title: Opposing Roles of Acetylation and Phosphorylation in LIFR-Dependent Self-Renewal Growth Signaling in Mouse Embryonic Stem Cells.
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.
authors.affiliation: 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.
authors.forename: Xiong-Jun
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: 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.
authors.forename: Minzhe M
authors.initials: MM
authors.lastname: Xiao
authors.affiliation: 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.
authors.forename: Lingbo
authors.initials: L
authors.lastname: Wang
authors.affiliation: 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; Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Lv
authors.affiliation: Department of Signal Transduction, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Signal Transduction, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Ming-Dian
authors.initials: MD
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Surgery, Boston University Medical School, Roger Williams Medical Center, Providence, RI 02908, USA.
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
authors.affiliation: Hongqiao Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: houzy@sjtu.edu.cn.
authors.forename: Zhaoyuan
authors.initials: Z
authors.lastname: Hou
authors.affiliation: 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. Electronic address: njing@sibs.ac.cn.
authors.forename: Naihe
authors.initials: N
authors.lastname: Jing
authors.affiliation: 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. Electronic address: yechin@sibs.ac.cn.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
mesh_terms: D000107:Acetylation / Q000187:drug effects; D020816:Amino Acid Motifs; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D000066673:Cell Self Renewal / Q000187:drug effects; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D006877:Hydroxamic Acids; C494200:Il6st protein, mouse; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507841:Lifr protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130; C012589:trichostatin A; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D006655:Histone Deacetylases
keywords: LIF; LIFR; MAPK; STAT3; acetylation; differentiation; embryonic stem cells; phosphorylation; self-renewal; signaling