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