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dc.contributor.authorKearney, Alison L
dc.contributor.authorNorris, Dougall M
dc.contributor.authorGhomlaghi, Milad
dc.contributor.authorKin Lok Wong, Martin
dc.contributor.authorHumphrey, Sean J
dc.contributor.authorCarroll, Luke
dc.contributor.authorYang, Guang
dc.contributor.authorCooke, Kristen C
dc.contributor.authorYang, Pengyi
dc.contributor.authorGeddes, Thomas A
dc.contributor.authorShin, Sungyoung
dc.contributor.authorFazakerley, Daniel
dc.contributor.authorNguyen, Lan K
dc.contributor.authorJames, David E
dc.contributor.authorBurchfield, James G
dc.date.accessioned2021-11-13T00:30:26Z
dc.date.available2021-11-13T00:30:26Z
dc.date.issued2021-07-13
dc.identifier.issn2050-084X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330626
dc.description.abstractThe 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.
dc.languageeng
dc.publishereLife Sciences Publications Ltd
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAkt
dc.subjectPI3K
dc.subjectcell biology
dc.subjectcomputational biology
dc.subjecthuman
dc.subjectinsulin
dc.subjectmouse
dc.subjectphosphorylation
dc.subjectplasma membrane
dc.subjectsignal transduction
dc.subjectsystems biology
dc.subjectAnimals
dc.subjectAntigens, CD
dc.subjectCell Membrane
dc.subjectComputational Biology
dc.subjectGlucose
dc.subjectHumans
dc.subjectInsulin
dc.subjectInsulin Receptor Substrate Proteins
dc.subjectMechanistic Target of Rapamycin Complex 1
dc.subjectMice
dc.subjectPhosphatidylinositol 3-Kinase
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectPhosphorylation
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectReceptor, Insulin
dc.subjectSignal Transduction
dc.titleAkt phosphorylates insulin receptor substrate to limit PI3K-mediated PIP3 synthesis.
dc.typeArticle
prism.publicationDate2021
prism.publicationNameeLife
prism.volume10
dc.identifier.doi10.17863/CAM.78070
dcterms.dateAccepted2021-05-30
rioxxterms.versionofrecord10.7554/eLife.66942
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-07-13
dc.contributor.orcidFazakerley, Daniel [0000-0001-8241-2903]
dc.identifier.eissn2050-084X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/S007091/1)
cam.issuedOnline2021-07-13


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International