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

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

Molecular and cellular biology (2009-02-19)
Matthew Bechard, Stephen Dalton
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.

MATERIALS
Product Number
Brand
Product Description

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4-Hydroxytamoxifen, ≥70% Z isomer (remainder primarily E-isomer)
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Anti-Actin antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
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