| First Author | Bechard M | Year | 2009 |
| Journal | Mol Cell Biol | Volume | 29 |
| Issue | 8 | Pages | 2092-104 |
| PubMed ID | 19223464 | Mgi Jnum | J:147766 |
| Mgi Id | MGI:3842064 | Doi | 10.1128/MCB.01405-08 |
| Citation | Bechard M, et al. (2009) Subcellular localization of glycogen synthase kinase 3beta controls embryonic stem cell self-renewal. Mol Cell Biol 29(8):2092-104 |
| abstractText | 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. |
