Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 35, Pages 18353-18369Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.745414
Keywords
cell signaling; differentiation; epithelial-mesenchymal transition (EMT); pluripotency; post-translational modification (PTM); stem cells; transcription factor; tumor cell biology
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Funding
- National Natural Science Foundation of China [31271465]
- First Affiliated Hospital, School of Medicine, Zhejiang University [b2697]
- Fundamental Research Funds for the Central Universities [2014QNA6004]
- Scientific Research Fund of Zhejiang Provincial Education Department Grant [Y201432207]
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Although the Oct4/Sox2 complex is crucial for maintaining the pluripotency of stem cells, the molecular basis underlying its regulation during lineage-specific differentiation remains unknown. Here, we revealed that the highly conserved Oct4/Lys-156 is important for maintaining the stability of the Oct4 protein and the intermolecular salt bridge between Oct4/Lys-151 and Sox2/Asp-107 that contributes to the Oct4/Sox2 interaction. Post-translational modifications at Lys-156 and K156N, a somatic mutation detected in bladder cancer patients, both impaired the Lys-151-Asp-107 salt bridge and the Oct4/Sox2 interaction. When produced as a recombinant protein or overexpressed in pluripotent stem cells, Oct4/K156N, with reduced binding to Sox2, significantly down-regulated the stemness genes that are cooperatively controlled by the Oct4/Sox2 complex and specifically up-regulated the mesendodermal genes and the SNAIL family genes that promote the epithelial-mesenchymal transition. Thus, we conclude that Oct4/Lys-156-modulated Oct4/Sox2 interaction coordinately controls the epithelial-mesenchymal transition and mesendoderm specification induced by specific differentiation signals.
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