Document Detail


Akt is efficiently activated by PIF-pocket- and PtdIns(3,4,5)P3-dependent mechanisms leading to resistance to PDK1 inhibitors.
MedLine Citation:
PMID:  23030823     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mutations leading to inappropriate activation of Akt isoforms contribute to proliferation and survival of a significant proportion of human cancers. Akt is activated by phosphorylation of its T-loop residue (Thr(308)) by PDK1 (3-phosphoinositide-dependent kinase-1) and its C-terminal hydrophobic motif (Ser(473)) by mTORC2 [mTOR (mammalian target of rapamycin) complex 2]. Potent PDK1 inhibitors such as GSK2334470 have recently been elaborated as potential anti-cancer agents. However, these compounds were surprisingly ineffective at suppressing Akt activation. In the present study we demonstrate that resistance to PDK1 inhibitors results from Akt being efficiently recruited to PDK1 via two alternative mechanisms. The first involves ability of Akt and PDK1 to mutually interact with the PI3K (phosphoinositide 3-kinase) second messenger PtdIns(3,4,5)P3. The second entails recruitment of PDK1 to Akt after its phosphorylation at Ser(473) by mTORC2, via a substrate-docking motif termed the PIF-pocket. We find that disruption of either the PtdIns(3,4,5)P3 or the Ser(473) phosphorylation/PIF-pocket mechanism only moderately impacts on Akt activation, but induces marked sensitization to PDK1 inhibitors. These findings suggest that suppression of Ser(473) phosphorylation by using mTOR inhibitors would disrupt the PIF-pocket mechanism and thereby sensitize Akt to PDK1 inhibitors. Consistent with this, we find combing PDK1 and mTOR inhibitors reduced Akt activation to below basal levels and markedly inhibited proliferation of all of the cell lines tested. Our results suggest further work is warranted to explore the utility of combining PDK1 and mTOR inhibitors as a therapeutic strategy for treatment of cancers that harbour mutations elevating Akt activity.
Authors:
Ayaz Najafov; Natalia Shpiro; Dario R Alessi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  448     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-08     Completed Date:  2013-01-10     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  285-95     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Cells, Cultured
Drug Resistance, Neoplasm
Enzyme Activation
HEK293 Cells
Humans
Indazoles / pharmacology
Mice
Molecular Sequence Data
Multiprotein Complexes / deficiency,  genetics
Mutation
Neoplasms / drug therapy,  genetics,  metabolism
Phosphatidylinositol Phosphates / metabolism*
Protein Kinase Inhibitors / pharmacology
Protein-Serine-Threonine Kinases / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / chemistry*,  genetics,  metabolism*
Pyrimidines / pharmacology
Recombinant Proteins / chemistry,  genetics,  metabolism
Ribosomal Protein S6 Kinases / metabolism
Serine / chemistry
TOR Serine-Threonine Kinases / antagonists & inhibitors,  deficiency,  genetics
Grant Support
ID/Acronym/Agency:
MC_U127015387//Medical Research Council; //Medical Research Council
Chemical
Reg. No./Substance:
0/GSK 2334470; 0/Indazoles; 0/Multiprotein Complexes; 0/Phosphatidylinositol Phosphates; 0/Protein Kinase Inhibitors; 0/Pyrimidines; 0/Recombinant Proteins; 0/TOR complex 2; 0/phosphatidylinositol 3,4,5-triphosphate; 452VLY9402/Serine; EC 2.7.1.1/MTOR protein, human; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.1/AKT1 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/Ribosomal Protein S6 Kinases; EC 2.7.11.2/pyruvate dehydrogenase (acetyl-transferring) kinase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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