Related Experiment Video

Updated: May 29, 2025

Spatial and Temporal Analysis of Active ERK in the C. elegans Germline
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Published on: November 29, 2016

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ERK phosphorylates ESRRB to regulate the self-renewal and differentiation of mouse embryonic stem cells

Xiaowei Duan1, Qingye Zhang1, Lulu Gao1

  • 1State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China.

Stem Cell Reports
|February 7, 2025
PubMed

Insights

Mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) signaling plays a dual role in pluripotent stem cell maintenance. ERK phosphorylation of ESRRB regulates both stem cell self-renewal and differentiation.

Area of Science:

  • Stem cell biology
  • Molecular signaling pathways
  • Epigenetics

Background:

  • Mitogen-activated protein kinase (MEK) inhibitors are crucial for pluripotent stem cell culture.
  • Prolonged MEK inhibition impairs mouse embryonic stem cell (ESC) developmental potential, suggesting a complex role for MEK/ERK signaling in pluripotency.

Purpose of the Study:

  • To elucidate the precise mechanisms by which MEK/ERK signaling influences pluripotency maintenance in ESCs.
  • To identify key substrates of ERK involved in regulating stem cell fate.

Main Methods:

  • Quantitative phosphoproteomic analysis to identify ERK substrates.
  • Western blotting and phospho-specific antibodies to validate ESRRB phosphorylation.
  • Chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) to assess gene binding.

Main Results:

  • Identified 169 ERK substrates, enriched in proteins regulating stem cell maintenance, embryonic development, and cell cycle.
  • Demonstrated that ERK phosphorylates the pluripotency factor ESRRB at Serine 42 and 43.
  • Showed that dephosphorylated ESRRB enhances pluripotency gene binding, promoting self-renewal, while phosphorylated ESRRB promotes extraembryonic endoderm (XEN) differentiation.

Conclusions:

  • ERK signaling regulates ESC self-renewal and differentiation through phosphorylation of multiple substrates, notably ESRRB.
  • ESRRB phosphorylation acts as a molecular switch, directing ESCs towards either self-renewal or XEN differentiation.
  • These findings provide critical insights into the dual role of ERK signaling in maintaining stem cell pluripotency and directing lineage commitment.
Keywords:
ERKESRRBXEN differentiationembryonic stem cellsself-renewal

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