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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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SUMMARY 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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Metadata
- Authors
- Singh, A. M., Reynolds, D., Cliff, T., Ohtsuka, S., Mattheyses, A. L., Sun, Y., Menendez, L., Kulik, M., & Dalton, S.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 10
- Issue
- 3
- Pages
- 312-326
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2002973634
- Cited by
- 356
- References
- 58
- FWCI
- 15.68
- Type
- journal article
- Language
- en
- Open access
- bronze
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