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Molecular and Cellular Biology, April 2009, p. 2092-2104, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01405-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Subcellular Localization of Glycogen Synthase Kinase 3β Controls Embryonic Stem Cell Self-Renewal {triangledown} ,{dagger}

Matthew Bechard1,2 and Stephen Dalton1,2*

Paul D. Coverdell Center for Biomedical and Health Sciences, Athens, Georgia 30602,1 Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 306022

Received 6 September 2008/ Returned for modification 20 November 2008/ Accepted 4 February 2009

Phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT1), and c-myc have well-established roles in promoting the maintenance of murine embryonic stem cells (mESCs). In contrast, the activity of glycogen synthase kinase 3β (GSK3β), a negatively regulated target of AKT1 signaling, antagonizes self-renewal. Here, we show that PI3K/AKT1 signaling promotes self-renewal by suppressing GSK3β activity and restricting its access to nuclear substrates such as c-myc. GSK3β shuttles between the cytoplasm and nucleus in mESCs but accumulates in the cytoplasm in an inactive form due to AKT1-dependent nuclear export and inhibitory phosphorylation. When PI3K/AKT1 signaling declines following leukemia inhibitory factor withdrawal, active GSK3β accumulates in the nucleus, where it targets c-myc through phosphorylation on threonine 58 (T58), promoting its degradation. Ectopic nuclear localization of active GSK3β promotes differentiation, but this process is blocked by a mutant form of c-myc (T58A) that evades phosphorylation by GSK3β. This novel mechanism explains how AKT1 promotes self-renewal by regulating the activity and localization of GSK3β. This pathway converges on c-myc, a key regulator of mESC self-renewal.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602. Phone: (706) 583-0480. Fax: (706) 583-8061. E-mail: sdalton{at}uga.edu

{triangledown} Published ahead of print on 17 February 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2009, p. 2092-2104, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01405-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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