scholarly journals Activation of S6K1 (p70 ribosomal protein S6 kinase 1) requires an initial calcium-dependent priming event involving formation of a high-molecular-mass signalling complex

2003 ◽  
Vol 370 (2) ◽  
pp. 469-477 ◽  
Author(s):  
Katherine M. HANNAN ◽  
George THOMAS ◽  
Richard B. PEARSON
Keyword(s):  
Ribosomal Protein ◽  
Molecular Mass ◽  
High Molecular Mass ◽  
Phosphorylation Sites ◽  
S6 Kinase ◽  
Calcium Dependent ◽  
Ribosomal Protein S6 ◽  
Calcium Chelation ◽  
Regulatory Phosphorylation ◽  
Ribosomal Protein S6 Kinase

The mitogen-stimulated protein kinase p70 ribosomal protein S6 kinase 1 (S6K1) is a key enzyme in the regulation of cell growth and proliferation. Activation of S6K1 requires a complex, ordered series of conformational changes and phosphorylation reactions. While the role of sequential, multi-site phosphorylation has been extensively detailed, characterization of the priming step required to initiate this cascade has remained elusive. In the present study we show for the first time that this priming process is dependent on calcium. Calcium-dependent regulation of S6K1 did not specifically target Thr-229 and Thr-389, the key regulatory phosphorylation sites; rather, calcium chelation resulted in a global inhibition of S6K1 phosphorylation. Mutation of individual phosphorylation sites in the auto-inhibitory and hydrophobic domains to acidic residues (to mimic phosphorylation) yields a kinase that remains sensitive to calcium chelation, while the combined mutations alleviate the requirement for calcium. Furthermore, deletion of the C-terminal residues (398—502) also renders the kinase insensitive to calcium. We hypothesize that the initial calcium-dependent process is required to release an inhibitory interaction between the C- and N-termini of S6K1, thus allowing phosphorylation of these key domains. The requirement for this priming step can only be overcome by mutations mimicking the phosphorylation of both the auto-inhibitory and hydrophobic domains. We further propose that the priming event involves formation of a calcium-dependent protein complex that releases the interaction between the N- and C-termini. S6K1 is then accessible for activation by the kinases that target the known regulatory phosphorylation sites. Consistent with this hypothesis, serum stimulation of S6K1 activity is associated with its incorporation into a calcium-dependent high-molecular-mass complex.

The adipose tissue triglyceride lipase ATGL/PNPLA2 is downregulated by insulin and TNF-α in 3T3-L1 adipocytes and is a target for transactivation by PPARγ

2006 ◽  
Vol 291 (1) ◽  
pp. E115-E127 ◽  
Author(s):  
Ji Young Kim ◽  
Kristin Tillison ◽  
Jun-Ho Lee ◽  
David A. Rearick ◽  
Cynthia M. Smas
Keyword(s):  
Adipose Tissue ◽  
Ribosomal Protein ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
S6 Kinase ◽  
Triglyceride Lipase ◽  
Ribosomal Protein S6 ◽  
Tnf Α ◽  
Adipose Tissue Triglyceride ◽  
Ribosomal Protein S6 Kinase

The minimal adipose phenotype of hormone-sensitive lipase (HSL)-null mice suggested that other hormonally responsive lipase(s) were present in adipocytes. Recent studies have characterized a new adipose tissue triglyceride lipase, ATGL/PNPLA2/destnutrin/iPLA2ζ/TTS2.2 (ATGL). We had previously cloned a novel adipose-enriched transcript by differential screening and recently determined its identity with murine ATGL. We report here on the regulation of ATGL by TNF-α and insulin in 3T3-L1 adipocytes and identify ATGL as a target for transcriptional activation by the key adipogenic transcription factor PPARγ. Insulin at 100 nM resulted in a marked decrease in ATGL transcript that was effectively blocked by inhibitors for PI 3-kinase and p70 ribosomal protein S6 kinase. TNF-α treatment decreased ATGL transcript in a time-dependent manner that paralleled TNF-α downregulation of PPARγ with a maximal decrease noted by 6 h. TNF-α effects on ATGL were attenuated by pretreatment with PD-98059, LY-294002, or rapamycin, suggesting involvement of the p44/42 MAP kinase, PI 3-kinase, and p70 ribosomal protein S6 kinase signals. To study transcriptional regulation of ATGL, we cloned 2,979 bp of the murine ATGL 5′-flanking region. Compared with promoterless pGL2-Basic, the −2979/+21 ATGL luciferase construct demonstrated 120- and 40-fold increases in activity in white and brown adipocytes, respectively. Luciferase reporter activities for a series of eight ATGL promoter deletions revealed that the −928/+21, −1738/+21, −1979/+21, and −2979/+21 constructs were transactivated by PPARγ. Our findings identify the novel lipase ATGL to be a target gene for TNF-α and insulin action in adipocytes and reveal that it is subject to transcriptional control by PPARγ-mediated signals.

scholarly journals pS6K1 as an efficacy marker of GnRH agonist with premenopausal breast cancer

2019 ◽  
Vol 8 (7) ◽  
pp. 863-869
Author(s):  
Chan Sub Park ◽  
Jihye Choi ◽  
Min-Ki Seong ◽  
Sung-Eun Hong ◽  
Jae-Sung Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ribosomal Protein ◽  
Growth Factor Receptor ◽  
Gonadotropin Releasing Hormone ◽  
S6 Kinase ◽  
Releasing Hormone ◽  
Gonadotropin Releasing Hormone Agonist ◽  
Ribosomal Protein S6 ◽  
Epidermal Growth ◽  
Ribosomal Protein S6 Kinase

Estradiol is a key factor for tumorigenesis and prognosis of hormone receptor-positive breast cancer. Adipocytes are one source of estradiol in patients with breast cancer. Recent studies have shown that phosphorylated ribosomal protein S6 kinase-1 plays a critical role in adipogenesis. Therefore, estrogen depletion therapy might have beneficial effects in phosphorylated ribosomal protein S6 kinase-1-positive breast cancer. This study was conducted to evaluate the value of phosphorylated ribosomal protein S6 kinase-1 as a marker for gonadotropin-releasing hormone agonist treatment, a form of estrogen depletion therapy, for premenopausal patients with HR-positive, human epidermal growth factor receptor 2-negative breast cancer. We reviewed the medical records of 296 premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary invasive breast cancer treated between 2008 and 2015. Phosphorylated ribosomal protein S6 kinase-1 positivity was defined by immunohistochemical staining scores of 1+, 2+ and 3+, whereas a score of 0 was considered negative. Phosphorylated ribosomal protein S6 kinase-1-positive tumors were found in 74.0% of the patients. In the phosphorylated ribosomal protein S6 kinase-1-positive group, disease-free survival of patients treated with a gonadotropin-releasing hormone agonist was significantly longer than that of patients treated without a gonadotropin-releasing hormone agonist (mean 106.7 months vs mean 91.1 months, P = 0.018). Phosphorylated ribosomal protein S6 kinase-1 is a potential biomarker for predicting the efficacy of gonadotropin-releasing hormone agonist therapy in premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer.

Regulation and localization of ribosomal protein S6 kinase 1 isoforms

2009 ◽  
Vol 27 (1) ◽  
pp. 12-21 ◽  
Author(s):  
Doyil Kim ◽  
Argun Akcakanat ◽  
Gopal Singh ◽  
Chandeshwar Sharma ◽  
Funda Meric-Bernstam
Keyword(s):  
Ribosomal Protein ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Ribosomal Protein S6 Kinase

scholarly journals Computer-aided discovery of phenylpyrazole based amides as potent S6K1 inhibitors

2020 ◽  
Vol 11 (5) ◽  
pp. 583-590
Author(s):  
Yan Yin ◽  
Yuxing Sun ◽  
Lianhua Zhao ◽  
Jinpeng Pan ◽  
Yangbo Feng
Keyword(s):  
Ribosomal Protein ◽  
Therapeutic Target ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Computer Aided ◽  
Attractive Therapeutic Target ◽  
Ribosomal Protein S6 Kinase

Ribosomal protein S6 kinase beta-1 (S6K1) is an attractive therapeutic target.

High mobility group box 2 regulates skeletal muscle development through ribosomal protein S6 kinase 1

2020 ◽  
Vol 34 (9) ◽  
pp. 12367-12378 ◽  
Author(s):  
Ying Fang ◽  
Feng Liang ◽  
Renqiang Yuan ◽  
Qi Zhu ◽  
Shufang Cai ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ribosomal Protein ◽  
Muscle Development ◽  
High Mobility ◽  
High Mobility Group ◽  
Skeletal Muscle Development ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Ribosomal Protein S6 Kinase
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