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PMID:12841848

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Citation

Lizcano, JM, Alrubaie, S, Kieloch, A, Deak, M, Leevers, SJ and Alessi, DR (2003) Insulin-induced Drosophila S6 kinase activation requires phosphoinositide 3-kinase and protein kinase B. Biochem. J. 374:297-306

Abstract

An important mechanism by which insulin regulates cell growth and protein synthesis is through activation of the p70 ribosomal S6 protein kinase (S6K). In mammalian cells, insulin-induced PI3K (phosphoinositide 3-kinase) activation, generates the lipid second messenger PtdIns(3,4,5) P (3), which is thought to play a key role in triggering the activation of S6K. Although the major components of the insulin-signalling pathway are conserved in Drosophila, recent studies suggested that S6K activation does not require PI3K in this system. To investigate further the role of dPI3K (Drosophila PI3K) in dS6K (Drosophila S6K) activation, we examined the effect of two structurally distinct PI3K inhibitors on insulin-induced dS6K activation in Kc167 and S2 Drosophila cell lines. We found that both inhibitors prevented insulin-stimulated phosphorylation and activation of dS6K. To investigate further the role of the dPI3K pathway in regulating dS6K activation, we also used dsRNAi (double-stranded RNA-mediated interference) to decrease expression of dPI3K and the PtdIns(3,4,5) P (3) phosphatase dPTEN ( Drosophila phosphatase and tensin homologue deleted on chromosome 10) in Kc167 and S2 cells. Knock-down of dPI3K prevented dS6K activation, whereas knock-down of dPTEN, which would be expected to increase PtdIns(3,4,5) P (3) levels, stimulated dS6K activity. Moreover, when the expression of the dPI3K target, dPKB (Drosophila protein kinase B), was decreased to undetectable levels, we found that insulin could no longer trigger dS6K activation. This observation provides the first direct demonstration that dPKB is required for insulin-stimulated dS6K activation. We also present evidence that the amino-acid-induced activation of dS6K in the absence of insulin, thought to be mediated by dTOR (Drosophila target of rapamycin), which is unaffected by the inhibition of dPI3K by wortmannin. The results of the present study support the view that, in Drosophila cells, dPI3K and dPKB, as well dTOR, are required for the activation of dS6K by insulin.

Links

PubMed PMC1223624 Online version:10.1042/BJ20030577

Keywords

Amino Acid Sequence; Amino Acids/pharmacology; Androstadienes/pharmacology; Animals; Cell Line; Chromones/pharmacology; Drosophila Proteins/metabolism; Enzyme Activation/drug effects; Enzyme Activation/genetics; Enzyme Activation/physiology; Enzyme Induction/drug effects; Enzyme Induction/genetics; Enzyme Induction/physiology; Enzyme Inhibitors/pharmacology; Insulin/pharmacology; Molecular Sequence Data; Morpholines/pharmacology; PTEN Phosphohydrolase; Peptides/metabolism; Phosphatidylinositol 3-Kinases/antagonists & inhibitors; Phosphatidylinositol 3-Kinases/physiology; Phosphoric Monoester Hydrolases/metabolism; Precipitin Tests; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-akt; RNA, Double-Stranded/pharmacology; RNA, Small Interfering/pharmacology; Ribosomal Protein S6 Kinases/antagonists & inhibitors; Ribosomal Protein S6 Kinases/metabolism; Tumor Suppressor Proteins/metabolism; Wortmannin

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:Q7KMQ6

involved_in

GO:0014067: negative regulation of phosphatidylinositol 3-kinase signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q94533

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:AKT1

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:P91634

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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