Disease relevance of RPS6KB1

• Support for this hypothesis comes from studies demonstrating that many of the amplified genes are over-expressed in breast cancer cell lines and tumors, and that the RPS6KB1, TBX2, and PPM1D genes from the region, that are amplified and over-expressed in breast tumors and cell lines, contribute to tumor formation and/or tumor progression [1].
• AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling [2].
• Fibronectin stimulates non-small cell lung carcinoma cell growth through activation of Akt/mammalian target of rapamycin/S6 kinase and inactivation of LKB1/AMP-activated protein kinase signal pathways [3].
• Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma [4].
• Transfection of neuroblastoma cells with activated Akt or ribosomal protein S6 kinase (S6K) decreased the sensitivity of the cells to NVP-AEW541 [5].

Psychiatry related information on RPS6KB1

• Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease [6].
• We find that mildly increasing systemic Rheb-TOR-S6K signaling sensitizes the whole organism to oxidative stress and promotes senescence of locomotor activity with age [7].

High impact information on RPS6KB1

• Phosphorylation results in S6K1 dissociation, activation, and subsequent phosphorylation of its translational targets, including eIF4B, which is then recruited into the complex in a phosphorylation-dependent manner [8].
• mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events [8].
• Raptor has a positive role in nutrient-stimulated signaling to the downstream effector S6K1, maintenance of cell size, and mTOR protein expression [9].
• mTOR controls cell growth, in part by regulating p70 S6 kinase alpha (p70alpha) and eukaryotic initiation factor 4E binding protein 1 (4EBP1) [10].
• Furthermore, polymerized collagen rapidly suppresses p70 S6 kinase, a possible regulator of p27Kip1 [11].

Chemical compound and disease context of RPS6KB1

• In 1321N1 astrocytoma cells, carbachol stimulation of M3 muscarinic cholinergic receptors, coupled to phospholipase C, evoked a persistent 10-20-fold activation of p70 S6 kinase (S6K1) [12].
• Muscarinic receptor-mediated activation of p70 S6 kinase 1 (S6K1) in 1321N1 astrocytoma cells: permissive role of phosphoinositide 3-kinase [12].
• Differential regulation of the p70 S6 kinase pathway by interferon alpha (IFNalpha) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells [13].
• Using a SH-SY5Y neuroblastoma cell model, we found that 100 micro mol/L zinc sulfate could induce p70 S6 kinase phosphorylation and activation, in particular at Thr421/Ser424 [6].
• Here, we report that paclitaxel, a microtubule-damaging agent, induces phosphorylation of p70S6K at threonine 421 and serine 424 (T421/S424) in a concentration- and time-dependent manner in multiple breast and ovarian cancer cell lines demonstrated by a T421/S424 phospho-p70S6K antibody [14].

Biological context of RPS6KB1

• In this review we summarize the structural studies of the amplicon that have been carried out, we outline the evidence implicating the RPS6KB1, TBX2, and PPM1D genes as oncogenes, and we describe some of the other candidate oncogenes from the region [1].
• The structure defines the hydrophobic pocket termed the "PIF-pocket", which plays a key role in mediating the interaction and phosphorylation of certain substrates such as S6K1 [15].
• The relative contribution of the RSK and S6K modules to the phosphorylation of eIF4B is growth factor-dependent, and the two phosphorylation events exhibit very different kinetics [16].
• Herein, we explore the role of the Akt/mTOR/p70S6K pathway in fibronectin-induced NSCLC cell growth [3].
• The Akt/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K) pathway is considered a central regulator of protein synthesis and of cell proliferation, differentiation, and survival [3].

Anatomical context of RPS6KB1

• Consistent with this, the Type I IFN-dependent phosphorylation/activation of p70 S6K is defective in embryonic fibroblasts from mice with targeted disruption of the p85alpha and p85beta subunits of the PI 3'-kinase (p85alpha-/-beta-/-) [17].
• To characterize the fetal hepatocyte pathway for S6 phosphorylation, we went on to study the sensitivity of hepatocyte proliferation to the S6 kinase inhibitor rapamycin [18].
• In mitotic HeLa cells, when the activity of Cdc2 is high, S6K1 is phosphorylated at multiple Ser/Thr, Pro (S/TP) sites, including Ser(371), Ser(411), Thr(421), and Ser(424) [19].
• Cooperative regulation of p70S6 kinase by receptor tyrosine kinases and G protein-coupled receptors augments airway smooth muscle growth [20].
• In this work we have investigated the intracellular pathways involved in insulin-induced and amino acid-induced p70/S6-K activations in human endothelial cells [21].

Associations of RPS6KB1 with chemical compounds

• In this study, we show that phorbol esters and activated Ras also induce the phosphorylation of tuberin and collaborates with the nutrient-sensing pathway to regulate mTOR effectors, such as p70 ribosomal S6 kinase 1 (S6K1) [22].
• Akt small interfering RNA (siRNA) and an antibody against the fibronectin-binding integrin alpha5beta1 also blocked the p70S6K phosphorylation in response to fibronectin [3].
• DHT treatment increased mTOR activity as assessed by phosphorylation of the downstream targets p70 S6 kinase and 4E-BP1, and mTOR inhibition with rapamycin blocked the DHT-stimulated increase in cyclin D proteins [23].
• Quantitative mass spectrometry reveals that serine 383/385 phosphorylation is sensitive to RNA interference (RNAi)-mediated S6K1 reduction, but not S6K2 reduction [24].
• Our data demonstrate that p70 S6K is rapidly phosphorylated on threonine 421 and serine 424 and is activated during treatment of cells with IFNalpha or IFNbeta [17].

Physical interactions of RPS6KB1

• Recently, amino acid sufficiency has been demonstrated to selectively regulate p70 S6 kinase (p70(s6k)) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), both of which are targeted by the anti-proliferative drug rapamycin [25].
• Inhibition of p90 ribosomal S6 kinase-mediated CCAAT/enhancer-binding protein beta activation and cyclooxygenase-2 expression by salicylate [26].
• Loss of TSC2 GAP activity or disruption of the TSC1/TSC2 complex dysregulates S6K1 activation, which leads to abnormal cell proliferation associated with LAM disease [27].
• The existence of a PI3-K-dependent signalling complex may enable efficient activation of p70S6K in cells [28].
• The selective blockade of the p70 S6 kinase activation cascade by the rapamycin-FKBP complex implicates this signalling pathway in the regulation of T cell entry into S phase [29].

Enzymatic interactions of RPS6KB1

• 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro [30].
• Our data indicate that S6 kinase is recruited into a complex with RTKs and src and becomes phosphorylated on tyrosine/s in response to PDGF or serum [31].
• Recent work has implicated the NIMA (never in mitosis, gene A)-related kinase-6 (NEK6) as the enzyme that phosphorylates the hydrophobic motif of S6K1 in vivo [32].
• Ribosomal protein S6 (S6rp) is phosphorylated by the p70S6K enzyme in mammals, under mitogen/IGF regulation [33].
• The levels of total p70 S6 kinase and p70 S6 kinase phosphorylated at Thr421/Ser424 showed significant correlations with the levels of both total tau and PHF-tau [6].

Regulatory relationships of RPS6KB1

• These results suggest that Cdc2 provides a signal that triggers inactivation of S6K1 in mitosis, presumably serving to spare energy for costly mitotic processes at the expense of ribosomal protein synthesis [19].
• hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase [34].
• SNT-1 PTB also inhibited the phosphorylation of p70S6K on Thr421/Ser424 and Ser411, which may result from the abrogation of MAP kinase activity [35].
• We find that serines 383 and 385 of human SKAR are insulin-stimulated and rapamycin-sensitive S6K1 phosphorylation sites [24].
• In contrast, an inhibitor of extracellular signal-regulated kinase 1/2 (PD98095) had no effect on fibronectin-induced phosphorylation of p70S6K [3].

Other interactions of RPS6KB1

• Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 [36].
• RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1 [37].
• RAFT1 phosphorylates p70(S6k) on Thr-389, a residue whose phosphorylation is rapamycin-sensitive in vivo and necessary for S6 kinase activity [37].
• Protein kinase B localization and activation differentially affect S6 kinase 1 activity and eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation [38].
• The C-terminal sequence of S6K2 is divergent from that of S6K1 [39].
• Growth factor stimulation induces disassembly of URI/PP1gamma complexes through S6K1-mediated phosphorylation of URI at serine 371 [40].

Analytical, diagnostic and therapeutic context of RPS6KB1

• Molecular cloning and characterization of a novel p70 S6 kinase, p70 S6 kinase beta containing a proline-rich region [41].
• Tumorous and adjacent normal tissues of 20 patients with papillary thyroid cancer were obtained at surgery, and expression of p70S6K and Akt were measured by Western blot [42].
• Overexpression of p70S6K in tumor tissues was further confirmed by immunohistochemistry [42].
• Only the p70 alpha I and alpha II polypeptides of slowest mobility on SDS-PAGE comigrate with the 70- and 90-kDa proteins observed in purified rat liver S6 kinase [43].
• By indirect enzyme-linked immunosorbent assay, phosphorylated p70 S6 kinase (Thr389 or Thr421/Ser424), total tau, and PHF-tau were found to be significantly increased in AD brain as compared to control cases [6].

References