Dataset Information

Akt phosphorylates insulin receptor substrate (IRS) to limit PI3K-mediated PI(3,4,5)P3 synthesis

ABSTRACT: The phosphoinositide 3-kinase (PI3K)-Akt network is tightly controlled by feedback mechanisms that regulate signal flow and ensure signal fidelity. Here, we show that Akt itself engages negative feedback by phosphorylating insulin receptor substrate (IRS) 1 and 2 on a number of residues. Mechanistically this serves to deplete plasma membrane-localised IRS1/2 and reduce its 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 another mechanism by which the kinase Akt auto-regulates its activity, through post-translational modification of the IRS scaffold that in turn controls PIP3 levels.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Fat Cell

SUBMITTER: Sean Humphrey

LAB HEAD: David James

PROVIDER: PXD023441 | Pride | 2021-07-14

REPOSITORIES: pride

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Publications

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

Kearney Alison L AL Norris Dougall M DM Ghomlaghi Milad M Kin Lok Wong Martin M Humphrey Sean J SJ Carroll Luke L Yang Guang G Cooke Kristen C KC Yang Pengyi P Geddes Thomas A TA Shin Sungyoung S Fazakerley Daniel J DJ Nguyen Lan K LK James David E DE Burchfield James G JG

eLife 20210713

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 result ...[more]

PMID: 34253290

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Project description:DallePezze2012 - TSC-independent mTORC2 regulation This model is described in the article: A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP, Thedieck K. Sci Signal 2012 Mar; 5(217): ra25 Abstract: The kinase mammalian target of rapamycin (mTOR) exists in two multiprotein complexes (mTORC1 and mTORC2) and is a central regulator of growth and metabolism. Insulin activation of mTORC1, mediated by phosphoinositide 3-kinase (PI3K), Akt, and the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2), initiates a negative feedback loop that ultimately inhibits PI3K. We present a data-driven dynamic insulin-mTOR network model that integrates the entire core network and used this model to investigate the less well understood mechanisms by which insulin regulates mTORC2. By analyzing the effects of perturbations targeting several levels within the network in silico and experimentally, we found that, in contrast to current hypotheses, the TSC1-TSC2 complex was not a direct or indirect (acting through the negative feedback loop) regulator of mTORC2. Although mTORC2 activation required active PI3K, this was not affected by the negative feedback loop. Therefore, we propose an mTORC2 activation pathway through a PI3K variant that is insensitive to the negative feedback loop that regulates mTORC1. This putative pathway predicts that mTORC2 would be refractory to Akt, which inhibits TSC1-TSC2, and, indeed, we found that mTORC2 was insensitive to constitutive Akt activation in several cell types. Our results suggest that a previously unknown network structure connects mTORC2 to its upstream cues and clarifies which molecular connectors contribute to mTORC2 activation. This model is hosted on BioModels Database and identified by: BIOMD0000000581. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Akt phosphorylates insulin receptor substrate (IRS) to limit PI3K-mediated PI(3,4,5)P3 synthesis

Publications

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

Similar Datasets

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