title: LIN28 phosphorylation by MAPK/ERK couples signalling to the post-transcriptional control of pluripotency.
abstract: Signalling and post-transcriptional gene control are both critical for the regulation of pluripotency, yet how they are integrated to influence cell identity remains poorly understood. LIN28 (also known as LIN28A), a highly conserved RNA-binding protein, has emerged as a central post-transcriptional regulator of cell fate through blockade of let-7 microRNA biogenesis and direct modulation of mRNA translation. Here we show that LIN28 is phosphorylated by MAPK/ERK in pluripotent stem cells, which increases its levels via post-translational stabilization. LIN28 phosphorylation had little impact on let-7 but enhanced the effect of LIN28 on its direct mRNA targets, revealing a mechanism that uncouples LIN28's let-7-dependent and -independent activities. We have linked this mechanism to the induction of pluripotency by somatic cell reprogramming and the transition from naive to primed pluripotency. Collectively, our findings indicate that MAPK/ERK directly impacts LIN28, defining an axis that connects signalling, post-transcriptional gene control, and cell fate regulation.
authors.affiliation: Stem Cell Transplantation Program, Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
authors.forename: Kaloyan M
authors.initials: KM
authors.lastname: Tsanov
authors.affiliation: Stem Cell Transplantation Program, Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pearson
authors.affiliation: Stem Cell Transplantation Program, Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
authors.forename: Zhaoting
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Stem Cell Transplantation Program, Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
authors.forename: Areum
authors.initials: A
authors.lastname: Han
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.|Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Robinson
authors.initials: R
authors.lastname: Triboulet
authors.affiliation: Stem Cell Transplantation Program, Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
authors.forename: Marc T
authors.initials: MT
authors.lastname: Seligson
authors.affiliation: Stem Cell Transplantation Program, Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Powers
authors.affiliation: Stem Cell Transplantation Program, Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
authors.forename: Jihan K
authors.initials: JK
authors.lastname: Osborne
authors.affiliation: Cell Signaling Technology, Inc., Danvers, Massachusetts 01923, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Kane
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.|Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Gregory
authors.affiliation: Stem Cell Transplantation Program, Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D020935:MAP Kinase Signaling System; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism; D010766:Phosphorylation; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000072417:Protein Domains; D055550:Protein Stability; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C488352:Lin-28 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse