title: Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Paul D. Coverdell Center for Biomedical and Health Sciences, The University of Georgia, Athens, GA 30602, USA.
authors.forename: Amar M
authors.initials: AM
authors.lastname: Singh
authors.forename: David
authors.initials: D
authors.lastname: Reynolds
authors.forename: Timothy
authors.initials: T
authors.lastname: Cliff
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohtsuka
authors.forename: Alexa L
authors.initials: AL
authors.lastname: Mattheyses
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Sun
authors.forename: Laura
authors.initials: L
authors.lastname: Menendez
authors.forename: Michael
authors.initials: M
authors.lastname: Kulik
authors.forename: Stephen
authors.initials: S
authors.lastname: Dalton
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D005812:Genes, Switch / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D008954:Models, Biological; D039904:Pluripotent Stem Cells / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012038:Regeneration; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism / Q000502:physiology*; D051900:Smad3 Protein / Q000378:metabolism / Q000502:physiology*
chemical_list: C497782:SMAD2 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein