Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 29, Issue 8, Pages 2092-2104Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01405-08
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Funding
- National Institute of Child Health and Human Development [HD-049647]
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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 3 beta (GSK3 beta), a negatively regulated target of AKT1 signaling, antagonizes self-renewal. Here, we show that PI3K/AKT1 signaling promotes self-renewal by suppressing GSK3 beta activity and restricting its access to nuclear substrates such as c-myc. GSK3 beta 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 GSK3 beta accumulates in the nucleus, where it targets c-myc through phosphorylation on threonine 58 (T58), promoting its degradation. Ectopic nuclear localization of active GSK3 beta promotes differentiation, but this process is blocked by a mutant form of c-myc (T58A) that evades phosphorylation by GSK3 beta. This novel mechanism explains how AKT1 promotes self-renewal by regulating the activity and localization of GSK3 beta. This pathway converges on c-myc, a key regulator of mESC self-renewal.
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