Affinage

RPS6KB1

Ribosomal protein S6 kinase beta-1 · UniProt P23443

Round 2 corrected
Length
525 aa
Mass
59.1 kDa
Annotated
2026-04-28
130 papers in source corpus 38 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RPS6KB1 (p70S6K/S6K1) is a serine/threonine kinase that functions as the principal effector of mTORC1 signaling to control cell growth, protein synthesis, and metabolic homeostasis. It is activated through a hierarchical phosphorylation cascade in which raptor-mediated TOS-motif docking recruits S6K1 to mTOR for T-389 hydrophobic-motif phosphorylation, which in turn creates a docking site for the PDK1 PIF-pocket to enable activation-loop (T-229) phosphorylation; this activity is reversed by PP2A-B’ (PPP2R5C)-mediated dephosphorylation (PMID:8887654, PMID:9445476, PMID:11500365, PMID:12604610, PMID:20444422). Once active, S6K1 phosphorylates substrates including rpS6, eIF4B, eEF2K, and PDCD4 to promote translation initiation and elongation, phosphorylates IRS-1 at multiple serines to create a negative feedback loop that drives insulin resistance, and phosphorylates RNF168 to attenuate the DNA damage response (PMID:11500364, PMID:17053147, PMID:18952604, PMID:29403037). Beyond its catalytic roles, S6K1 forms a kinase-activity-independent complex with STING and TBK1 to promote IRF3-dependent antiviral innate immunity, and regulates systemic lipid metabolism through hepatic amino-acid sensing that signals via vagal afferent and sympathetic efferent nerves (PMID:27043414, PMID:26268630).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    Mapping the activation mechanism: identification of T-389 as the principal rapamycin-sensitive regulatory phosphorylation site resolved how extracellular signals converge on S6K1 activity, with autoinhibitory-domain phosphorylation and T-229 activation-loop phosphorylation constituting additional, distinctly regulated layers.

    Evidence Site-directed mutagenesis with kinase activity assays, truncation mutants, and inhibitor panels in cultured cells

    PMID:8887654

    Open questions at the time
    • Identity of the T-389 kinase was not established
    • Structural basis of autoinhibition was unknown
  2. 1998 High

    Establishing the hierarchical phosphorylation cascade: PDK1 was identified as the activation-loop kinase for S6K1, with prior T-389 phosphorylation creating a PIF-pocket docking site on PDK1 — explaining why hydrophobic-motif phosphorylation is prerequisite for full activation.

    Evidence In vitro kinase assays with purified PDK1 and S6K1, cooperative mutagenesis of autoinhibitory and hydrophobic-motif sites, reported independently in two concurrent papers

    PMID:9427642 PMID:9445476 PMID:9614086

    Open questions at the time
    • Identity of the upstream T-389 kinase remained unresolved at this point
    • How PDK1 PIF-pocket selectivity distinguishes S6K1 from PKB was not yet dissected
  3. 1998 High

    Genetic loss-of-function in mice established that S6K1 controls organismal body size and 5’TOP mRNA translation, while revealing compensatory S6K2 upregulation that preserves residual S6 phosphorylation.

    Evidence Homozygous S6K1 knockout mice and targeted ES cells with polysome profiling, translational assays, and Northern/Western identification of S6K2

    PMID:9560223 PMID:9822608

    Open questions at the time
    • S6K2 functional overlap precluded definitive assignment of all S6K1-specific functions
    • Whether reduced body size reflects cell size versus cell number was not resolved
  4. 1999 Medium

    Upstream input integration was expanded to include amino acid sensing via tRNA aminoacylation, mechanical load-correlated muscle hypertrophy, and reactive oxygen species signaling, establishing S6K1 as a multi-input growth integrator.

    Evidence Amino acid alcohol inhibitors and ts-histidyl-tRNA synthetase mutant for nutrient sensing; exercise-induced kinase activity correlation with muscle mass; H₂O₂ activation via Ca²⁺-dependent PI3K/mTOR pathway

    PMID:10551813 PMID:9873056 PMID:9886927

    Open questions at the time
    • Molecular identity of the amino acid sensor upstream of mTOR/S6K was unknown
    • Muscle hypertrophy correlation was not causal
    • Ca²⁺-ROS link lacked molecular target identification
  5. 2001 High

    The PDK1 PIF-pocket was shown to be essential for S6K1 activation but dispensable for PKBα, resolving how PDK1 achieves substrate selectivity; concurrently, eEF2K was identified as a direct S6K1 substrate, extending S6K1 function from translational initiation to elongation control.

    Evidence PIF-pocket mutations in PDK1 in cells and in vitro; in vitro kinase assay of S6K1 on eEF2K combined with PDK1 knockout cells

    PMID:11500364 PMID:11500365

    Open questions at the time
    • Structural basis of PIF-pocket selectivity was inferred, not crystallographically resolved at this point
    • Physiological importance of eEF2K phosphorylation by S6K1 versus ERK was not delineated
  6. 2003 High

    Placement of the TSC1/TSC2-Rheb module upstream of mTOR/S6K1 established the complete PI3K→Akt→TSC→Rheb→mTOR→S6K1 signaling axis, explaining how growth factor and nutrient signals converge on S6K1.

    Evidence Biochemical GAP assays for TSC2 on Rheb, Drosophila epistasis, disease-associated TSC2 mutations, S6K phosphorylation readouts

    PMID:12766775 PMID:12820960

    Open questions at the time
    • Direct Rheb-mTOR activation mechanism was biochemically undefined
    • Whether Rheb activates mTORC1 at endomembranes was unknown
  7. 2005 High

    The raptor TOS-motif docking mechanism and the dynamic S6K1-eIF3 scaffold model resolved how mTORC1 recruits and activates S6K1 at the ribosome: inactive S6K1 resides on eIF3, mTOR/raptor is recruited upon stimulation, phosphorylates T-389, and released active S6K1 then phosphorylates eIF4B and mTOR Ser-2448 (positive feedback).

    Evidence TOS motif mutagenesis with in vitro mTOR kinase assay; mass spectrometry identification of eIF3 complex interactions; rapamycin-resistant S6K1 rescue for Ser-2448 feedback

    PMID:12604610 PMID:15899889 PMID:16286006

    Open questions at the time
    • Whether eIF3-scaffold model operates in all cell types was untested
    • Stoichiometry of S6K1 on eIF3 was not determined
  8. 2006 High

    PDCD4 was identified as a direct S6K1 substrate whose phosphorylation at Ser67 triggers βTRCP-dependent degradation, relieving inhibition of eIF4A helicase activity and promoting translation of structured mRNAs — linking S6K1 to cap-dependent translation beyond rpS6.

    Evidence In vitro S6K1 kinase assay, βTRCP interaction mapping, PDCD4 non-degradable mutant with cell size and translation readouts

    PMID:17053147

    Open questions at the time
    • Full spectrum of mRNAs regulated via the S6K1-PDCD4-eIF4A axis was not defined
    • Whether S6K2 also phosphorylates PDCD4 was not tested
  9. 2008 High

    The negative feedback loop was molecularly detailed: S6K1 directly phosphorylates IRS-1 at Ser-270, -307, -636, and -1101, with Ser-270 serving as a docking site; TNFα activates this loop through IKK2, explaining how chronic mTORC1/S6K1 activation produces insulin resistance.

    Evidence In vitro kinase assay with purified proteins, site-specific IRS-1 mutants, S6K1 RNAi, IKK2 knockout cells, glucose uptake assays

    PMID:18952604

    Open questions at the time
    • Relative contribution of individual IRS-1 phosphorylation sites in vivo was not resolved
    • Whether S6K1 phosphorylates IRS-2 at analogous sites was not tested
  10. 2010 High

    PP2A-B’ (PPP2R5C) was identified as a conserved negative regulator that directly dephosphorylates S6K, with Drosophila knockout phenocopying hyperactive insulin signaling; concurrently, constitutively active S6K1 in pancreatic β-cells was shown to induce insulin resistance and apoptosis through IRS/Akt impairment.

    Evidence Drosophila PP2A-B’ knockout with mammalian PPP2R5C validation via Co-IP; transgenic β-cell-specific active S6K1 mice with cell cycle and apoptosis analysis

    PMID:20444422 PMID:20622167

    Open questions at the time
    • Phosphatase specificity for T-389 versus T-229 was not resolved
    • Whether PP2A-B’ regulation is nutrient-sensitive was not tested
  11. 2015 High

    Hepatic S6K1 was found to control systemic lipid metabolism through a neural circuit involving vagal afferent and sympathetic efferent signaling to adipose tissue, establishing S6K1 as a node for inter-organ metabolic communication.

    Evidence Adenoviral hepatic expression of active/dominant-negative S6K, surgical and pharmacological denervation, serum triglyceride and adipose LPL measurements

    PMID:26268630

    Open questions at the time
    • Molecular identity of the hepatic afferent signal was not identified
    • Whether this neural relay is conserved in humans was untested
  12. 2016 High

    A non-catalytic immune function was uncovered: S6K1 kinase domain (but not activity) scaffolds a STING-TBK1 complex upon DNA virus sensing by cGAS, enabling IRF3 activation and antiviral gene expression — the first kinase-independent function of S6K1.

    Evidence Reciprocal Co-IP with kinase-dead S6K1, cGAS knockout cells, TBK1 inhibitor, antiviral gene expression readouts

    PMID:27043414

    Open questions at the time
    • Structural basis of the non-catalytic STING interaction was not resolved
    • Whether mTORC1-driven S6K1 phosphorylation modulates the immune scaffolding function was not tested
  13. 2018 High

    S6K1 was shown to phosphorylate the E3 ligase RNF168 at Ser60, accelerating its proteolysis and impairing the DNA damage response; this linked hyperactive mTORC1/S6K signaling (e.g., from LKB1 loss) to genomic instability and tumorigenesis.

    Evidence In vitro S6K kinase assay on RNF168, phospho-deficient S60A rescue of DDR, LKB1 knockout mouse model, tumor xenografts

    PMID:29403037

    Open questions at the time
    • Whether S6K1 targets other DDR factors was not explored
    • Contribution of S6K2 to RNF168 regulation was not assessed
  14. 2020 High

    Mitotic suppression of mTORC1/S6K1 via raptor phosphorylation was shown to be functionally important for Taxol cytotoxicity through PDCD4 stabilization; reactivation of S6K1 during mitotic arrest degraded PDCD4 and conferred Taxol resistance.

    Evidence Non-phosphorylatable raptor mutant, PDCD4 stability assays, pharmacological eIF4A inhibition restoring Taxol sensitivity

    PMID:33027666

    Open questions at the time
    • Whether other S6K1 substrates contribute to mitotic drug resistance was not tested
    • Clinical relevance of eIF4A inhibitor combination was not validated in patient-derived models

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the full substrate repertoire of S6K1 versus S6K2, the structural basis for S6K1's non-catalytic immune scaffolding function, the molecular identity of the hepatic afferent signal mediating S6K1-driven lipid metabolism, and whether the S6K1-RNF168-DDR axis contributes to therapy resistance in human cancers.
  • Comprehensive substrate identification (e.g., phosphoproteomics in S6K1/2 double knockouts) is lacking
  • No high-resolution structure of S6K1 in complex with STING or eIF3
  • In vivo physiological relevance of many substrates has not been confirmed in conditional tissue-specific knockouts

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 7 GO:0140096 catalytic activity, acting on a protein 6 GO:0060090 molecular adaptor activity 1
Localization
GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-392499 Metabolism of proteins 5 R-HSA-1430728 Metabolism 1 R-HSA-1640170 Cell Cycle 1 R-HSA-168256 Immune System 1 R-HSA-73894 DNA Repair 1
Partners
IRS1MTORPDPK1PPP2R5CRNF168RPTORTBK1TMEM173
Complex memberships
S6K1-STING-TBK1eIF3 preinitiation complex (dynamic)

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 T-389 is the principal regulatory phosphorylation site of p70(S6K); phosphorylation of T-389 together with hyperphosphorylation of autoinhibitory domain S/TP sites acutely regulates kinase activity, while T-229 in the activation loop is regulated by distinct, rapamycin-insensitive kinases. Mutation of T-389 to an acidic residue confers rapamycin and wortmannin resistance. Site-directed mutagenesis of phosphorylation sites combined with kinase activity assays, truncation mutant analysis, and inhibitor studies (rapamycin, wortmannin, SQ20006) Molecular and cellular biology High 8887654
1998 PDK1 directly phosphorylates p70S6K at T-229 (Thr229) in the activation loop, activating it in vitro and in vivo; PDK1-mediated p70S6K phosphorylation is dependent on prior phosphorylation of the carboxy-terminal tail (T-389/Thr412 in the p70 numbering used), establishing hierarchical phosphorylation as the activation mechanism. In vitro kinase assay with purified PDK1 and p70S6K, co-expression in cells, site-specific mutagenesis, phosphospecific antibody analysis Science / Current biology High 9427642 9445476
1998 Phosphorylation of the autoinhibitory domain S/TP sites acts cooperatively with T-389 phosphorylation to control T-229 (activation loop) phosphorylation through an intrasteric mechanism; T-389 acidic substitution plus S/TP acidic substitutions markedly increase basal T-229 phosphorylation and kinase activity, making the resulting mutant an excellent PDK1 substrate in vitro. Truncation and point mutants analyzed by kinase activity assay and in vitro PDK1 phosphorylation The Journal of biological chemistry High 9614086
1998 Homozygous disruption of the p70(S6K)/p85(S6K) gene in mice reduces body size (especially during embryogenesis) but does not abolish S6 phosphorylation in liver or fibroblasts; a novel homolog S6K2 is upregulated in knockout tissues and can compensate for S6K1 function, accounting for residual S6 phosphorylation. Gene knockout in mice, Western blot for S6 phosphorylation, polysome profiling, Northern/Western analysis of S6K2 The EMBO journal High 9822608
1998 Targeted disruption of p70(S6K) in murine embryonic stem cells abolishes ribosomal S6 phosphorylation, prevents serum-stimulated translational upregulation of ribosomal protein mRNAs (5'TOP mRNAs), and slows proliferation; rapamycin-sensitive inhibition of 4E-BP1 phosphorylation and general protein synthesis occurs independently of p70(S6K). Gene targeting in ES cells, 35S-methionine incorporation, sucrose gradient polysome analysis, immunoblotting Proceedings of the National Academy of Sciences of the United States of America High 9560223
1999 p70(S6K) activity measured 6 h post-exercise in rat skeletal muscle correlates tightly (r = 0.998) with percent increase in muscle mass after 6 weeks of resistance training; polysome analysis suggests increased translation initiation after lengthening contractions, implicating p70(S6K) in load-induced muscle hypertrophy. Animal exercise model, immunoprecipitation kinase assay, polysome profiling, muscle mass measurement The American journal of physiology Medium 9886927
1999 Amino acid-dependent activation of p70(S6K) involves tRNA aminoacylation: amino acid alcohols that inhibit tRNA synthetases suppress p70(S6K) activity; cycloheximide or puromycin block suppression by amino acid withdrawal; a temperature-sensitive histidyl-tRNA synthetase mutant reduces p70(S6K) at non-permissive temperature. Deacylated tRNA may be a negative regulator of p70(S6K). Chemical inhibitors of tRNA aminoacylation, temperature-sensitive mutant cell line, rapamycin-resistant mTOR mutant, kinase activity assays The Journal of biological chemistry Medium 9873056
1999 p70(S6K) activity in Xenopus oocytes is high at rest and decreases upon progesterone-induced maturation; rapamycin (which inhibits p70S6K) accelerates germinal vesicle breakdown and increases mos mRNA translation (a non-5'TOP mRNA), while 5'TOP-containing mRNAs are translated less efficiently under rapamycin. A constitutively active rapamycin-resistant p70(S6K) reverses rapamycin effects, defining p70(S6K) as the relevant effector. Xenopus oocyte system, rapamycin-resistant constitutively active S6K1 rescue, in vivo translation assays with 5'TOP and IRES reporters, S6 phosphorylation immunoblotting Molecular and cellular biology High 10082514
1999 Hydrogen peroxide activates p70(S6K) upstream of rapamycin-sensitive FRAP/mTOR and wortmannin-sensitive PI3K; Ca2+ chelation blocks H2O2-induced p70(S6K) activation, identifying Ca2+ as a mediator; PKC is not required. Growth factor-induced H2O2 generation contributes to p70(S6K) activation. Chemical inhibitors (rapamycin, wortmannin), Ca2+ chelation, PKC downregulation, glucose oxidase-generated H2O2, catalase pretreatment, kinase activity assays The Journal of biological chemistry Medium 10551813
2001 The PIF-binding pocket in PDK1 is essential for T-loop phosphorylation and activation of S6K1 and SGK but not PKBα; prior phosphorylation of S6K1 at its hydrophobic motif (T-389) promotes docking into the PDK1 PIF-binding pocket, thereby enabling T-loop phosphorylation—establishing that hydrophobic motif phosphorylation converts S6K1 into a PDK1 substrate. PIF-binding pocket mutations in PDK1 expressed in cells, in vitro kinase assays, immunoprecipitation The EMBO journal High 11500365
2001 Drosophila PDK1 (dPDK1) activates both dAkt and dS6K to control cell and organismal growth; genetic interactions show dPDK1 is required for dRSK but not dPKN function; dPDK1-dS6K constitutes an independent branch of insulin-mediated growth downstream of PI3K. Drosophila genetics, epistasis analysis, cell size measurements, kinase activity assays Proceedings of the National Academy of Sciences of the United States of America High 11752451
2001 p70 S6K1 phosphorylates eEF2 kinase (eEF2K) at a conserved serine, inhibiting eEF2K activity and thereby promoting eEF2 activity and peptide elongation; this rapamycin-sensitive pathway requires PDK1 and links mTOR/S6K1 signaling to translational elongation control. In vitro kinase assay with purified S6K1 and eEF2K, PDK1 knockout cells, rapamycin treatment, Erk inhibitor studies The EMBO journal High 11500364
2001 MEK/ERK signaling activates S6K2 (but not S6K1) in cardiomyocytes in response to phenylephrine in a PKB-independent manner; insulin activates S6K2 via both MEK/ERK and PKB-dependent pathways; both activation routes require mTOR (rapamycin-sensitive), establishing S6K2 as a point of convergence for MEK and mTOR signaling. Pharmacological MEK inhibitors, dominant-negative PKB expression, constitutively active MEK1 expression, immunoprecipitation kinase assays in adult rat ventricular cardiomyocytes The Journal of biological chemistry High 11431469
2003 TSC1/2 acts as a GAP for the small GTPase Rheb; insulin-mediated Rheb activation is PI3K-dependent; Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation; a TSC2 disease-associated GAP-domain point mutation fails to stimulate Rheb GTPase activity or block Rheb activation of S6K1. GTPase activity assays, co-immunoprecipitation, overexpression of Rheb and TSC constructs, phosphospecific immunoblotting Molecular cell High 12820960
2003 Drosophila Rheb functions downstream of TSC1-TSC2 and upstream of TOR/S6K to control cell growth; genetic loss-of-function of Rheb inhibits growth while overexpression promotes growth; S6K is identified as a major effector of Rheb function. Drosophila genetics (loss-of-function and overexpression), epistasis with TSC1/TSC2 and TOR, cell size measurements, biochemical S6K activity assays Nature cell biology High 12766775
2003 In Drosophila, RNAi of dAkt also affects insulin-stimulated dS6K phosphorylation, indicating Akt influences dS6K phosphorylation; in contrast, 4E-BP phosphorylation is PI3K- and Akt-dependent while S6K phosphorylation has an additional PI3K/Akt-independent component through TOR. RNA interference of pathway components in Drosophila S2 cells, isoelectric focusing-SDS-PAGE for 4E-BP phosphorylation states, immunoblotting for dS6K Molecular and cellular biology Medium 14645523
2004 Constitutive activation of the Rheb/mTOR/S6K cassette (by TSC1/TSC2 deletion or Rheb overexpression) induces IRS-1 and IRS-2 downregulation, creating insulin resistance and blocking IGF-I/insulin-stimulated Akt activation; S6K-mediated negative feedback on IRS proteins is sufficient to impair cell survival. TSC1/TSC2 genetic deletion, Rheb overexpression, immunoprecipitation, immunoblotting, cell survival/apoptosis assays Current biology High 15380067
2004 S6K1 (p70S6K) is localized to the actin arc (a caveolin-enriched cytoskeletal structure at the leading edge of migrating cells), co-sediments with F-actin, and is required for EGF-induced actin arc formation and cell migration; rapamycin blocks actin arc formation; fibronectin-induced stress fibers suppress p70(S6K) activity. Subcellular fractionation, co-sedimentation with F-actin, immunocytochemistry, rapamycin treatment, cytochalasin D and Y-27632 pharmacology Experimental cell research Medium 15149849
2004 Scylla and Charybdis (REDD1 homologs) act as negative regulators of growth in Drosophila by reducing S6K (but not PKB/Akt) activity; they function downstream of PKB and upstream of TSC, establishing a pathway position; REDD1/Scylla is induced by HIF-1 under hypoxia. Drosophila genetics (EP overexpression screen, double mutants), S6K and Akt kinase activity assays, epistasis analysis Genes & development High 15545626
2005 mTOR and S6K1 dynamically associate with the eIF3 translation preinitiation complex; inactive S6K1 is associated with eIF3 while mTOR/raptor is absent; cell stimulation recruits mTOR/raptor to eIF3 where it phosphorylates S6K1 at the hydrophobic motif, causing S6K1 dissociation and activation, followed by phosphorylation of eIF4B which is then recruited to the complex. Co-immunoprecipitation, mass spectrometry identification of eIF3 complex components, phosphospecific immunoblotting, rapamycin treatment, siRNA knockdown Cell High 16286006
2005 Raptor binds p70S6K1 and 4E-BP1 through their TOS (TOR signaling) motifs; TOS motif mutation abolishes mTOR-catalyzed phosphorylation in vitro and eliminates rapamycin sensitivity and amino acid responsiveness in vivo, establishing raptor as the scaffold that recruits S6K1 to mTOR for phosphorylation. Co-immunoprecipitation, in vitro mTOR kinase assay, TOS motif mutagenesis, rapamycin and amino acid withdrawal experiments The Journal of biological chemistry High 12604610
2005 p70S6K phosphorylates mTOR at Ser-2448 in vitro and in cells; rapamycin blocks Ser-2448 phosphorylation in a manner not explained by Akt inhibition; rapamycin-resistant S6K1 restores Ser-2448 phosphorylation in rapamycin-treated cells; siRNA depletion of S6K1 reduces Ser-2448 phosphorylation, identifying S6K1 as a positive feedback kinase on mTOR. In vitro kinase assay with purified S6K1, rapamycin-resistant S6K1 rescue, siRNA knockdown, amino acid deprivation The Journal of biological chemistry High 15899889
2006 In response to mitogens, S6K1 phosphorylates PDCD4 at Ser67, targeting it for SCF(βTRCP)-mediated ubiquitin-proteasome degradation; stable PDCD4 that cannot bind βTRCP inhibits translation of mRNAs with structured 5'UTRs, reduces cell size, and slows cell cycle progression. In vitro S6K1 kinase assay, ubiquitination assays, stable PDCD4 mutant expression, translation reporter assays, cell size measurements Science High 17053147
2007 Mechanical stretch activates mTOR as the rapamycin-sensitive kinase responsible for T-389 phosphorylation in p70(S6K) through a PI3K-independent mechanism; rapamycin-resistant mTOR mutants restore mechanically-induced T-389 phosphorylation in rapamycin-treated cells. Rapamycin-resistant mTOR mutant expression combined with mechanical stretch, phosphospecific immunoblotting FEBS letters High 17825298
2007 SF2/ASF splicing factor controls alternative splicing of S6K1 to generate an unusual isoform (isoform-2) that lacks the autoinhibitory domain and is constitutively active; this isoform recapitulates the transforming activity of SF2/ASF, and knockdown of either SF2/ASF or S6K1 isoform-2 reverses transformation in vitro and in vivo. Alternative splicing analysis, RT-PCR, siRNA knockdown, soft agar colony assay, nude mouse xenograft Nature structural & molecular biology High 17310252
2008 S6K1 directly phosphorylates IRS-1 at Ser-270, Ser-307, Ser-636, and Ser-1101 in response to TNF-α, with Ser-270 phosphorylation being a key docking site for S6K1 on IRS-1; TNF-α activates S6K1 via an IKK2-dependent pathway; RNAi knockdown of S6K1 prevents TNF-α-induced IRS-1 inhibition and impaired glucose uptake. In vitro kinase assay with purified IRS-1 and S6K1, point mutant IRS-1 (S270A), RNAi knockdown, dominant-negative S6K1, IKK2 knockout cells, glucose uptake assay The Journal of biological chemistry High 18952604
2009 IFN-α and IFN-γ stimulate phosphorylation of eIF4B at Ser422 in a cell-type-specific manner via p70 S6K1; S6K1-mediated eIF4B phosphorylation enhances eIF4B interaction with eIF3A and increases associated ATPase activity; S6K1/S6K2 double-knockout MEFs show diminished IFN-inducible ISG15 and CXCL10 protein expression, establishing S6K as a mediator of IFN-dependent translation. S6K1/S6K2 double-knockout MEFs, siRNA knockdown of eIF4B/eIF3A, ATPase activity assays, co-immunoprecipitation, phosphospecific immunoblotting Molecular and cellular biology High 19289497
2010 PP2A-B' (PPP2R5C in humans) specifically targets the PP2A holoenzyme to dephosphorylate S6K; PP2A-B' physically interacts with S6K; Drosophila PP2A-B' knockout elevates S6K phosphorylation and phenocopies elevated insulin signaling; human PPP2R5C counteracts S6K1 phosphorylation, indicating a conserved mechanism. Drosophila knockout genetics, co-immunoprecipitation (PP2A-B' with S6K), phosphospecific immunoblotting, mammalian PPP2R5C overexpression/knockdown Cell metabolism High 20444422
2010 Leucine activates the cardiac mTOR/p70(S6K) pathway through a PDK1-dependent but PKB/Akt-independent mechanism; leucine also phosphorylates PRAS40, a key mTOR regulator; the PDK1 L155E mutation (preserving insulin/Akt-dependent mTOR signaling) abolishes leucine effects, demonstrating leucine uses a distinct PDK1 interaction interface. PDK1 knockout hearts, PDK1 L155E knock-in, leucine and insulin stimulation, p70S6K kinase assays, PRAS40 phosphospecific immunoblotting American journal of physiology. Endocrinology and metabolism High 20051528
2010 Constitutively active S6K1 in pancreatic β-cells impairs IRS/Akt signaling (negative feedback), decreases G1-S progression, increases apoptosis via elevated p16 and p27 and reduced Cdk2, and improves insulin secretion without expanding β-cell mass, demonstrating that S6K-mediated IRS downregulation induces β-cell insulin resistance in vivo. Transgenic mice with β-cell-specific constitutively active S6K1, cell cycle protein analysis, Akt phosphorylation, insulin secretion assays, TUNEL apoptosis Diabetes High 20622167
2010 mTOR-mediated activation of p70 S6K1 induces differentiation of human embryonic stem cells; constitutively active p70 S6K1 (but not wild-type) triggers differentiation; siRNA knockdown of TSC2 and Rictor elevates S6K1 activity and induces differentiation; hESCs preferentially express rapamycin-insensitive mTORC2 and high TSC1/TSC2 levels to restrain mTORC1/S6K1 activity. siRNA knockdown, constitutively active S6K1 expression, rapamycin treatment, pluripotency marker analysis (Oct4, Nanog), differentiation assays Cellular reprogramming Medium 20698768
2016 S6K1 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 promotes formation of a tripartite S6K1-STING-TBK1 complex required for IRF3 activation and early antiviral gene expression. Co-immunoprecipitation, kinase-dead S6K1 mutants, cGAS knockout cells, TBK1 inhibitor, antiviral response assays (IRF3 target gene expression, T cell responses) Nature immunology High 27043414
2018 The mTOR-S6K pathway phosphorylates RNF168 at Ser60 to inhibit its E3 ligase activity, accelerate its proteolysis, and impair DNA damage response (DDR); loss of LKB1 hyperactivates mTORC1-S6K, decreasing RNF168 expression; phospho-deficient RNF168-S60A rescues DDR defects and suppresses tumorigenesis caused by Lkb1 loss. In vitro S6K kinase assay on RNF168, phospho-deficient mutant rescue, ubiquitination assays, γH2AX DDR readouts, LKB1 knockout mouse model, tumor xenografts Nature cell biology High 29403037
2020 During mitotic arrest, mTORC1/S6K activity is dramatically reduced due to mitotic phosphorylation of raptor; expression of a non-phosphorylatable raptor mutant reactivates mTORC1 and reduces Taxol cytotoxicity via S6K-mediated phosphorylation and degradation of the eIF4A inhibitor PDCD4, promoting translation; pharmacological eIF4A inhibition enhances Taxol effects and restores sensitivity in resistant cells. Non-phosphorylatable raptor mutant, mTORC1 activity immunoblotting, PDCD4 stability assays, pharmacological eIF4A inhibition, Taxol sensitivity assays Cell reports High 33027666
2004 Specific interaction between S6K1 and CoA synthase is detected by co-immunoprecipitation of native and overexpressed proteins and by BIAcore in vitro; the interaction maps to the C-terminal regions of both proteins; CoA synthase is not a substrate for S6K1 and the interaction does not affect enzymatic activities of either partner, suggesting a regulatory scaffolding role linking mTOR/S6K signaling to CoA biosynthesis and energy metabolism. Co-immunoprecipitation, BIAcore binding analysis, in vitro kinase assay, C-terminal deletion mapping FEBS letters Medium 15589845
2015 Hepatic amino acid/mTORC1/S6K signaling modulates systemic lipid metabolism via neuronal inter-tissue communication; hepatic active-S6K expression elevates serum triglycerides and downregulates adipose lipoprotein lipase (LPL); dominant-negative S6K expression blocks TG elevation; denervation, pharmacological deafferentation, and β-blockade suppress hypertriglyceridemia with adipose LPL upregulation, indicating signal transduction via afferent vagal and efferent sympathetic nerves. Adenoviral hepatic expression of active/dominant-negative S6K, SNAT2, Rheb; surgical/pharmacological denervation; metabolic measurements Nature communications High 26268630
2016 Loss of S6K in Drosophila fat body blocks rapamycin-mediated lifespan extension and causes accumulation of multilamellar lysosomes; Syntaxin 13 mediates TORC1-S6K effects on lysosome morphology and inflammaging (age-related NF-κB-like immune pathway hyperactivation); rapamycin also elevates Syntaxin 12/13 levels in mouse liver and prevents age-related non-canonical NF-κB signaling, indicating a conserved mechanism. Tissue-specific S6K activation in Drosophila fat body, lifespan assays, lysosome morphology analysis, Syntaxin 13 genetic interaction, mouse liver proteomic/biochemical analysis Nature aging High 38413780

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2004 Upstream and downstream of mTOR. Genes & development 3419 15314020
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2446 12150925
1997 Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Current biology : CB 2434 9094314
2011 Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2101 21833088
2002 Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 1482 12150926
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
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
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
2007 PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Molecular cell 1006 17386266
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