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

Author:

Kearney Alison L1ORCID,Norris Dougall M12,Ghomlaghi Milad34ORCID,Kin Lok Wong Martin1,Humphrey Sean J1,Carroll Luke1,Yang Guang1,Cooke Kristen C1,Yang Pengyi56,Geddes Thomas A16,Shin Sungyoung34,Fazakerley Daniel J2,Nguyen Lan K34ORCID,James David E17ORCID,Burchfield James G1ORCID

Affiliation:

1. Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia

2. Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom

3. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Australia

4. Biomedicine Discovery Institute, Monash University, Clayton, Australia

5. Charles Perkins Centre, School of Mathematics and Statistics, University of Sydney, Sydney, Australia

6. Computational Systems Biology Group, Children's Medical Research Institute, University of Sydney, Westmead, Australia

7. School of Medical Sciences, University of Sydney, Sydney, Australia

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.

Funder

Australian Research Council

National Health and Medical Research Council

University of Sydney

Medical Research Council

Victorian Cancer Agency

National Breast Cancer Foundation

Cancer Council Victoria

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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