@article{922db8df363343c1905928087a858b6d,
title = "Akt phosphorylates insulin receptor substrate to limit PI3K-mediated PIP3 synthesis",
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.",
author = "Kearney, {Alison L.} and Norris, {Dougall M.} and Milad Ghomlaghi and Wong, {Martin Kin Lok} and Humphrey, {Sean J.} and Luke Carroll and Guang Yang and Cooke, {Kristen C.} and Pengyi Yang and Geddes, {Thomas A.} and Sungyoung Shin and Fazakerley, {Daniel J.} and Nguyen, {Lan K.} and James, {David E.} and Burchfield, {James G.}",
note = "Funding Information: The authors acknowledge the facilities, and the scientific and technical assistance, of the Australian Microscopy and Microanalysis Research Facility at the Charles Perkins Centre, University of Sydney. In particular, we would like to thank Neftali Florez-Rodriguez for technical assistance. This research was also facilitated by access to Sydney Mass Spectrometry, a core research facility at the University of Sydney. This work was funded by Australian Research Council (ARC) project grant number DP180103482 awarded to DEJ and JGB, and National Health and Medical Research Council (NHMRC) project grant number GNT1120201 awarded to DEJ. ALK was supported by a Research Training Program Scholarship, University of Sydney Postgraduate Merit Award and the Chen Family Research Scholarship. DMN and MKLW were supported by Australian Postgraduate Award Scholarships. SJH was supported by a fellowship from the University of Sydney (G197569). DJF was supported by a Medical Research Council Career Development Award (MR/S007091/1). LKN was supported by a Victorian Cancer Agency Mid-Career Research Fellowship (MCRF18026), an Investigator Initiated Research Scheme grant from National Breast Cancer Foundation (IIRS-20–094) and the Metcalf Venture Grants Scheme administered by Cancer Council Victoria, Australia. DEJ was supported by an NHMRC Senior Principal Research Fellowship. Publisher Copyright: {\textcopyright} Kearney et al. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = jul,
doi = "10.7554/eLife.66942",
language = "English",
volume = "10",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Organisation, Ltd.",
}