scholarly journals The Opposing Actions of Target of Rapamycin and AMP-Activated Protein Kinase in Cell Growth Control

2015 ◽  
Vol 7 (8) ◽  
pp. a019141 ◽  
Author(s):  
Sravanth K. Hindupur ◽  
Asier González ◽  
Michael N. Hall
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Growth Control ◽  
Target Of Rapamycin ◽  
Amp Activated Protein Kinase ◽  
Cell Growth Control

scholarly journals A new twist on cell growth control

Cell Cycle ◽  
2014 ◽  
Vol 13 (22) ◽  
pp. 3474-3475 ◽  
Author(s):  
Joseph F Cardiello ◽  
Jennifer F Kugel ◽  
James A Goodrich
Keyword(s):  
Cell Growth ◽  
Growth Control ◽  
Cell Growth Control

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.

Lysozyme-dependent Proliferation Switch: Hematopoietic and Hybridoma Cell Growth Control with the Use of Antibody/GP130 Chimera

2002 ◽  
pp. 337-341
Author(s):  
Masahiro Kawahara ◽  
Akito Natsume ◽  
Satoshi Terada ◽  
Koichi Kato ◽  
Kouhei Tsumoto ◽  
...  
Keyword(s):  
Cell Growth ◽  
Growth Control ◽  
Cell Growth Control
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