A Regulatory Network Involving β-Catenin, e-Cadherin, PI3k/Akt, and Slug Balances Self-Renewal and Differentiation of Human Pluripotent Stem Cells In Response to Wnt Signaling

Stem Cells. 2015 May;33(5):1419-33. doi: 10.1002/stem.1944.


The mechanisms underlying disparate roles of the canonical Wnt signaling pathway in maintaining self-renewal or inducing differentiation and lineage specification in embryonic stem cells (ESCs) are not clear. In this study, we provide the first demonstration that self-renewal versus differentiation of human ESCs (hESCs) in response to Wnt signaling is predominantly determined by a two-layer regulatory circuit involving β-catenin, E-cadherin, PI3K/Akt, and Slug in a time-dependent manner. Short-term upregulation of β-catenin does not lead to the activation of T-cell factor (TCF)-eGFP Wnt reporter in hESCs. Instead, it enhances E-cadherin expression on the cell membrane, thereby enhancing hESC self-renewal through E-cadherin-associated PI3K/Akt signaling. Conversely, long-term Wnt activation or loss of E-cadherin intracellular β-catenin binding domain induces TCF-eGFP activity and promotes hESC differentiation through β-catenin-induced upregulation of Slug. Enhanced expression of Slug leads to a further reduction of E-cadherin that serves as a β-catenin "sink" sequestering free cytoplasmic β-catenin. The formation of such a framework reinforces hESCs to switch from a state of temporal self-renewal associated with short-term Wnt/β-catenin activation to definitive differentiation. Stem Cells 2015;33:1419-1433.

Keywords: Differentiation; E-cadherin; Human embryonic stem cell; Self-renewal; Slug; Wnt; β-Catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / metabolism*
  • Cell Differentiation* / drug effects
  • Cell Self Renewal / drug effects
  • Down-Regulation / drug effects
  • Enzyme Activation / drug effects
  • Gene Regulatory Networks* / drug effects
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Snail Family Transcription Factors
  • TCF Transcription Factors / metabolism
  • Transcription Factors / metabolism*
  • Up-Regulation / drug effects
  • Wnt Signaling Pathway / drug effects
  • beta Catenin / metabolism*


  • Cadherins
  • Protein Kinase Inhibitors
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • TCF Transcription Factors
  • Transcription Factors
  • beta Catenin
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3