Subcellular Localization of Glycogen Synthase Kinase 3β Controls Embryonic Stem Cell Self-Renewal
Subcellular Localization of Glycogen Synthase Kinase 3β Controls Embryonic Stem Cell Self-Renewal
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DOI：
10.1128/mcb.01405-08
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发表时间：
2009-04-15
影响因子：
5.3
通讯作者：
Dalton, Stephen
中科院分区：
文献类型：
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作者：
Bechard, Matthew;Dalton, Stephen
磷脂酰肌醇3-激酶(PI3K)、蛋白激酶B(AKT1)和c-myc在促进小鼠胚胎干细胞(MESCs)的维持方面具有公认的作用。相反，糖原合成酶3β(GSK3β)的活性是AKT1信号的负调控靶标，它拮抗自我更新。在这里，我们发现PI3K/AKT1信号通过抑制GSK3β活性和限制其对c-myc等核底物的访问来促进自我更新。在mESCs中，GSK3β穿梭于胞浆和胞核之间，但由于AKT1依赖的核输出和抑制的磷酸化，GSK3β以不活跃的形式积聚在胞浆中。当PI3K/AKT1信号在白血病抑制因子停用后下降时，活跃的GSK3β在细胞核内积聚，在那里它通过苏氨酸58(T58)的磷酸化来靶向c-myc，促进其降解。活性GSK3β的异位核定位促进分化，但这一过程被c-myc(T58A)的突变形式阻止，该突变形式逃避GSK3β的磷酸化。这一新机制解释了AKT1如何通过调节GSK3β的活性和定位来促进自我更新。C-myc是mESC自我更新的关键调控因子。
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.