西亚试剂：Signaling Network Crosstalk in Human Pluripotent Cells: A S

Signaling Network Crosstalk in Human Pluripotent Cells: A Smad2/3-Regulated Switch that Controls the Balance between Self-Renewal and Differentiation

Amar M. Singh, David Reynolds, Timothy Cliff, Satoshi Ohtsuka, Alexa L. Mattheyses, Yuhua Sun, Laura Menendez, Michael Kulik, Stephen Dalton

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.

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