title: ERK1 phosphorylates Nanog to regulate protein stability and stem cell self-renewal.
abstract: Nanog regulates human and mouse embryonic stem (ES) cell self-renewal activity. Activation of ERKs signaling negatively regulates ES cell self-renewal and induces differentiation, but the mechanisms are not understood. We found that ERK1 binds and phosphorylates Nanog. Activation of MEK/ERKs signaling and phosphorylation of Nanog inhibit Nanog transactivation, inducing ES cell differentiation. Conversely, suppression of MEK/ERKs signaling enhances Nanog transactivation to inhibit ES cell differentiation. We observed that phosphorylation of Nanog by ERK1 decreases Nanog stability through ubiquitination-mediated protein degradation. Further, we found that this phosphorylation induces binding of FBXW8 with Nanog to reduce Nanog protein stability. Overall, our results demonstrated that ERKs-mediated Nanog phosphorylation plays an important role in self-renewal of ES cells through FBXW8-mediated Nanog protein stability.
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA; Kyungpook National University, Center for Laboratory Animal Resources, School of Animal BT Science, Department of Biochemistry, School of Dentistry, Dae-gu, Republic of Korea.
authors.forename: Sung-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA; Kyungpook National University, Center for Laboratory Animal Resources, School of Animal BT Science, Department of Biochemistry, School of Dentistry, Dae-gu, Republic of Korea.
authors.forename: Myoung Ok
authors.initials: MO
authors.lastname: Kim
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA.
authors.forename: Yong-Yeon
authors.initials: YY
authors.lastname: Cho
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Yao
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA.
authors.forename: Dong Joon
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Jeong
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Yu
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA.
authors.forename: Ki Beom
authors.initials: KB
authors.lastname: Bae
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA.
authors.forename: Eun Jin
authors.initials: EJ
authors.lastname: Cho
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA.
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA.
authors.forename: Mee Hyun
authors.initials: MH
authors.lastname: Lee
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Kyungpook National University, Center for Laboratory Animal Resources, School of Animal BT Science, Department of Biochemistry, School of Dentistry, Dae-gu, Republic of Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA. Electronic address: zgdong@hi.umn.edu.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D000071317:Nanog Homeobox Protein; D010766:Phosphorylation; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D048052:Mitogen-Activated Protein Kinase 3