drosophila B' regulatory subunit of PP2A (PP2A-B') directly dephosphorylates S6K; PP2A-B' knockout flies exhibit elevated S6K phosphorylation. The human homolog PPP2R5C also counteracts S6K1 phosphorylation, indicating a conserved mechanism. PP2A-B' physically and genetically interacts with S6K. PP2A-B' knockout Drosophila, S6K phosphorylation Western blot, co-immunoprecipitation (physical interaction), genetic interaction studies, PPP2R5C knockdown in human cells Cell metabolism High 20444422
2018 The mTOR-S6K pathway phosphorylates RNF168 at Ser60, inhibiting its E3 ubiquitin ligase activity, accelerating its proteolysis, and impairing DNA damage response (DDR). Loss of LKB1 hyperactivates mTORC1-S6K, decreases RNF168 expression, and causes DDR defects; a phospho-deficient RNF168-S60A mutant rescues DDR and suppresses tumorigenesis caused by Lkb1 loss. Phosphorylation site identification (Ser60 on RNF168), S6K kinase assay, RNF168 ubiquitin ligase activity assay, RNF168 stability/proteolysis assays, phospho-deficient mutant rescue in Lkb1-null cells/tumors Nature cell biology High 29403037
2016 S6K1 physically interacts with the signaling adaptor STING in a cGAS-dependent manner upon DNA virus infection. The kinase domain (but not kinase activity) of S6K1 is required for the S6K1-STING interaction; TBK1 critically promotes formation of a tripartite S6K1-STING-TBK1 complex, which is necessary for IRF3 activation and antiviral gene expression. Co-immunoprecipitation, kinase-dead S6K1 mutants, cGAS-deficient cells, TBK1 inhibition/depletion, IRF3 activation assays, antiviral immune response assays in vivo Nature immunology High 27043414
2004 p70(S6K) associates with the F-actin cytoskeleton (cosedimentation and subcellular fractionation) and localizes with activated mTOR at the actin arc (a caveolin-enriched structure at the leading edge of migrating cells) along with Akt1, PDK1, and p85-PI3K. EGF-induced actin arc formation (a correlate of migration) is blocked by rapamycin. Stress fibers down-regulate p70(S6K) activity; disruption of stress fibers increases p70(S6K) activity, establishing a functional link between the actin cytoskeleton and p70(S6K) in cell migration. F-actin cosedimentation, subcellular fractionation, immunocytochemistry with phospho-specific mTOR antibody, rapamycin treatment, cytochalasin D and Rho kinase inhibitor treatment Experimental cell research Medium 15149849
2009 S6K1 interferon-dependent phosphorylates eIF4B at Ser422, enhancing eIF4B interaction with eIF3A and increasing eIF3A-associated ATPase activity. IFN-inducible eIF4B activity and downstream protein expression (ISG15, CXCL-10) are diminished in S6k1/S6k2 double-knockout MEFs, establishing S6K1 as required for IFN-dependent mRNA translation. S6k1/S6k2 double-knockout MEFs, eIF4B Ser422 phosphorylation assay, eIF3A co-immunoprecipitation, ATPase activity assay, ISG15/CXCL-10 protein expression, eIF4B/eIF3A siRNA knockdown Molecular and cellular biology High 19289497
2004 S6K1 specifically binds CoA synthase; the interaction involves the C-terminal regions of both proteins (mapped by in vivo co-immunoprecipitation and in vitro BIAcore analysis). CoA synthase is not a substrate for S6K1 and the interaction does not affect their enzymatic activities, but the association suggests a link between mTOR/S6K signaling and CoA biosynthesis/energy metabolism. Co-immunoprecipitation of native and transiently overexpressed proteins, BIAcore binding analysis, C-terminal domain mapping, in vitro kinase assay FEBS letters Medium 15589845
2004 PILSAP (a leucyl aminopeptidase) binds PDK1 and removes 9 amino acids from its N-terminus, which allows S6K to associate with the PDK1-PILSAP complex and become activated upon VEGF stimulation. Mutant PILSAP lacking aminopeptidase activity but retaining PDK1 binding acts as a dominant-negative inhibitor of S6K activation and angiogenesis in vivo. Co-immunoprecipitation, dominant-negative PILSAP mutant, N-terminal truncated PDK1 rescue, CDK4/6 activity and Rb phosphorylation assays, in vivo tumor angiogenesis model Blood High 15187024
1999 p70(S6K) phosphorylation (activity) in rat skeletal muscle 6 h after high-resistance exercise correlates (r=0.998) with long-term skeletal muscle hypertrophy after 6 weeks of training. Polysome profiles after high-resistance contractions indicate increased translational initiation rate, and p70(S6K) activity is elevated 3.5-fold in the EDL and TA muscles. Rat resistance exercise model, immune complex p70(S6K) kinase assay, polysome profiling, muscle mass measurement after training The American journal of physiology Medium 9886927
1999 H2O2 generated by glucose/glucose oxidase activates p70(S6K) in mouse epidermal cells (JB6) via a Ca2+-dependent mechanism acting upstream of PI3K and mTOR/FRAP. Growth factors (PDGF, EGF) induce p70(S6K) activation through H2O2 generation; catalase blocks both growth factor-induced H2O2 and p70(S6K) activation. TPA-responsive PKC is not required for ROS-induced p70(S6K) activation. Exogenous H2O2, glucose/glucose oxidase system, catalase treatment, rapamycin and wortmannin inhibition, Ca2+ chelation, PKC downregulation, immune complex kinase assay The Journal of biological chemistry Medium 10551813
2020 During mitosis, mTORC1 activity is dramatically reduced, which prevents S6K-mediated phosphorylation and degradation of the tumor suppressor PDCD4. PDCD4 inhibits eIF4A activity; the mTORC1/S6K/PDCD4/eIF4A axis determines the outcome (death vs. slippage) during mitotic arrest. Expression of a non-phosphorylatable raptor mutant reactivates mTORC1 during mitosis, promotes PDCD4 degradation, and reduces Taxol cytotoxicity. Non-phosphorylatable raptor mutant expression, PDCD4 stability assays, eIF4A inhibition, Taxol sensitivity assays, cell death vs. slippage quantification Cell reports High 33027666
2001 In Drosophila, dPDK1 controls cellular and organism growth by activating both dAkt and dS6K (ribosomal S6 kinase); dPDK1 genetically interacts with dRSK but not dPKN, indicating dPDK1 regulates insulin-mediated growth through two main branches: dAkt and dS6K. Drosophila genetic epistasis, dPDK1 loss-of-function and gain-of-function, dAkt and dS6K activity measurements, genetic interaction tests with dRSK and dPKN Proceedings of the National Academy of Sciences of the United States of America High 11752451
2010 In Drosophila, TSC1/2 loss causes rapid intestinal stem cell (ISC) loss through TORC1 hyperactivation; ISCs are rescued by S6K mutation or rapamycin treatment. Rheb overexpression recapitulates TSC1/2 disruption phenotype. Reduced TORC1-S6K signaling by S6K mutation alone has no effect on ISC maintenance, establishing that hyperactivation (not basal S6K activity) is detrimental. Drosophila genetic epistasis (Tsc1/Tsc2, S6k, Rheb mutants), rapamycin rescue, intestinal stem cell lineage tracing Journal of cell science High 23843608
2010 Constitutively active p70 S6K (but not wild-type p70 S6K) expression in human embryonic stem cells induces differentiation; siRNA knockdown of both TSC2 and Rictor elevates p70 S6K activation and also induces hESC differentiation, establishing that mTORC1/p70 S6K-mediated protein translation must be suppressed (via high TSC1/TSC2) to maintain pluripotency. Constitutively active p70 S6K expression, siRNA knockdown of TSC2 and Rictor, pluripotency marker (Oct4, Nanog) expression, rapamycin treatment Cellular reprogramming Medium 20698768
2010 Leucine-induced activation of the cardiac mTOR/p70(S6K) pathway requires PDK1 via a mechanism independent of PKB/Akt: in PDK1 knockout hearts, leucine fails to phosphorylate mTOR, PRAS40, and p70(S6K); a PDK1 L155E mutation (which preserves insulin/PKB-dependent mTOR/S6K phosphorylation) abolishes all leucine effects, distinguishing leucine and insulin signaling routes to p70(S6K). PDK1 cardiac-specific knockout mice, PDK1 L155E knock-in, leucine and insulin stimulation, mTOR/p70(S6K)/PRAS40 phosphorylation Western blot American journal of physiology. Endocrinology and metabolism High 20051528
2012 S6K inhibition (by rapamycin or PF-4708671) after myocardial infarction enhances Akt Thr308 phosphorylation via PDK1; cardiomyocyte-specific deletion of PDK1 and Akt1/3 abolishes the cardioprotective effect, establishing that S6K inhibition protects the heart by relieving negative feedback on the PDK1-Akt axis. Rapamycin and PF-4708671 treatment in MI mouse model, PDK1 and Akt1/3 cardiomyocyte-specific knockout, Akt Thr308 phosphorylation Western blot, cardiac function measurements The Biochemical journal High 21906027
2016 In C. elegans, rsks-1/S6K loss-of-function extends lifespan and requires the creatine kinase ortholog ARGK-1. ARGK-1 is the most enriched protein in rsks-1 mutants by proteomics; ARGK-1 overexpression extends lifespan in part by activating AMPK (AAK-2). ARGK-1 is also required for reduced body size and increased stress resistance in rsks-1 mutants. Creatine kinase levels are elevated in brains of S6K1 knockout mice. C. elegans proteomics comparing rsks-1 mutants vs. wild-type, ARGK-1 overexpression lifespan assay, aak-2/AMPK epistasis, S6K1 knockout mouse brain creatine kinase measurement Cell reports Medium 26923601
2024 S6K in Drosophila fat body mediates TORC1-dependent regulation of lysosome morphology (multilamellar lysosomes) and inflammaging via the NF-κB-like IMD pathway. Syntaxin 13 mediates the effects of TORC1-S6K on lysosome morphology and inflammaging. Rapamycin treatment in mice elevates Syntaxin 12/13 levels in liver and prevents age-related increase in noncanonical NF-κB signaling, indicating conservation of the mechanism. Tissue-specific S6K expression in Drosophila fat body, rapamycin treatment, Syntaxin 13 genetic epistasis, lysosome morphology analysis, IMD pathway activity assays, mouse liver rapamycin treatment with NF-κB measurement Nature aging Medium 38413780
2015 Hepatic amino acid/mTORC1/S6K signaling modulates systemic lipid metabolism via neuronal inter-tissue communication. Hepatic expression of active S6K elevates serum triglycerides and downregulates adipose lipoprotein lipase (LPL); dominant-negative S6K inhibits TG elevation; denervation, deafferentation, and β-blockers suppress the effect, demonstrating that S6K signals from liver to adipose via afferent vagal and efferent sympathetic nerves. Hepatic SNAT2/Rheb/active-S6K/DN-S6K viral expression, serum TG measurement, adipose LPL activity, surgical denervation, pharmacological deafferentation, β-blocker administration Nature communications Medium 26268630
1999 The 17q23 gene PS6K (RPS6KB1) is amplified in breast cancer; amplification is accompanied by corresponding increases in both mRNA and protein expression, localizing the gene to chromosome 17q23. Comparative genomic hybridization, FISH localization to 17q23, Northern blot, Western blot in breast tumor tissues and cell lines Cancer research Medium 10197603
2013 In C. elegans, rsks-1/S6K promotes germline stem cell (GSC) fate cell-autonomously, acts in parallel with glp-1/Notch and daf-2/insulin-IGF receptor pathways, and requires a conserved TOR phosphorylation site; rsks-1 promotes cell cycle progression and inhibits differentiation in the germline progenitor pool. C. elegans rsks-1 null mutants, germline-specific rescue, double-mutant analysis with glp-1, daf-2, ife-1, let-363/TOR, daf-15/RAPTOR, TOR phosphorylation site mutant Development (Cambridge, England) High 22278922
2010 Overexpression of constitutively active S6K in pancreatic β-cells improves insulin secretion but reduces β-cell mass by impairing G1-S cell cycle progression (increased p16, p27; decreased Cdk2) and increasing apoptosis. This is accompanied by downregulated IRS/Akt signaling, establishing that in vivo S6K activation creates β-cell insulin resistance via IRS negative feedback. Transgenic mice with rat insulin promoter-driven constitutively active S6K, β-cell mass and proliferation analysis, cell cycle marker Western blot, IRS/Akt phosphorylation, insulin secretion assay Diabetes High 20622167

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal immunology 1000 24917457
2012 Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. The Biochemical journal 817 22168436
2004 Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Current biology : CB 673 15380067
1999 Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise. The American journal of physiology 559 9886927
1998 Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. The EMBO journal 553 9822608
2004 Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. The Journal of cell biology 408 15533996
2001 The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB. The EMBO journal 320 11500365
2010 Sex peptide receptor and neuronal TOR/S6K signaling modulate nutrient balancing in Drosophila. Current biology : CB 258 20471268
2002 Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. BioEssays : news and reviews in molecular, cellular and developmental biology 242 11782951
1996 The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases. Molecular and cellular biology 229 8887654
2015 The S6K protein family in health and disease. Life sciences 187 25818187
1999 Amino acid-dependent control of p70(s6k). Involvement of tRNA aminoacylation in the regulation. The Journal of biological chemistry 182 9873056
2009 Polycystin-1 regulates extracellular signal-regulated kinase-dependent phosphorylation of tuberin to control cell size through mTOR and its downstream effectors S6K and 4EBP1. Molecular and cellular biology 164 19255143
1998 Targeted disruption of p70(s6k) defines its role in protein synthesis and rapamycin sensitivity. Proceedings of the National Academy of Sciences of the United States of America 163 9560223
1999 Cyclin D1 expression mediated by phosphatidylinositol 3-kinase through mTOR-p70(S6K)-independent signaling in growth factor-stimulated NIH 3T3 fibroblasts. Molecular and cellular biology 161 9891068
2005 Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway. Diabetologia 151 15692808
2001 PDK1 regulates growth through Akt and S6K in Drosophila. Proceedings of the National Academy of Sciences of the United States of America 141 11752451
2009 LKB1 is required for adiponectin-mediated modulation of AMPK-S6K axis and inhibition of migration and invasion of breast cancer cells. Oncogene 139 19483724
2002 Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation. Diabetes 138 11916914
2003 Differential activation mechanisms of Erk-1/2 and p70(S6K) by glucose in pancreatic beta-cells. Diabetes 137 12663469
1999 Hydrogen peroxide activates p70(S6k) signaling pathway. The Journal of biological chemistry 123 10551813
1999 NRG-1-induced cardiomyocyte hypertrophy. Role of PI-3-kinase, p70(S6K), and MEK-MAPK-RSK. The American journal of physiology 120 10564160
2001 Cross-talk between the ERK and p70 S6 kinase (S6K) signaling pathways. MEK-dependent activation of S6K2 in cardiomyocytes. The Journal of biological chemistry 117 11431469
1998 Phosphorylation sites in the autoinhibitory domain participate in p70(s6k) activation loop phosphorylation. The Journal of biological chemistry 117 9614086
2004 Role of the p70(S6K) pathway in regulating the actin cytoskeleton and cell migration. Experimental cell research 115 15149849
2010 PP2A regulatory subunit PP2A-B' counteracts S6K phosphorylation. Cell metabolism 112 20444422
1999 p70(s6k) integrates phosphatidylinositol 3-kinase and rapamycin-regulated signals for E2F regulation in T lymphocytes. Molecular and cellular biology 111 10373522
2002 Inhibition of PI3K/p70 S6K and p38 MAPK cascades increases osteoblastic differentiation induced by BMP-2. FEBS letters 110 11755539
2018 The mTOR-S6K pathway links growth signalling to DNA damage response by targeting RNF168. Nature cell biology 108 29403037
2003 Signaling from Akt to FRAP/TOR targets both 4E-BP and S6K in Drosophila melanogaster. Molecular and cellular biology 107 14645523
2010 mTOR-mediated activation of p70 S6K induces differentiation of pluripotent human embryonic stem cells. Cellular reprogramming 104 20698768
1999 Localization of PS6K to chromosomal region 17q23 and determination of its amplification in breast cancer. Cancer research 85 10197603
2012 S6K links cell fate, cell cycle and nutrient response in C. elegans germline stem/progenitor cells. Development (Cambridge, England) 82 22278922
2000 17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K, and SIGma1B genes. Cancer research 78 11034073
2015 Alpha-synuclein overexpression negatively regulates insulin receptor substrate 1 by activating mTORC1/S6K1 signaling. The international journal of biochemistry & cell biology 77 25813876
1999 Differential regulation of MAP kinase, p70(S6K), and Akt by contraction and insulin in rat skeletal muscle. The American journal of physiology 77 10329981
2005 Cell size reduction induced by inhibition of the mTOR/S6K-signaling pathway protects Jurkat cells from apoptosis. Cell death and differentiation 75 15905878
2011 Cot/tpl2 activity is required for TLR-induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression. European journal of immunology 74 21469113
2000 Nitric oxide increases p21(Waf1/Cip1) expression by a cGMP-dependent pathway that includes activation of extracellular signal-regulated kinase and p70(S6k). The Journal of biological chemistry 74 10753954
2013 Tanshinone IIA induces autophagic cell death via activation of AMPK and ERK and inhibition of mTOR and p70 S6K in KBM-5 leukemia cells. Phytotherapy research : PTR 73 23813779
2010 The degree of p70 S6k and S6 phosphorylation in human skeletal muscle in response to resistance exercise depends on the training volume. European journal of applied physiology 72 20617335
2002 Ultraviolet-induced phosphorylation of p70(S6K) at Thr(389) and Thr(421)/Ser(424) involves hydrogen peroxide and mammalian target of rapamycin but not Akt and atypical protein kinase C. Cancer research 69 12384526
2001 Alterations of Akt1 (PKBalpha) and p70(S6K) in transient focal ischemia. Neurobiology of disease 64 11162248
2009 Interferon-dependent engagement of eukaryotic initiation factor 4B via S6 kinase (S6K)- and ribosomal protein S6K-mediated signals. Molecular and cellular biology 63 19289497
2016 S6K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3. Nature immunology 62 27043414
2010 Decreased IRS signaling impairs beta-cell cycle progression and survival in transgenic mice overexpressing S6K in beta-cells. Diabetes 55 20622167
2008 Arginine activates intestinal p70(S6k) and protein synthesis in piglet rotavirus enteritis. The Journal of nutrition 55 18156399
2000 Glucocorticoids abate p70(S6k) and eIF4E function in L6 skeletal myoblasts. American journal of physiology. Endocrinology and metabolism 55 10893325
2012 S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt. The Biochemical journal 54 21906027
2022 Beyond controlling cell size: functional analyses of S6K in tumorigenesis. Cell death & disease 53 35879299
1999 p70(S6K) controls selective mRNA translation during oocyte maturation and early embryogenesis in Xenopus laevis. Molecular and cellular biology 53 10082514
2018 Guanidinoacetic Acid Regulates Myogenic Differentiation and Muscle Growth Through miR-133a-3p and miR-1a-3p Co-mediated Akt/mTOR/S6K Signaling Pathway. International journal of molecular sciences 52 30235878
2005 Homocysteine thiolactone inhibits insulin-stimulated DNA and protein synthesis: possible role of mitogen-activated protein kinase (MAPK), glycogen synthase kinase-3 (GSK-3) and p70 S6K phosphorylation. Journal of molecular endocrinology 52 15691882
2015 A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals. Nature communications 50 26268630
2003 Age-related differences in the des IGF-I-mediated activation of Akt-1 and p70 S6K in mouse skeletal muscle. Mechanisms of ageing and development 50 12875741
2013 TGF-β1 up-regulates the expression of PDGF-β receptor mRNA and induces a delayed PI3K-, AKT-, and p70(S6K) -dependent proliferative response in activated hepatic stellate cells. Alcoholism, clinical and experimental research 48 23895226
2007 Noradrenaline enhances the expression of the neuronal monocarboxylate transporter MCT2 by translational activation via stimulation of PI3K/Akt and the mTOR/S6K pathway. Journal of neurochemistry 47 17394554
2004 Puromycin-insensitive leucyl-specific aminopeptidase (PILSAP) binds and catalyzes PDK1, allowing VEGF-stimulated activation of S6K for endothelial cell proliferation and angiogenesis. Blood 47 15187024
2001 Growth factor-stimulated phosphorylation of Akt and p70(S6K) is differentially inhibited by LY294002 and Wortmannin. Endocrinology 46 11145615
2016 C. elegans S6K Mutants Require a Creatine-Kinase-like Effector for Lifespan Extension. Cell reports 45 26923601
2007 Reversine stimulates adipocyte differentiation and downregulates Akt and p70(s6k) signaling pathways in 3T3-L1 cells. Biochemical and biophysical research communications 45 17490611
2010 Activation of the cardiac mTOR/p70(S6K) pathway by leucine requires PDK1 and correlates with PRAS40 phosphorylation. American journal of physiology. Endocrinology and metabolism 44 20051528
1999 Inhibition of DNA synthesis by a farnesyltransferase inhibitor involves inhibition of the p70(s6k) pathway. The Journal of biological chemistry 44 9988711
2020 Attenuation of Free Fatty Acid (FFA)-Induced Skeletal Muscle Cell Insulin Resistance by Resveratrol is Linked to Activation of AMPK and Inhibition of mTOR and p70 S6K. International journal of molecular sciences 43 32664532
2011 Yeast 3-phosphoinositide-dependent protein kinase-1 (PDK1) orthologs Pkh1-3 differentially regulate phosphorylation of protein kinase A (PKA) and the protein kinase B (PKB)/S6K ortholog Sch9. The Journal of biological chemistry 43 21531713
2024 Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system. Nature aging 42 38413780
2012 Enhanced expression of glucose transporter-1 in vascular smooth muscle cells via the Akt/tuberous sclerosis complex subunit 2 (TSC2)/mammalian target of rapamycin (mTOR)/ribosomal S6 protein kinase (S6K) pathway in experimental renal failure. Journal of vascular surgery 42 23265586
1997 Rapamycin dissociates p70(S6K) activation from DNA synthesis stimulated by bombesin and insulin in Swiss 3T3 cells. The Journal of biological chemistry 41 8999966
2017 Inhibition of Human Lung Cancer Cell Proliferation and Survival by Post-Exercise Serum Is Associated with the Inhibition of Akt, mTOR, p70 S6K, and Erk1/2. Cancers 40 28481292
1998 Cloning and characterization of p70(S6K beta) defines a novel family of p70 S6 kinases. Biochemical and biophysical research communications 40 9878560
2001 Elevated IGF-II mRNA and phosphorylation of 4E-BP1 and p70(S6k) in muscle showing clenbuterol-induced anabolism. American journal of physiology. Endocrinology and metabolism 39 11551843
2001 PS6K amplification characterizes a small subset of anaplastic meningiomas. American journal of clinical pathology 38 11211609
2017 Blocking Stemness and Metastatic Properties of Ovarian Cancer Cells by Targeting p70S6K with Dendrimer Nanovector-Based siRNA Delivery. Molecular therapy : the journal of the American Society of Gene Therapy 37 29241971
2004 The mTOR/S6K signalling pathway: the role of the TSC1/2 tumour suppressor complex and the proto-oncogene Rheb. Novartis Foundation symposium 37 15562827
2019 ROS Inhibits Cell Growth by Regulating 4EBP and S6K, Independent of TOR, during Development. Developmental cell 33 31063760
2013 TSC1/2 regulates intestinal stem cell maintenance and lineage differentiation through Rheb-TORC1-S6K but independently of nutritional status or Notch regulation. Journal of cell science 33 23843608
2015 Huaier Extract Induces Autophagic Cell Death by Inhibiting the mTOR/S6K Pathway in Breast Cancer Cells. PloS one 32 26134510
2013 Focal adhesion kinase mediates atrial fibrosis via the AKT/S6K signaling pathway in chronic atrial fibrillation patients with rheumatic mitral valve disease. International journal of cardiology 32 23639457
2022 Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway. International journal of molecular sciences 31 35955892
2011 The exquisite regulation of PLD2 by a wealth of interacting proteins: S6K, Grb2, Sos, WASp and Rac2 (and a surprise discovery: PLD2 is a GEF). Cellular signalling 31 21740967
2020 The mTORC1/S6K/PDCD4/eIF4A Axis Determines Outcome of Mitotic Arrest. Cell reports 30 33027666
2006 EGF AND TGF-alpha motogenic activities are mediated by the EGF receptor via distinct matrix-dependent mechanisms. Experimental cell research 30 17196962
2019 Alleviation of sepsis‑induced cardiac dysfunction by overexpression of Sestrin2 is associated with inhibition of p‑S6K and activation of the p‑AMPK pathway. Molecular medicine reports 29 31524263
2004 Functional characterization of a maize ribosomal S6 protein kinase (ZmS6K), a plant ortholog of metazoan p70(S6K). Biochemistry 29 14717609
2004 Specific interaction between S6K1 and CoA synthase: a potential link between the mTOR/S6K pathway, CoA biosynthesis and energy metabolism. FEBS letters 29 15589845
2018 Functional Interactions Between rsks-1/S6K, glp-1/Notch, and Regulators of Caenorhabditis elegans Fertility and Germline Stem Cell Maintenance. G3 (Bethesda, Md.) 28 30126834
2016 Grifolin induces autophagic cell death by inhibiting the Akt/mTOR/S6K pathway in human ovarian cancer cells. Oncology reports 28 27277722
2006 Effects of rapamycin on cell proliferation and phosphorylation of mTOR and p70(S6K) in HepG2 and HepG2 cells overexpressing constitutively active Akt/PKB. Biochimica et biophysica acta 28 16952420
2023 Lactoferrin attenuates cardiac fibrosis and cardiac remodeling after myocardial infarction via inhibiting mTORC1/S6K signaling pathway. Theranostics 27 37351157
2020 FoxO directly regulates the expression of TOR/S6K and vitellogenin to modulate the fecundity of the brown planthopper. Science China. Life sciences 27 32567002
2019 Eribulin Synergistically Increases Anti-Tumor Activity of an mTOR Inhibitor by Inhibiting pAKT/pS6K/pS6 in Triple Negative Breast Cancer. Cells 27 31480338
2013 S6K in geroconversion. Cell cycle (Georgetown, Tex.) 26 24036549
2000 Autocrine phosphorylation of p70(S6k) in response to acute stretch in myotubes. Molecular cell biology research communications : MCBRC 26 11170836
2017 Global Phosphoproteomic Analysis of Insulin/Akt/mTORC1/S6K Signaling in Rat Hepatocytes. Journal of proteome research 25 28689409
2013 Regulation of matrix metalloproteinase-1, -3, and -9 in Mycobacterium tuberculosis-dependent respiratory networks by the rapamycin-sensitive PI3K/p70(S6K) cascade. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 24076964
2011 Luteolin, a novel natural inhibitor of tumor progression locus 2 serine/threonine kinase, inhibits tumor necrosis factor-alpha-induced cyclooxygenase-2 expression in JB6 mouse epidermis cells. The Journal of pharmacology and experimental therapeutics 25 21705614
2015 IL-37b suppresses T cell priming by modulating dendritic cell maturation and cytokine production via dampening ERK/NF-κB/S6K signalings. Acta biochimica et biophysica Sinica 24 26094142
2006 Intestinal ribosomal p70(S6K) signaling is increased in piglet rotavirus enteritis. American journal of physiology. Gastrointestinal and liver physiology 24 17138969
2022 Thermal stress affects proliferation and differentiation of turkey satellite cells through the mTOR/S6K pathway in a growth-dependent manner. PloS one 23 35025965
2003 Hydrogen peroxide mediates arsenite activation of p70(s6k) and extracellular signal-regulated kinase. Experimental cell research 23 14516795

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