PXD023441

PXD023441 is an original dataset announced via ProteomeXchange.

Title	Akt phosphorylates insulin receptor substrate (IRS) to limit PI3K-mediated PI(3,4,5)P3 synthesis
Description	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.
HostingRepository	PRIDE
AnnounceDate	2021-07-14
AnnouncementXML	Submission_2021-07-13_22:08:17.602.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sean Humphrey
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2021-01-06 03:56:46	ID requested
⏵ 1	2021-07-13 22:08:19	announced

Kearney AL, Norris DM, Ghomlaghi M, Kin Lok Wong M, Humphrey SJ, Carroll L, Yang G, Cooke KC, Yang P, Geddes TA, Shin S, Fazakerley DJ, Nguyen LK, James DE, Burchfield JG, Akt phosphorylates insulin receptor substrate to limit PI3K-mediated PIP3 synthesis. Elife, 10():(2021) [pubmed]

submitter keyword: AKT, PI3K, IRS1, IRS2, phosphorylation, signal transduction

David James
contact affiliation	School of Life and Environmental Sciences, Charles Perkins Centre, The University of Sydney, Australia
contact email	david.james@sydney.edu.au
lab head
Sean Humphrey
contact affiliation	The University of Sydney
contact email	sean.j.humphrey@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD023441
     1. Label: PRIDE project
     2. Name: Akt phosphorylates insulin receptor substrate (IRS) to limit PI3K-mediated PI(3,4,5)P3 synthesis