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Akt phosphorylates insulin receptor substrate to limit PI3K-mediated PIP3 synthesis.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Kearney, Alison L 
Norris, Dougall M 
Ghomlaghi, Milad 
Kin Lok Wong, Martin 
Humphrey, Sean J 

Abstract

The phosphoinositide 3-kinase (PI3K)-Akt network is tightly controlled by feedback mechanisms that regulate signal flow and ensure signal fidelity. A rapid overshoot in insulin-stimulated recruitment of Akt to the plasma membrane has previously been reported, which is indicative of negative feedback operating on acute timescales. Here, we show that Akt itself engages this negative feedback by phosphorylating insulin receptor substrate (IRS) 1 and 2 on a number of residues. Phosphorylation results in the depletion of plasma membrane-localised IRS1/2, reducing the pool available for interaction with the insulin receptor. Together these events limit plasma membrane-associated PI3K and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) synthesis. We identified two Akt-dependent phosphorylation sites in IRS2 at S306 (S303 in mouse) and S577 (S573 in mouse) that are key drivers of this negative feedback. These findings establish a novel mechanism by which the kinase Akt acutely controls PIP3 abundance, through post-translational modification of the IRS scaffold.

Description

Keywords

Akt, PI3K, cell biology, computational biology, human, insulin, mouse, phosphorylation, plasma membrane, signal transduction, systems biology, Animals, Antigens, CD, Cell Membrane, Computational Biology, Glucose, Humans, Insulin, Insulin Receptor Substrate Proteins, Mechanistic Target of Rapamycin Complex 1, Mice, Phosphatidylinositol 3-Kinase, Phosphatidylinositol 3-Kinases, Phosphorylation, Proto-Oncogene Proteins c-akt, Receptor, Insulin, Signal Transduction

Journal Title

eLife

Conference Name

Journal ISSN

2050-084X
2050-084X

Volume Title

10

Publisher

eLife Sciences Publications Ltd
Sponsorship
Medical Research Council (MR/S007091/1)