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Noncanonical regulation of insulin-mediated ERK activation by phosphoinositide 3-kinase ?.

ABSTRACT: Classically Class IB phosphoinositide 3-kinase (PI3K?) plays a role in extracellular signal-regulated kinase (ERK) activation following G-protein coupled receptor (GPCR) activation. Knock-down of PI3K? unexpectedly resulted in loss of ERK activation to receptor tyrosine kinase agonists such as epidermal growth factor or insulin. Mouse embryonic fibroblasts (MEFs) or primary adult cardiac fibroblasts isolated from PI3K? knock-out mice (PI3K?KO) showed decreased insulin-stimulated ERK activation. However, expression of kinase-dead PI3K? resulted in rescue of insulin-stimulated ERK activation. Mechanistically, PI3K? sequesters protein phosphatase 2A (PP2A), disrupting ERK-PP2A interaction, as evidenced by increased ERK-PP2A interaction and associated PP2A activity in PI3K?KO MEFs, resulting in decreased ERK activation. Furthermore, ?-blocker carvedilol-mediated ?-arrestin-dependent ERK activation is significantly reduced in PI3K?KO MEF, suggesting accelerated dephosphorylation. Thus, instead of classically mediating the kinase arm, PI3K? inhibits PP2A by scaffolding and sequestering, playing a key parallel synergistic step in sustaining the function of ERK, a nodal enzyme in multiple cellular processes.

SUBMITTER: Mohan ML

PROVIDER: S-EPMC5662266 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Noncanonical regulation of insulin-mediated ERK activation by phosphoinositide 3-kinase γ.

Mohan Maradumane L ML Chatterjee Arunachal A Ganapathy Swetha S Mukherjee Sromona S Srikanthan Sowmya S Jolly George P GP Anand Rohit S RS Naga Prasad Sathyamangla V SV

Molecular biology of the cell 20170906 22

Classically Class IB phosphoinositide 3-kinase (PI3Kγ) plays a role in extracellular signal-regulated kinase (ERK) activation following G-protein coupled receptor (GPCR) activation. Knock-down of PI3Kγ unexpectedly resulted in loss of ERK activation to receptor tyrosine kinase agonists such as epidermal growth factor or insulin. Mouse embryonic fibroblasts (MEFs) or primary adult cardiac fibroblasts isolated from PI3Kγ knock-out mice (PI3KγKO) showed decreased insulin-stimulated ERK activation. ...[more]

PMID: 28877982

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Project description: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.

Dataset Information

Noncanonical regulation of insulin-mediated ERK activation by phosphoinositide 3-kinase ?.

Publications

Noncanonical regulation of insulin-mediated ERK activation by phosphoinositide 3-kinase γ.

Similar Datasets

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