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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Dataset's files

Source:

			Action	DRS
	20200220_HFX4_SeHu_Ali_IP_IRS1_Basal_1.raw	Raw
	20200220_HFX4_SeHu_Ali_IP_IRS1_Basal_2.raw	Raw
	20200220_HFX4_SeHu_Ali_IP_IRS1_Basal_3.raw	Raw
	20200220_HFX4_SeHu_Ali_IP_IRS1_GDC_1.raw	Raw
	20200220_HFX4_SeHu_Ali_IP_IRS1_GDC_2.raw	Raw

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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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