STAT3 Phosphorylation at Tyrosine 705 and Serine 727 Differentially Regulates Mouse ESC Fates

Authors

  • Guanyi Huang,

    1. 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
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  • Hexin Yan,

    1. 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
    2. Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Shoudong Ye,

    1. 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
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  • Chang Tong,

    1. 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
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  • Qi-Long Ying

    Corresponding author
    1. 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
    • Correspondence: Qi-Long Ying, Ph.D., 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 90033, USA. Telephone: 323 442 3308; Fax: 323 442 4040; e-mail: qying@med.usc.edu

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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. Stem Cells 2014;32:1149–1160

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