Abstract
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.
Highlights
Stem cells possess the properties of self-renewal and differentiation potential
It is known that SATB1 transcriptionally represses the expression of Klf4 and Nanog, we hypothesized that Akt signaling is probably involved in regulation of stemness through phosphorylation of SATB1, Oct4 and Klf4 and by enhancing the antagonistic role of SATB1 on Nanog and Klf4
We demonstrate that Akt phosphorylates SATB1, a chromatin organizer and global regulator for gene expression, thereby keeping it intact and maintaining its inhibitory effects on the expression of Nanog
Summary
Stem cells possess the properties of self-renewal and differentiation potential. Modulators of the PI3K/Akt signaling pathway including PTEN [1,2], PML (promyelocytic leukemia) [3], TSC [4] and Fbxw7 [5,6] and effectors including FoxO transcriptional factors [7,8,9] and p21Cip [10] are indispensible for the homeostasis of normal hematopoietic stem cells (HSCs), implying that abnormal activation of Akt negatively regulates HSC stemness. The functions of Akt in embryonic stem cells (ESCs) [11], adult stem cells [12] and cancer stem cells (CSCs) [8] have been investigated, but its precise role in the maintenance of stem cell homeostasis and the mechanism by which Akt modulates differentiation are yet to be clarified. Common approaches such as forced gene expression, genetic knockdown and the use of pathway agonists/inhibitors all give clues as to the functions of Akt, these manipulations always lead to global and promiscuous effects. One common feature shared by SATB1, Oct, Sox and Klf is that they all have a consensus Akt phosphorylation motif (RxRxxS/T) [19,20], which raises the possibility that Akt is a master signaling molecule to modulate the antagonizing status between SATB1 and pluripotency factors
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