Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China; Hongqiao Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China.
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China; iHuman Institute, Shanghai Tech University, 99 Haike Road, Shanghai 201210, China.
Cell Rep. 2017 Jan 24;18(4):933-946. doi: 10.1016/j.celrep.2016.12.081.
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.
LIF 促进小鼠胚胎干细胞（mESCs）的自我更新，而当其不存在时，细胞会分化。LIF 与 LIF 受体（LIFR）结合并激活 JAK-STAT3 通路，但受体复合物如何触发分化或自我更新仍不清楚。在这里，我们报告 LIFR 胞质域在跨膜区含有一个自我更新域和一个 C 末端的分化域。分化域包含四个 SPXX 重复序列，被 MAPK 磷酸化以限制 STAT3 的激活；自我更新域的特征是 3K 基序，其被 p300 乙酰化。在 mESCs 中，乙酰化 LIFR 发生同源二聚化，根据 gp130 的存在与否导致 STAT3 低激活或高激活。LIFR 激活的 STAT3 通过细胞因子诱导限制分化。因此，LIFR 的乙酰化和丝氨酸磷酸化可促进干细胞的自我更新和分化。
