Subcellular localization of glycogen synthase kinase 3beta controls embryonic stem cell self-renewal.
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.
Bechard
Matthew
M
Paul D. Coverdell Center for Biomedical and Health Sciences, Athens, Georgia 30602, USA.
Dalton
Stephen
S
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C514862:Akt1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3