Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
Dougall M Norris
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia; Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Australia; Biomedicine Discovery Institute, Monash University, Clayton, Australia
Martin Kin Lok Wong
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
Sean J Humphrey
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
Luke Carroll
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
Guang Yang
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
Kristen C Cooke
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
Pengyi Yang
Charles Perkins Centre, School of Mathematics and Statistics, University of Sydney, Sydney, Australia; Computational Systems Biology Group, Children's Medical Research Institute, University of Sydney, Westmead, Australia
Thomas A Geddes
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia; Computational Systems Biology Group, Children's Medical Research Institute, University of Sydney, Westmead, Australia
Sungyoung Shin
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Australia; Biomedicine Discovery Institute, Monash University, Clayton, Australia
Daniel J Fazakerley
Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Australia; Biomedicine Discovery Institute, Monash University, Clayton, Australia
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia; School of Medical Sciences, University of Sydney, Sydney, Australia
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.
