Phosphorylation stabilizes Nanog by promoting its interaction with Pin1

Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13312-7. doi: 10.1073/pnas.1005847107. Epub 2010 Jul 9.

Abstract

Embryonic stem cells (ESCs) can undergo unlimited self-renewal and retain the pluripotency to differentiate into all cell types in the body, thus holding great promise as a renewable source of cells for human therapy. The mechanisms that maintain self-renewal of ESCs remain unclear. Here we show that Nanog, a transcription factor crucial for the self-renewal of ESCs, is phosphorylated at multiple Ser/Thr-Pro motifs. This phosphorylation promotes the interaction between Nanog and the prolyl isomerase Pin1, leading to Nanog stabilization by suppressing its ubiquitination. Inhibition of Pin1 activity or disruption of Pin1-Nanog interaction in ESCs suppresses their capability to self-renew and to form teratomas in immunodeficient mice. Therefore, in addition to the stringent transcriptional regulation of Nanog, the expression level of Nanog is also modulated by posttranslational mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / genetics
  • Amino Acid Sequence
  • Animals
  • Binding Sites / genetics
  • Blotting, Western
  • Cell Line
  • Cells, Cultured
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Mice
  • Mice, SCID
  • Molecular Sequence Data
  • Mutation
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Nanog Homeobox Protein
  • Peptidylprolyl Isomerase / antagonists & inhibitors
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism*
  • Phenanthrolines / pharmacology
  • Phosphorylation
  • Protein Binding / drug effects
  • Protein Stability
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Teratoma / pathology
  • Teratoma / prevention & control
  • Ubiquitination

Substances

  • Enzyme Inhibitors
  • Homeodomain Proteins
  • NANOG protein, human
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Nanog Homeobox Protein
  • Phenanthrolines
  • diethyl-1,3,6,8-tetrahydro-1,3,6,8-tetraoxobenzo(lmn)(3,8)phenanthroline-2,7-diacetate
  • PIN1 protein, human
  • Peptidylprolyl Isomerase
  • Pin1 protein, mouse