title: STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates mouse ESC fates.
abstract: STAT3 can be transcriptionally activated by phosphorylation of its tyrosine 705 or serine 727 residue. In mouse embryonic stem cells (mESCs), leukemia inhibitory factor (LIF) signaling maintains pluripotency by inducing JAK-mediated phosphorylation of STAT3 Y705 (pY705). However, the function of phosphorylated S727 (pS727) in mESCs remains unclear. In this study, we examined the roles of STAT3 pY705 and pS727 in regulating mESC identities, using a small molecule-based system to post-translationally modulate the quantity of transgenic STAT3 in STAT3(-/-) mESCs. We demonstrated that pY705 is absolutely required for STAT3-mediated mESC self-renewal, while pS727 is dispensable, serving only to promote proliferation and optimal pluripotency. S727 phosphorylation is regulated directly by fibroblast growth factor/Erk signaling and crucial in the transition of mESCs from pluripotency to neuronal commitment. Loss of S727 phosphorylation resulted in significantly reduced neuronal differentiation potential, which could be recovered by a S727 phosphorylation mimic. Moreover, loss of pS727 sufficed LIF to reprogram epiblast stem cells to naïve pluripotency, suggesting a dynamic equilibrium of STAT3 pY705 and pS727 in the control of mESC fate.
authors.affiliation: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Guanyi
authors.initials: G
authors.lastname: Huang
authors.forename: Hexin
authors.initials: H
authors.lastname: Yan
authors.forename: Shoudong
authors.initials: S
authors.lastname: Ye
authors.forename: Chang
authors.initials: C
authors.lastname: Tong
authors.forename: Qi-Long
authors.initials: QL
authors.lastname: Ying
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D053605:Leukemia Inhibitory Factor; D064231:Nestin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014443:Tyrosine; D012694:Serine; C506614:mirdametinib; D004159:Diphenylamine
keywords: Differentiation; Embryonic stem cell; Phosphorylation; STAT3; Self-renewal