scholarly journals Cross-talk between Sirtuin and Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in the Regulation of S6 Kinase 1 (S6K1) Phosphorylation

2014 ◽  
Vol 289 (19) ◽  
pp. 13132-13141 ◽  
Author(s):  
Sungki Hong ◽  
Bin Zhao ◽  
David B. Lombard ◽  
Diane C. Fingar ◽  
Ken Inoki
Keyword(s):  
Cross Talk ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
S6 Kinase ◽  
Mtorc1 Signaling

scholarly journals Glucagon acts in a dominant manner to repress insulin-induced mammalian target of rapamycin complex 1 signaling in perfused rat liver

2009 ◽  
Vol 297 (2) ◽  
pp. E410-E415 ◽  
Author(s):  
Jamie I. Baum ◽  
Scot R. Kimball ◽  
Leonard S. Jefferson
Keyword(s):  
Protein Metabolism ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Perfused Rat Liver ◽  
S6 Kinase ◽  
Akt Phosphorylation ◽  
Ribosomal Protein S6 ◽  
Mtorc1 Signaling ◽  
Kinase A

The opposing actions of insulin and glucagon on hepatic carbohydrate metabolism are well documented. In contrast, relatively little is known about how the two hormones interact to regulate hepatic protein metabolism. Previously, we reported that glucagon in the absence of insulin represses signaling through the mammalian target of rapamycin complex 1 (mTORC1). In the present study, we sought to determine whether or not the action of one hormone would dominate over the other in the regulation of mTORC1 signaling. Livers were perfused in situ with medium containing either no added hormones (control), 10 nM insulin, 100 nM glucagon, or a combination of the hormones. Compared with control livers, insulin stimulated Akt phosphorylation and mTORC1 signaling, as assessed by increased phosphorylation of the mTORC1 targets eIF4E-binding protein (4E-BP)1 and ribosomal protein S6 kinase (S6K)1, and promoted assembly of the eIF4G·eIF4E complex. Glucagon alone had no effect on mTORC1 signaling but stimulated the activity of protein kinase A (PKA). In the presence of a combination of insulin and glucagon, Akt and TSC2 phosphorylation and PKA activity were all increased compared with controls. However, mTORC1 signaling was repressed compared with livers perfused with medium containing insulin alone, and this effect was associated with reduced assembly of the mTORC1·eIF3 complex. Overall, the results suggest that glucagon acts in a dominant manner to repress insulin-induced mTORC1 signaling, which is in contrast to previous studies showing a dominant action of insulin in the control of hepatic gluconeogenesis.

scholarly journals Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)

2009 ◽  
Vol 421 (1) ◽  
pp. 29-42 ◽  
Author(s):  
Juan M. García-Martínez ◽  
Jennifer Moran ◽  
Rosemary G. Clarke ◽  
Alex Gray ◽  
Sabina C. Cosulich ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Mammalian Target Of Rapamycin ◽  
Specific Inhibitor ◽  
Initiation Factor ◽  
Target Of Rapamycin ◽  
S6 Kinase ◽  
Class 1 ◽  
Hydrophobic Motif ◽  
Ribosomal S6 Kinase

mTOR (mammalian target of rapamycin) stimulates cell growth by phosphorylating and promoting activation of AGC (protein kinase A/protein kinase G/protein kinase C) family kinases such as Akt (protein kinase B), S6K (p70 ribosomal S6 kinase) and SGK (serum and glucocorticoid protein kinase). mTORC1 (mTOR complex-1) phosphorylates the hydrophobic motif of S6K, whereas mTORC2 phosphorylates the hydrophobic motif of Akt and SGK. In the present paper we describe the small molecule Ku-0063794, which inhibits both mTORC1 and mTORC2 with an IC50 of ∼10 nM, but does not suppress the activity of 76 other protein kinases or seven lipid kinases, including Class 1 PI3Ks (phosphoinositide 3-kinases) at 1000-fold higher concentrations. Ku-0063794 is cell permeant, suppresses activation and hydrophobic motif phosphorylation of Akt, S6K and SGK, but not RSK (ribosomal S6 kinase), an AGC kinase not regulated by mTOR. Ku-0063794 also inhibited phosphorylation of the T-loop Thr308 residue of Akt phosphorylated by PDK1 (3-phosphoinositide-dependent protein kinase-1). We interpret this as implying phosphorylation of Ser473 promotes phosphorylation of Thr308 and/or induces a conformational change that protects Thr308 from dephosphorylation. In contrast, Ku-0063794 does not affect Thr308 phosphorylation in fibroblasts lacking essential mTORC2 subunits, suggesting that signalling processes have adapted to enable Thr308 phosphorylation to occur in the absence of Ser473 phosphorylation. We found that Ku-0063794 induced a much greater dephosphorylation of the mTORC1 substrate 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1) than rapamycin, even in mTORC2-deficient cells, suggesting a form of mTOR distinct from mTORC1, or mTORC2 phosphorylates 4E-BP1. Ku-0063794 also suppressed cell growth and induced a G1-cell-cycle arrest. Our results indicate that Ku-0063794 will be useful in delineating the physiological roles of mTOR and may have utility in treatment of cancers in which this pathway is inappropriately activated.

scholarly journals Immunopurified Mammalian Target of Rapamycin Phosphorylates and Activates p70 S6 Kinase αin Vitro

1999 ◽  
Vol 274 (48) ◽  
pp. 34493-34498 ◽  
Author(s):  
Shuji Isotani ◽  
Kenta Hara ◽  
Chiharu Tokunaga ◽  
Hitomi Inoue ◽  
Joseph Avruch ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
S6 Kinase ◽  
P70 S6 Kinase

scholarly journals p53/TAp63 and AKT Regulate Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling through Two Independent Parallel Pathways in the Presence of DNA Damage

2013 ◽  
Vol 289 (7) ◽  
pp. 4083-4094 ◽  
Author(s):  
Maren Cam ◽  
Hemant K. Bid ◽  
Linlin Xiao ◽  
Gerard P. Zambetti ◽  
Peter J. Houghton ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Parallel Pathways ◽  
Mtorc1 Signaling

Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation

2014 ◽  
Vol 307 (9) ◽  
pp. F1023-F1032 ◽  
Author(s):  
Junhua Mao ◽  
Zhifeng Zeng ◽  
Zhuo Xu ◽  
Jiangzhong Li ◽  
Lei Jiang ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Target Of Rapamycin ◽  
Crescent Formation ◽  
Glomerular Diseases ◽  
Mtorc1 Signaling ◽  
Cellular Crescent ◽  
Underlying Mechanisms ◽  
Mtorc1 Activation ◽  
Glomerular Tuft

Podocytes play a key role in the formation of cellular crescents in experimental and human diseases. However, the underlying mechanisms for podocytes in promoting crescent formation need further investigation. Here, we demonstrated that mammalian target of rapamycin complex 1 (mTORC1) signaling was remarkably activated and hypoxia-inducible factor (HIF) 1α expression was largely induced in cellular crescents from patients with crescentic glomerular diseases. Specific deletion of Tsc1 in podocytes led to mTORC1 activation in podocytes and kidney dysfunction in mice. Interestingly, 33 of 36 knockouts developed cellular or mixed cellular and fibrous crescents at 7 wk of age (14.19 ± 3.86% of total glomeruli in knockouts vs. 0% in control littermates, n = 12–36, P = 0.04). All of the seven knockouts developed crescents at 12 wk of age (30.92 ± 11.961% of total glomeruli in knockouts vs. 0% in control littermates, n = 4–7, P = 0.002). Most notably, bridging cells between the glomerular tuft and the parietal basement membrane as well as the cellular crescents were immunostaining positive for WT1, p-S6, HIF1α, and Cxcr4. Furthermore, continuously administrating rapamycin starting at 7 wk of age for 5 wk abolished crescents as well as the induction of p-S6, HIF1α, and Cxcr4 in the glomeruli from the knockouts. Together, it is concluded that mTORC1 activation in podocytes promotes cellular crescent formation, and targeting this signaling may shed new light on the treatment of patients with crescentic glomerular diseases.

scholarly journals Spinal 5-HT7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling

2015 ◽  
Vol 114 (3) ◽  
pp. 2015-2022 ◽  
Author(s):  
D. P. Fields ◽  
S. R. Springborn ◽  
G. S. Mitchell
Keyword(s):  
Protein Kinase ◽  
Cross Talk ◽  
Receptor Agonist ◽  
Mammalian Target Of Rapamycin ◽  
Receptor Activation ◽  
Therapeutic Advantage ◽  
Spinal Motor ◽  
Signaling Mechanisms ◽  
Mtorc1 Signaling ◽  
Kinase A

Spinal serotonin type 7 (5-HT7) receptors elicit complex effects on motor activity. Whereas 5-HT7 receptor activation gives rise to long-lasting phrenic motor facilitation (pMF), it also constrains 5-HT2 receptor-induced pMF via “cross-talk inhibition.” We hypothesized that divergent cAMP-dependent signaling pathways give rise to these distinct 5-HT7 receptor actions. Specifically, we hypothesized that protein kinase A (PKA) mediates cross-talk inhibition of 5-HT2 receptor-induced pMF whereas 5-HT7 receptor-induced pMF results from exchange protein activated by cAMP (EPAC) signaling. Anesthetized, paralyzed, and ventilated rats receiving intrathecal (C4) 5-HT7 receptor agonist (AS-19) injections expressed pMF for >90 min, an effect abolished by pretreatment with a selective EPAC inhibitor (ESI-05) but not a selective PKA inhibitor (KT-5720). Furthermore, intrathecal injections of a selective EPAC activator (8-pCPT-2′-Me-cAMP) were sufficient to elicit pMF. Finally, spinal mammalian target of rapamycin complex-1 (mTORC1) inhibition via intrathecal rapamycin abolished 5-HT7 receptor- and EPAC-induced pMF, demonstrating that spinal 5-HT7 receptors elicit pMF by an EPAC-mTORC1 signaling pathway. Thus 5-HT7 receptors elicit and constrain spinal phrenic motor plasticity via distinct signaling mechanisms that diverge at cAMP (EPAC vs. PKA). Selective manipulation of these molecules may enable refined regulation of serotonin-dependent spinal motor plasticity for therapeutic advantage.

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