F-box Protein FBXL16 Binds PP2A-B55α and Regulates Differentiation of Embryonic Stem Cells along the FLK1+ Lineage

Narimon Honarpour; Christopher M Rose; Justin Brumbaugh; Jody Anderson; Robert L J Graham; Michael J Sweredoski; Sonja Hess; Joshua J Coon; Raymond J Deshaies

doi:10.1074/mcp.M113.031765

F-box Protein FBXL16 Binds PP2A-B55α and Regulates Differentiation of Embryonic Stem Cells along the FLK1+ Lineage

Narimon Honarpour, Christopher M Rose, Justin Brumbaugh, Jody Anderson, Robert L J Graham, Michael J Sweredoski, Sonja Hess, Joshua J Coon, Raymond J Deshaies

School of Biological Sciences

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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.

Original language	English
Pages (from-to)	780-791
Number of pages	12
Journal	Molecular & cellular proteomics : MCP
Volume	13
Issue number	3
Early online date	05 Jan 2014
DOIs	https://doi.org/10.1074/mcp.M113.031765
Publication status	Published - 01 Mar 2014

Keywords

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

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10.1074/mcp.M113.031765Licence: CC BY

F-box Protein FBXL16 Binds PP2A-B55α and Regulates Differentiation of Embryonic Stem Cells along the FLK1+ Lineage
Copyright 2014 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 999 KBLicence: CC BY

Bobby Graham
- R.Grahamqub.acuk
- School of Biological Sciences - Professor
- Institute for Global Food Security
Person: Academic

Cite this

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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. ",

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

author = "Narimon Honarpour and Rose, {Christopher M} and Justin Brumbaugh and Jody Anderson and Graham, {Robert L J} and Sweredoski, {Michael J} and Sonja Hess and Coon, {Joshua J} and Deshaies, {Raymond J}",

year = "2014",

month = mar,

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doi = "10.1074/mcp.M113.031765",

language = "English",

volume = "13",

pages = "780--791",

journal = "Molecular & cellular proteomics : MCP",

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publisher = "American Society for Biochemistry and Molecular Biology Inc.",

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AU - Honarpour, Narimon

AU - Rose, Christopher M

AU - Brumbaugh, Justin

AU - Anderson, Jody

AU - Graham, Robert L J

AU - Sweredoski, Michael J

AU - Hess, Sonja

AU - Coon, Joshua J

AU - Deshaies, Raymond J

PY - 2014/3/1

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N2 - 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.

AB - 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.

KW - 3T3 Cells

KW - Animals

KW - Biocatalysis

KW - Cell Differentiation

KW - Cell Lineage

KW - Cullin Proteins/metabolism

KW - Embryonic Stem Cells/cytology

KW - F-Box Proteins/metabolism

KW - Holoenzymes/metabolism

KW - Humans

KW - Immunoprecipitation

KW - Mass Spectrometry

KW - Mice

KW - Myocytes, Cardiac/cytology

KW - Phosphoproteins/metabolism

KW - Phosphorylation

KW - Protein Binding

KW - Protein Phosphatase 2/metabolism

KW - Proteomics

KW - SKP Cullin F-Box Protein Ligases/metabolism

KW - Vascular Endothelial Growth Factor Receptor-2/metabolism

U2 - 10.1074/mcp.M113.031765

DO - 10.1074/mcp.M113.031765

M3 - Article

C2 - 24390425

SN - 1535-9476

VL - 13

SP - 780

EP - 791

JO - Molecular & cellular proteomics : MCP

JF - Molecular & cellular proteomics : MCP

IS - 3

ER -

F-box Protein FBXL16 Binds PP2A-B55α and Regulates Differentiation of Embryonic Stem Cells along the FLK1+ Lineage

Abstract

Keywords

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