Disease relevance of Rps6kb1

• Selective inhibition of either p70S6K or ERK blocked myocardial hypertrophy [1].
• Regulation of ERK/JNK/p70S6K in two rat models of liver injury and fibrosis [2].
• These results indicate divergent roles for the ERK and p70S6K pathways in the phenotypic changes associated with cardiac hypertrophy [3].
• Antiserum raised against rat liver S6 kinase specifically immunoprecipitates the purified 32P-labeled H4 hepatoma insulin-stimulated S6 kinase [4].
• Here we demonstrate that primary tumors from tuberous sclerosis complex (TSC) patients and the Eker rat model of TSC expressed elevated levels of phosphorylated mammalian target of rapamycin (mTOR) and its effectors: p70S6K, S6 ribosomal protein, 4E-BP1, and eIF4G [5].

Psychiatry related information on Rps6kb1

• When we were studying phosphorylated proteins in the rat brain after electroconvulsive shock (ECS), we observed the rapid phosphorylation of a 75-kDa protein, which cross-reacted with the anti-phospho-p70 S6 kinase antibody [6].

High impact information on Rps6kb1

• We therefore examined the role of PI(3)K, its upstream effector Ras, and its putative downstream protein kinase effectors PKB/Akt and p70S6K (ref. 5) in the modulation of apoptosis induced in fibroblasts by the oncoprotein c-Myc [7].
• Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways [8].
• Bile acid-induced proliferation is mediated by activation of a protein kinase C/extracellular signal-regulated kinase/p70S6K-dependent pathway [9].
• In addition, activation of other downstream components including PI3K, Akt, GSK3beta, Bad, and p70S6 kinase was studied [10].
• Regulation of protein synthesis by cholecystokinin in rat pancreatic acini involves PHAS-I and the p70 S6 kinase pathway [11].

Chemical compound and disease context of Rps6kb1

• Resveratrol suppresses angiotensin II-induced Akt/protein kinase B and p70 S6 kinase phosphorylation and subsequent hypertrophy in rat aortic smooth muscle cells [12].
• Thus, long-acting dihydropyridine calcium channel blockers inhibited cardiac hypertrophy induced by chronic inhibition of NO synthesis by inhibiting both p70S6K and ERK in vivo [13].
• Stimulation of serine protein kinase activity (referred to as S6 kinase) occurs within minutes of addition of nerve growth factor (NGF) to PC12 rat pheochromocytoma cells [14].
• The data suggest that p70S6K activation may be required for PE-stimulated hypertrophy of cardiac myocytes [15].
• These results suggest that Ang II induces cardiac hypertrophy by activating p70S6K [16].

Biological context of Rps6kb1

• p70 S6 kinase (p70(S6k)) is a mitogen-activated protein kinase that plays a central role in the control of mRNA translation [17].
• The results suggest that normalization of Ki-ras-induced transformed phenotypes by U0126 is a consequence of concurrent inhibition of the MAPK and p70S6K pathways [18].
• Rapamycin did not inhibit insulin induced p70S6K phosphorylation and activity in cells transfected with the rapamycin-resistant mutant [19].
• Insulin promotes rat retinal neuronal cell survival in a p70S6K-dependent manner [19].
• Betaxolol inhibits extracellular signal-regulated kinase and P70S6 kinase activities and gene expressions of platelet-derived growth factor A-chain and transforming growth factor-beta1 in Dahl salt-sensitive hypertensive rats [20].

Anatomical context of Rps6kb1

• Neurabin is a synaptic protein linking p70 S6 kinase and the neuronal cytoskeleton [17].
• In our previous work, we showed that 10 nmol/L insulin stimulated neither mitogen-activated protein kinase (MAP kinase) activity nor [3H]thymidine incorporation but did stimulated S6 kinase through the specific insulin receptors in cultured rat vascular smooth muscle cells (VSMCs) [21].
• The L-NAME group showed both p70S6K and ERK activation in the myocardium (2.3-fold and 2.0-fold increases, respectively), as compared with the control group, which was not reversed by hydralazine [1].
• METHODS: Extracellular signal-regulated kinases (ERK)1/2, c-Jun terminal kinase (JNK) and p70S6-kinase (p70(S6K)) were studied in vivo in the whole liver, in liver sections and in isolated hepatocytes, cholangiocytes and hepatic stellate cells (HSC) [2].
• Inhibition of phosphatidylinositol 3-kinase and p70S6 kinase blocks osteogenic protein-1 induction of alkaline phosphatase activity in fetal rat calvaria cells [22].

Associations of Rps6kb1 with chemical compounds

• In contrast, phosphorylation of the p85 variant of S6K in response to T3 was not blocked by LY294002, wortmannin, or rapamycin, thus supporting a T3-activated pathway independent of PI3K and mTOR [23].
• Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways [23].
• The L-NAME was also used with hydralazine, the p70S6K inhibitor rapamycin, or the mitogen-activated protein kinase inhibitor PD98059 [1].
• Opening of the adenosine triphosphate-sensitive potassium channel attenuates cardiac remodeling induced by long-term inhibition of nitric oxide synthesis: role of 70-kDa S6 kinase and extracellular signal-regulated kinase [1].
• Rottlerin, which selectively inhibits PKCdelta, also prevented PE-induced S6K activation [24].

Physical interactions of Rps6kb1

• Additionally, rapamycin prevented the stimulatory effects of leucine on eIF4E availability for binding eIF4G and inhibited leucine-dependent phosphorylation of S6K1 [25].
• In cultured cells, growth factor-induced phosphorylation of two translation modulators, p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), is blocked by nanomolar concentrations of the immunosuppressant rapamycin [26].

Enzymatic interactions of Rps6kb1

• Activation of 70 kD S6 kinase (p70S6K) phosphorylates the 40S ribosomal protein S6 that regulates protein synthesis [27].
• The phosphatase 2A-deactivated 70-kDa S6 kinase is neither reactivated nor phosphorylated by partially purified insulin-stimulated microtubule-associated protein 2 kinase, in experiments where Xenopus S6 kinase II undergoes phosphorylation and partial reactivation [4].
• In addition, p70S6 kinase can regulate protein synthesis by phosphorylating eEF2 kinase or via phosphorylation of ribosomal protein S6 [28].

Regulatory relationships of Rps6kb1

• Both AG1478 and PD98059 inhibited ET-1-induced phosphorylation and activation of p70S6K [29].
• The S6 kinase activated by insulin was highly specific for the ribosomal protein S6 when compared with various substrates, including casein, glycogen synthase, phosphorylase b, phosvitin, histone HIII-S, and histone HVIII-S [30].
• ACEIs inactivated p70S6K and ARBs inactivated ERK in myocardium, but hydralazine did not change activation of either kinase [31].
• Moreover, IGF-1-induced phosphorylation of BAD Ser-136 was abolished in p70S6K-deficient cells [32].
• Freshly isolated hepatocytes from normal animals show low levels of S6 kinase activity which can be stimulated by epidermal growth factor and insulin [33].

Other interactions of Rps6kb1

• U0126 reverses Ki-ras-mediated transformation by blocking both mitogen-activated protein kinase and p70 S6 kinase pathways [18].
• CONCLUSIONS: The KCOs modulate p70S6K, not ERK, to attenuate myocardial hypertrophy induced by long-term inhibition of NO synthesis in vivo [1].
• Overall, the results suggest that the leucine-induced enhancement of protein synthesis and the phosphorylation states of 4E-BP1 and S6K1 are facilitated by the transient increase in serum insulin [34].
• However, RAP, which inhibits S6K (ca. 100%) but not TK or MAPK, only delays Prl-mediated anabolism [35].
• Furthermore, inhibition of mTOR/p70S6 kinase, JNK or p38MAPK had no effect on insulin-stimulated IRS-1 tyrosine phosphorylation [36].

Analytical, diagnostic and therapeutic context of Rps6kb1

• This effect was checked by Western blot with specific antibodies against the phosphorylated S6 kinase [37].
• Oral administration of leucine stimulates phosphorylation of 4E-bP1 and S6K 1 in skeletal muscle but not in liver of diabetic rats [38].
• Northern blot analysis revealed four transcripts of 2.5, 3.2, 4.0, and 6.0 kilobases, and five S6 kinase clones were obtained by screening the library [39].
• Rapamycin blocked the activation of p70 S6 kinase in response to partial hepatectomy in a dose-dependent manner, but 4E-BP1 phosphorylation was not inhibited [26].
• The kinase is not detected by immunoblotting with antibodies directed against protein kinase C or type II S6 kinase [40].

References