Dataset Information

The GATOR2–mTORC2 axis mediates Sestrin2-induced AKT Ser/Thr kinase activation

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte

SUBMITTER: Jun Hee Lee

LAB HEAD: Jun Hee Lee

PROVIDER: PXD015824 | Pride | 2020-01-15

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	HomosapiensSwissProtTaxID9606.fasta	Fasta
	UM_F_50cm_2018_0034.msf	Msf
	UM_F_50cm_2018_0034.raw	Raw
	UM_F_50cm_2018_0035.msf	Msf
	UM_F_50cm_2018_0035.raw	Raw

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Publications

The GATOR2-mTORC2 axis mediates Sestrin2-induced AKT Ser/Thr kinase activation.

Kowalsky Allison Ho AH Namkoong Sim S Mettetal Eric E Park Hwan-Woo HW Kazyken Dubek D Fingar Diane C DC Lee Jun Hee JH

The Journal of biological chemistry 20200108 7

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-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. ...[more]

PMID: 31915252

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