Format

Send to

Choose Destination
Mol Cell Biol. 2009 Apr;29(8):2092-104. doi: 10.1128/MCB.01405-08. Epub 2009 Feb 17.

Subcellular localization of glycogen synthase kinase 3beta controls embryonic stem cell self-renewal.

Author information

1
Paul D. Coverdell Center for Biomedical and Health Sciences, Athens, Georgia 30602, USA.

Abstract

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 3beta (GSK3beta), a negatively regulated target of AKT1 signaling, antagonizes self-renewal. Here, we show that PI3K/AKT1 signaling promotes self-renewal by suppressing GSK3beta activity and restricting its access to nuclear substrates such as c-myc. GSK3beta 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 GSK3beta accumulates in the nucleus, where it targets c-myc through phosphorylation on threonine 58 (T58), promoting its degradation. Ectopic nuclear localization of active GSK3beta promotes differentiation, but this process is blocked by a mutant form of c-myc (T58A) that evades phosphorylation by GSK3beta. This novel mechanism explains how AKT1 promotes self-renewal by regulating the activity and localization of GSK3beta. This pathway converges on c-myc, a key regulator of mESC self-renewal.

PMID:
19223464
PMCID:
PMC2663310
DOI:
10.1128/MCB.01405-08
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center