Disease relevance of Rps6kb1

• The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation [1].
• Here we show that overexpression of S6K1 induced a modest degree of hypertrophy, whereas overexpression of S6K2 resulted in no obvious cardiac phenotype [2].
• A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells [3].
• Overexpression of the active form of S6K increased the sensitivity of LLC cells to hypoxia [4].
• Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced beta-oxidation [5].

Psychiatry related information on Rps6kb1

• Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling [5].

High impact information on Rps6kb1

• The 70 kDa ribosomol S6 kinase (pp70S6k) plays an important role in the progression of cells through G1 phase of the cell cycle [6].
• Detailed kinetics reveal that EGF-induced S6 kinase activation is biphasic: an early phase appears at 10-15 min, followed by a late phase between 30 and 60 min [7].
• Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice [8].
• The critical autophosphorylation site for p70s6k/p85s6k activation within this domain is a tyrosine at residue 751 [9].
• A mitogen-activated S6 kinase of relative molecular mass 70,000 (70K) has been isolated from mouse fibroblasts as well as from avian, rat and rabbit tissues [10].

Chemical compound and disease context of Rps6kb1

• However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet [5].
• The PI3-kinase inhibitor LY294002 and P70 S6 kinase inhibitor rapamycin partially blocked both G-1 and G-5 cell growth, suggesting that these two kinases are involved in hepatoma cell growth [11].
• Vascular hypertrophy and increased P70S6 kinase in mice lacking the angiotensin II AT(2) receptor [12].

Biological context of Rps6kb1

• In parallel, a great deal of information has accumulated concerning the identification of the signaling pathway and the regulatory phosphorylation sites involved in controlling S6K activation [13].
• S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway [14].
• Deletion of the S6K1 gene in mouse cells led to an animal of reduced size and the identification of the S6K1 homolog, S6K2, whereas loss of dS6K function in Drosophila demonstrated its paramount importance in development and growth control [13].
• Translational homeostasis: eukaryotic translation initiation factor 4E control of 4E-binding protein 1 and p70 S6 kinase activities [15].
• Analysis of S6 phosphorylation in the cytoplasm and nucleoli of cells derived from the distinct S6K genotypes suggests that both kinases are required for full S6 phosphorylation but that S6K2 may be more prevalent in contributing to this response [14].

Anatomical context of Rps6kb1

• Thus, mTOR plays a critical role in the regulation of ribosome biogenesis via a mechanism that requires S6K1 activation and phosphorylation of UBF [16].
• Moreover, overexpression of a dominant-negative S6K1 mutant repressed transcription in exponentially growing NIH 3T3 cells [16].
• This study thus identifies mTOR/S6K as an essential signaling pathway engaged in the stimulation of cell survival in osteoclasts [17].
• However, the inhibition of activity was not complete, but only a 40-50%, indicating that neutrophil p70S6K activity has a rapamycin-resistant component [18].
• We have examined the role of endogenous 70-kDa S6 kinase (p70(S6K)) in actin cytoskeletal organization and cell migration in Swiss 3T3 fibroblasts [19].

Associations of Rps6kb1 with chemical compounds

• The mammalian target of rapamycin activity (measured as phospho-p70S6 kinase) was activated by LPS but not significantly blocked by LY2 [20].
• Upon mu-opioid receptor stimulation, p70 S6 kinase is activated and phosphorylated at threonine 389 and at threonine 421/serine 424 [21].
• This selective synaptic activation of mTOR-S6K is also resistant to APV and inhibited by Ca(2+) channel blockers and higher concentrations of glutamate [22].
• Several S6 kinase agonists not previously known to activate phosphatidylinositol 3-kinase (A23187, bombesin and phorbol 12-myristate 13-acetate) were found to increase the production of phosphatidylinositol 3,4,5-trisphosphate in a wortmannin-sensitive manner [23].
• However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization [5].

Physical interactions of Rps6kb1

• Loss of tuberous sclerosis complex 1 (Tsc1) expression results in increased Rheb/S6K pathway signaling important for astrocyte cell size regulation [24].
• Activation was mediated by a JAK-2-dependent pathway coupled to the activation of phosphatidylinositol 3-kinase and p70S6 kinase [25].

Enzymatic interactions of Rps6kb1

• BMP-4 time-dependently phosphorylated p70 S6 kinase [26].

Regulatory relationships of Rps6kb1

• Cdc42 promotes G1 progression through p70 S6 kinase-mediated induction of cyclin E expression [27].
• Likewise suppression of p70S6 kinase with rapamycin down-regulated phagocytic efficiency conferred by the expression of constitutively active Akt [28].
• In contrast, the impact of SHIP2 expression was diminished in insulin-induced phosphorylation of p70S6-kinase and S6, but not of Akt, after the incubation for 16 h [29].
• The expression of DNM-Akt1 also suppressed EGF-induced p70 S6K activation as well as Akt activation [30].
• Consistently, Gas6 activates the P13K downstream targets S6K and Akt, whose activation is abrogated by addition of wortmannin [31].

Other interactions of Rps6kb1

• mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF [16].
• Compared to wild-type mice, S6K1(-/-) mice are significantly smaller, whereas S6K2(-/-) mice tend to be slightly larger [14].
• In contrast, sustained glutamatergic stimulation inhibits ERK, Akt, and S6K [22].
• These findings provide genetic evidence that the phosphate groove of PDK1 is required for maximal activation of isoforms of S6K, SGK and RSK, but not PKC [32].
• The considerable residual differentiation in the presence of rapamycin, despite the complete blockade of p70 S6K activation, prompted us to measure the phosphorylation of another rapamycin-sensitive protein, eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) [33].

Analytical, diagnostic and therapeutic context of Rps6kb1

• Western-blot analysis and immunocomplex kinase assays showed that wortmannin and demethoxyviridin specifically block the phosphorylation and activation of p70 S6 kinase without affecting the M(r) 90,000 ribosomal S6 kinase (p90rsk) or mitogen-activated protein kinases [23].
• Microinjection of highly specific inhibitors of PI3K or Rac1, or treatment with the p70s6k inhibitor rapamycin, impaired cAMP-stimulated DNA synthesis, demonstrating that PKA-dependent and -independent pathways contribute to cAMP-mediated mitogenesis [34].
• Pituitary growth hormone (GH) co-ordinately stimulates three distinct signalling pathways in 3T3-F442A preadipocytes, the STAT (signal transducer and activator of transcription) pathway, the mitogen-activated protein (MAP) kinase cascade and p70s6k [35].
• All the mutants strongly activated Akt and p70S6K compared with wild-type p110alpha as determined by immunoblotting using phospho-specific antibodies [36].
• Alterations in the degree of the phosphorylation of ERKI/2, Akt-1 and p70 S6K in mouse skeletal and cardiac muscle was examined in vivo following an intraperitoneal injection of des IGF-I [37].

References