PXD015824

PXD015824 is an original dataset announced via ProteomeXchange.

Title	The GATOR2–mTORC2 axis mediates Sestrin2-induced AKT Ser/Thr kinase activation
Description	Sestrins represent a family of stress-inducible proteins that prevent the progression of many age- and obesity-associated disorders. Endogenous Sestrins maintain insulin-dependent AKT Ser/Thr kinase (AKT) activation during high-fat diet (HFD)-induced obesity, and overexpressed Sestrins activate AKT in various cell types, including liver and skeletal muscle cells. Although Sestrin-mediated AKT activation improves metabolic parameters, the mechanistic details underlying such improvement remain elusive. Here, we investigated how Sestrin2, the Sestrin homolog highly expressed in liver, induces strong AKT activation. We found that two known targets of Sestrin2, mTOR complex 1 (mTORC1) and AMP-activated protein kinase (AMPK), are not required for Sestrin2-induced AKT activation. Rather, phosphoinositol-3-kinase (PI3K) and mTORC2, kinases upstream of AKT and important for its activation, were essential for Sestrin2-induced AKT activation. Among these kinases, mTORC2 catalytic activity was strongly up-regulated upon Sestrin2 overexpression in an in vitro kinase assay, indicating that mTORC2 may represent the major link between Sestrin2 and AKT. As reported previously, Sestrin2 interacted with mTORC2; however, we found here that this interaction occurs indirectly through GATOR2, a pentameric protein complex that directly interacts with Sestrin2. Deleting or silencing WD repeat domain 24 (WDR24), the GATOR2 component essential for the Sestrin2–GATOR2 interaction, or WDR59, the GATOR2 component essential for the GATOR2–mTORC2 interaction, completely ablated Sestrin2’s effect on AKT activation. We also noted that Sestrin2 directly binds to the pleckstrin homology (PH) domain of AKT and induces AKT translocation to the plasma membrane. These results uncover a signaling mechanism whereby Sestrin2 activates AKT through GATOR2 and mTORC2.
HostingRepository	PRIDE
AnnounceDate	2020-01-17
AnnouncementXML	Submission_2020-01-17_05:58:42.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jun Hee Lee
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue; deamidated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2019-10-15 01:21:47	ID requested
⏵ 1	2020-01-17 05:58:44	announced

Kowalsky AH, Namkoong S, Mettetal E, Park HW, Kazyken D, Fingar DC, Lee JH, The GATOR2-mTORC2 axis mediates Sestrin2-induced AKT Ser/Thr kinase activation. J Biol Chem, 295(7):1769-1780(2020) [pubmed]

submitter keyword: Sestrin2, Akt PKB, GATOR2, mTOR, liver metabolism

Jun Hee Lee
contact affiliation	Department of molecular and integrative physiology, university of michigan, ann arbor MI 48109
contact email	leeju@umich.edu
lab head
Jun Hee Lee
contact affiliation	University of Michigan
contact email	leeju@umich.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD015824
     1. Label: PRIDE project
     2. Name: The GATOR2–mTORC2 axis mediates Sestrin2-induced AKT Ser/Thr kinase activation