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

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Norris, Dougall M 
Kin Lok Wong, Martin 


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.



Human, Insulin, Cell biology, Phosphorylation, Signal transduction, Mouse, Plasma membrane, systems biology, computational biology, PI3K, AKT

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Medical Research Council (MR/S007091/1)
National Health and Medical Research Council (GNT1120201)
Cancer Council Victoria (Metcalf Venture Grant)
National Breast Cancer Foundation (IIRS-20-094)
University of Sydney (G197569, Chen Family Research Scholarship, Australian Postgraduate Award Scholarships, Postgraduate Merit Award, Research Training Program Scholarship)
Australian Research Council (DP180103482)
Victorian Cancer Agency (MCRF18026)