Akt phosphorylates insulin receptor substrate to limit PI3K-mediated PIP3 synthesis.
View / Open Files
Authors
Kearney, Alison L
Norris, Dougall M
Ghomlaghi, Milad
Kin Lok Wong, Martin
Humphrey, Sean J
Carroll, Luke
Yang, Guang
Cooke, Kristen C
Yang, Pengyi
Geddes, Thomas A
Shin, Sungyoung
Fazakerley, Daniel J
Nguyen, Lan K
James, David E
Burchfield, James G
Publication Date
2021-07-13Journal Title
eLife
ISSN
2050-084X
Publisher
eLife Sciences Publications Ltd
Volume
10
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Kearney, A. L., Norris, D. M., Ghomlaghi, M., Kin Lok Wong, M., Humphrey, S. J., Carroll, L., Yang, G., et al. (2021). Akt phosphorylates insulin receptor substrate to limit PI3K-mediated PIP3 synthesis.. eLife, 10 https://doi.org/10.7554/eLife.66942
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.
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
Sponsorship
Medical Research Council (MR/S007091/1)
Identifiers
External DOI: https://doi.org/10.7554/eLife.66942
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330626
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.