Opposing Roles of Acetylation and Phosphorylation in LIFR-Dependent Self-Renewal Growth Signaling in Mouse Embryonic Stem Cells

Cell Rep. 2017 Jan 24;18(4):933-946. doi: 10.1016/j.celrep.2016.12.081.

Abstract

LIF promotes self-renewal of mouse embryonic stem cells (mESCs), and in its absence, the cells differentiate. LIF binds to the LIF receptor (LIFR) and activates the JAK-STAT3 pathway, but it remains unknown how the receptor complex triggers differentiation or self-renewal. Here, we report that the LIFR cytoplasmic domain contains a self-renewal domain within the juxtamembrane region and a differentiation domain within the C-terminal region. The differentiation domain contains four SPXX repeats that are phosphorylated by MAPK to restrict STAT3 activation; the self-renewal domain is characterized by a 3K motif that is acetylated by p300. In mESCs, acetyl-LIFR undergoes homodimerization, leading to STAT3 hypo- or hyper-activation depending on the presence or absence of gp130. LIFR-activated STAT3 restricts differentiation via cytokine induction. Thus, LIFR acetylation and serine phosphorylation differentially promote stem cell self-renewal and differentiation.

Keywords: LIF; LIFR; MAPK; STAT3; acetylation; differentiation; embryonic stem cells; phosphorylation; self-renewal; signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Amino Acid Motifs
  • Animals
  • Cell Differentiation / drug effects
  • Cell Line
  • Cell Self Renewal / drug effects
  • Cytokine Receptor gp130 / metabolism
  • E1A-Associated p300 Protein / antagonists & inhibitors
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism
  • HEK293 Cells
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology
  • Leukemia Inhibitory Factor / pharmacology
  • Leukemia Inhibitory Factor Receptor alpha Subunit / chemistry
  • Leukemia Inhibitory Factor Receptor alpha Subunit / genetics
  • Leukemia Inhibitory Factor Receptor alpha Subunit / metabolism*
  • Mice
  • Mice, Knockout
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • Phosphorylation / drug effects
  • RNA Interference
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects

Substances

  • Hydroxamic Acids
  • Il6st protein, mouse
  • Leukemia Inhibitory Factor
  • Leukemia Inhibitory Factor Receptor alpha Subunit
  • Lifr protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Cytokine Receptor gp130
  • trichostatin A
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse
  • Histone Deacetylases