title: F-box protein FBXL16 binds PP2A-B55α and regulates differentiation of embryonic stem cells along the FLK1+ lineage.
abstract: 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.
authors.affiliation: Division of Biology, California Institute of Technology, California;
authors.forename: Narimon
authors.initials: N
authors.lastname: Honarpour
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Rose
authors.forename: Justin
authors.initials: J
authors.lastname: Brumbaugh
authors.forename: Jody
authors.initials: J
authors.lastname: Anderson
authors.forename: Robert L J
authors.initials: RL
authors.lastname: Graham
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sweredoski
authors.forename: Sonja
authors.initials: S
authors.lastname: Hess
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Coon
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Deshaies
mesh_terms: D016475:3T3 Cells; D000818:Animals; D055162:Biocatalysis; D002454:Cell Differentiation; D019070:Cell Lineage; D044842:Cullin Proteins / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000382:microbiology*; D044783:F-Box Proteins / Q000378:metabolism*; D020035:Holoenzymes / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D040901:Proteomics; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: C100318:Cullin 1; D044842:Cullin Proteins; D044783:F-Box Proteins; D020035:Holoenzymes; D010750:Phosphoproteins; D044843:SKP Cullin F-Box Protein Ligases; D040301:Vascular Endothelial Growth Factor Receptor-2; C581986:Ppp2r2a protein, mouse; D054648:Protein Phosphatase 2