F-box protein FBXL16 binds PP2A-B55α and regulates differentiation of embryonic stem cells along the FLK1+ lineage

Mol Cell Proteomics. 2014 Mar;13(3):780-91. doi: 10.1074/mcp.M113.031765. Epub 2014 Jan 5.


The programmed formation of specific tissues from embryonic stem cells is a major goal of regenerative medicine. To identify points of intervention in cardiac tissue formation, we performed an siRNA screen in murine embryonic stem cells to identify ubiquitin system genes that repress cardiovascular tissue formation. Our screen uncovered an F-box protein, Fbxl16, as a repressor of one of the earliest steps in the cardiogenic lineage: FLK1+ progenitor formation. Whereas F-box proteins typically form SCF ubiquitin ligases, shotgun mass spectrometry revealed that FBXL16 instead binds protein phosphatase 2A (PP2A) containing a B55 specificity subunit (PP2A(B55)). Phosphoproteomic analyses indicate that FBXL16 negatively regulates phosphorylation of the established PP2A(B55) substrate, vimentin. We suggest that FBXL16 negatively regulates the activity of B55α-PP2A to modulate the genesis of FLK1+ progenitor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Biocatalysis
  • Cell Differentiation*
  • Cell Lineage*
  • Cullin Proteins / metabolism
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / microbiology*
  • F-Box Proteins / metabolism*
  • Holoenzymes / metabolism
  • Humans
  • Immunoprecipitation
  • Mass Spectrometry
  • Mice
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Phosphatase 2 / metabolism*
  • Proteomics
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*


  • Cullin 1
  • Cullin Proteins
  • F-Box Proteins
  • Holoenzymes
  • Phosphoproteins
  • SKP Cullin F-Box Protein Ligases
  • Vascular Endothelial Growth Factor Receptor-2
  • Ppp2r2a protein, mouse
  • Protein Phosphatase 2