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

Publication date: 24 January 2017
Source:Cell Reports, Volume 18, Issue 4
Author(s): Xiong-jun Wang, Yunbo Qiao, Minzhe M. Xiao, Lingbo Wang, Jun Chen, Wenjian Lv, Li Xu, Yan Li, Yumei Wang, Ming-dian Tan, Chao Huang, Jinsong Li, Ting C. Zhao, Zhaoyuan Hou, Naihe Jing, Y. Eugene Chin
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.

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Teaser

Using spectrum analysis, Wang et al. identify acetylation sites within the LIFR juxtamembrane region that promote ESC self-renewal and phosphorylation sites within the cytoplasmic domain that promote differentiation. Thus, LIFR acetylation and serine phosphorylation differentially promote self-renewal and differentiation in stem cells.


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