Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation.
Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation.
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人类多能细胞中的信号网络串扰：SMAD2/3调节的开关，可控制自我更新和分化之间的平衡。
DOI：
10.1016/j.stem.2012.01.014
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发表时间：
2012-03-02
期刊：
影响因子：
23.9
通讯作者：
Dalton S
中科院分区：
文献类型：
--
作者：
Singh AM;Reynolds D;Cliff T;Ohtsuka S;Mattheyses AL;Sun Y;Menendez L;Kulik M;Dalton S
人类多能细胞中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，我们描述了一种新型信号传导机制，其中PI 3 K/Akt活性通过抑制Raf/Mek/Erk和经典Wnt信号传导途径来抑制促分化信号传导，从而维持自我更新。当激活时，PI 3 K/Akt建立激活素A/Smad 2，3通过激活靶基因（包括Nanog）执行促自我更新功能的条件。当PI 3 K/Akt信号传导低时，Wnt效应物被激活并与Smad 2，3一起起作用以促进分化。PI 3 K/Akt失活后Smad 2，3活性的转换需要Erk激活经典Wnt信号传导，Erk靶向Gsk 3 β。总之，我们定义了一个信号框架，收敛于Smad 2，3，并确定其调节替代细胞状态之间的平衡的能力。这种信号模式对早期胚胎发育过程中的细胞命运决定具有深远的影响。
A general mechanism for how intracellular signaling pathways in human pluripotent cells are co-ordinated and how they maintain self-renewal remain to be elucidated. In this report, we describe a novel signaling mechanism where PI3K/Akt activity maintains self-renewal by restraining pro-differentiation 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 following 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.
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