Department of Biochemistry and Molecular Biology, Paul D. Coverdell Center for Biomedical and Health Sciences, The University of Georgia, Athens, GA 30602, USA.
Cell Stem Cell. 2012 Mar 2;10(3):312-26. doi: 10.1016/j.stem.2012.01.014.
A general mechanism for how intracellular signaling pathways in human pluripotent cells are coordinated and how they maintain self-renewal remain to be elucidated. In this report, we describe a signaling mechanism where PI3K/Akt activity maintains self-renewal by restraining prodifferentiation signaling through suppression of the Raf/Mek/Erk and canonical Wnt signaling pathways. When active, PI3K/Akt establishes conditions where Activin A/Smad2,3 performs a pro-self-renewal function by activating target genes, including Nanog. When PI3K/Akt signaling is low, Wnt effectors are activated and function in conjunction with Smad2,3 to promote differentiation. The switch in Smad2,3 activity after inactivation of PI3K/Akt requires the activation of canonical Wnt signaling by Erk, which targets Gsk3β. In sum, we define a signaling framework that converges on Smad2,3 and determines its ability to regulate the balance between alternative cell states. This signaling paradigm has far-reaching implications for cell fate decisions during early embryonic development.
一个关于人类多能细胞内信号通路如何协调以及它们如何维持自我更新的一般机制仍有待阐明。在本报告中，我们描述了一种信号机制，其中 PI3K/Akt 活性通过抑制 Raf/Mek/Erk 和经典 Wnt 信号通路来抑制分化信号，从而维持自我更新。当处于活跃状态时，PI3K/Akt 建立了条件，使 Activin A/Smad2,3 通过激活包括 Nanog 在内的靶基因发挥促自我更新功能。当 PI3K/Akt 信号较低时，Wnt 效应物被激活，并与 Smad2,3 协同作用促进分化。PI3K/Akt 失活后 Smad2,3 活性的转换需要 Erk 激活经典 Wnt 信号，该信号靶向 Gsk3β。总之，我们定义了一个信号框架，该框架集中在 Smad2,3 上，并确定了其调节替代细胞状态之间平衡的能力。这种信号范例对早期胚胎发育过程中的细胞命运决定具有深远的影响。
