Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
PLoS One. 2013 Jun 6;8(6):e64877. doi: 10.1371/journal.pone.0064877. Print 2013.
The mechanism by which Akt modulates stem cell homeostasis is still incompletely defined. Here we demonstrate that Akt phosphorylates special AT-rich sequences binding protein 1 (SATB1) at serine 47 and protects SATB1 from apoptotic cleavage. Meanwhile, Akt phosphorylates Oct4 at threonine 228 and Klf4 at threonine 399, and accelerates their degradation. Moreover, PI3K/Akt signaling enhances the binding of SATB1 to Sox2, thereby probably impairing the formation of Oct4/Sox2 regulatory complexes. During retinoic acid (RA)-induced differentiation of mouse F9 embryonal carcinoma cells (ECCs), the Akt activation profile as well as its substrate spectrum is strikingly correlated with the down-regulation of Oct4, Klf4 and Nanog, which suggests Akt activation is coupled to the onset of differentiation. Accordingly, Akt-mediated phosphorylation is crucial for the capability of SATB1 to repress Nanog expression and to activate transcription of Bcl2 and Nestin genes. Taken together, we conclude that Akt is involved in the differentiation of ECCs through coordinated phosphorylations of pluripotency/differentiation factors.
Akt 调节干细胞动态平衡的机制尚不完全明确。本文中我们证明 Akt 可使富含特殊 AT 的序列结合蛋白 1（SATB1）在丝氨酸 47 位发生磷酸化，从而保护 SATB1 免受凋亡切割。同时，Akt 使 Oct4 在苏氨酸 228 位和 Klf4 在苏氨酸 399 位发生磷酸化，从而加速它们的降解。此外，PI3K/Akt 信号增强了 SATB1 与 Sox2 的结合，从而可能破坏了 Oct4/Sox2 调控复合物的形成。在维甲酸（RA）诱导的小鼠 F9 胚胎癌细胞（ECC）分化过程中，Akt 的激活谱及其底物谱与 Oct4、Klf4 和 Nanog 的下调显著相关，这表明 Akt 的激活与分化的开始相关。因此，Akt 介导的磷酸化对于 SATB1 抑制 Nanog 表达和激活 Bcl2 和 Nestin 基因转录的能力至关重要。综上所述，我们得出结论，Akt 通过协调多能性/分化因子的磷酸化参与 ECC 的分化。
