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

SummaryA 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (182 K)Download as PowerPoint slideHighlights► Akt promotes pluripotency by modulating Activin/Smad2,3 activity and repressing Erk ► Erk and Wnt cooperate to inhibit Gsk3β and promote differentiation ► β-catenin and Smad2,3 cooperate to induce mesendoderm differentiation ► At low doses, Gsk3 inhibitors promote self-renewal by increasing Myc stability