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

• Published in: Cell stem cell Vol. 10; no. 3; pp. 312 - 326
• Main Authors: Singh, Amar M., Reynolds, David, Cliff, Timothy, Ohtsuka, Satoshi, Mattheyses, Alexa L., Sun, Yuhua, Menendez, Laura, Kulik, Michael, Dalton, Stephen
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 02-03-2012; Cell Press
• Subjects: Biological and medical sciences; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cells, Cultured; Fundamental and applied biological sciences. Psychology; Genes, Switch - physiology; Humans; Immunoblotting; Models, Biological; Molecular and cellular biology; Pluripotent Stem Cells - physiology; Polymerase Chain Reaction; Regeneration; Signal Transduction; Smad2 Protein - metabolism; Smad2 Protein - physiology; Smad3 Protein - metabolism; Smad3 Protein - physiology; Human; Smad protein; Regulation(control); Pluripotent cell; Stem cell; Crosstalk; Differentiation
• ISSN: 1934-5909; 1875-9777
• 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.
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► 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