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Vascular Endothelial Receptor Tyrosine Phosphatase: Identification of Novel Substrates Related to Junctions and a Ternary Complex with EPHB4 and TIE2

View ORCID ProfileHannes C. A. Drexler  Correspondence email, Matthias Vockel, Christian Polaschegg, Maike Frye, Kevin Peters and Dietmar Vestweber  Correspondence email
Molecular & Cellular Proteomics October 1, 2019, First published on August 19, 2019, 18 (10) 2058-2077; https://doi.org/10.1074/mcp.RA119.001716
Hannes C. A. Drexler
Bioanalytical Mass Spectrometry, Max Planck Institute for Molecular Biomedicine, Röntgenstr. 20, 48149 Münster, Germany
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  • ORCID record for Hannes C. A. Drexler
  • For correspondence: hannes.drexler@mpi-muenster.mpg.de
Matthias Vockel
Department of Vascular Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstr. 20, 48149 Münster, GermanyInstitute of Human Genetics, University Hospital Münster, 48149 Münster, Germany
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Christian Polaschegg
Department of Vascular Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstr. 20, 48149 Münster, Germany
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Maike Frye
Department of Vascular Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstr. 20, 48149 Münster, Germany
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Kevin Peters
Aerpio Pharmaceuticals, Cincinnati, OH 45242
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Dietmar Vestweber
Department of Vascular Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstr. 20, 48149 Münster, Germany
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  • For correspondence: vestweb@mpi-muenster.mpg.de
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Graphical Abstract

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Highlights

  • Identification of the substrates profile of the endothelial phosphatase VE-PTP.

  • A large fraction of VE-PTP substrate candidates (29%) is cell junction related.

  • Tie-2 and EPHB are substrates which associate as ternary complex with VE-PTP.

Abstract

Vascular endothelial protein tyrosine phosphatase (VE-PTP, PTPRB) is a receptor type phosphatase that is crucial for the regulation of endothelial junctions and blood vessel development. We and others have shown recently that VE-PTP regulates vascular integrity by dephosphorylating substrates that are key players in endothelial junction stability, such as the angiopoietin receptor TIE2, the endothelial adherens junction protein VE-cadherin and the vascular endothelial growth factor receptor VEGFR2. Here, we have systematically searched for novel substrates of VE-PTP in endothelial cells by utilizing two approaches. First, we studied changes in the endothelial phosphoproteome on exposing cells to a highly VE-PTP-specific phosphatase inhibitor followed by affinity isolation and mass-spectrometric analysis of phosphorylated proteins by phosphotyrosine-specific antibodies. Second, we used a substrate trapping mutant of VE-PTP to pull down phosphorylated substrates in combination with SILAC-based quantitative mass spectrometry measurements. We identified a set of substrate candidates of VE-PTP, of which a remarkably large fraction (29%) is related to cell junctions. Several of those were found in both screens and displayed very high connectivity in predicted functional interaction networks. The receptor protein tyrosine kinase EPHB4 was the most prominently phosphorylated protein on VE-PTP inhibition among those VE-PTP targets that were identified by both proteomic approaches. Further analysis revealed that EPHB4 forms a ternary complex with VE-PTP and TIE2 in endothelial cells. VE-PTP controls the phosphorylation of each of these two tyrosine kinase receptors. Despite their simultaneous presence in a ternary complex, stimulating each of the receptors with their own specific ligand did not cross-activate the respective partner receptor. Our systematic approach has led to the identification of novel substrates of VE-PTP, of which many are relevant for the control of cellular junctions further promoting the importance of VE-PTP as a key player of junctional signaling.

  • substrate identification
  • cell adhesion
  • cell-cell interactions
  • tyrosine kinases
  • phosphorylation
  • immunoaffinity
  • protein complex analysis
  • protein phosphatases
  • substrate trapping

Footnotes

  • Author contributions: H.C.A.D., M.V., C.P., and D.V. designed research; H.C.A.D., M.V., C.P., and M.F. performed research; H.C.A.D., M.V., C.P., and D.V. analyzed data; H.C.A.D., M.V., C.P., K.P., and D.V. wrote the paper; K.P. contributed new reagents/analytic tools.

  • ↵* This work was supported by funds from the Deutsche Forschungsgemeinschaft (SFB1348, B1) (D.V.) and from the Max Planck Society and was performed as part of the Deutsche Forschungsgemeinschaft Clusters of Excellence Cells in Motion program.

  • ↵Embedded Image This article contains supplemental Figures and Tables.

  • Received August 6, 2019.
  • © 2019 Drexler et al.

Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

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Vascular Endothelial Receptor Tyrosine Phosphatase: Identification of Novel Substrates Related to Junctions and a Ternary Complex with EPHB4 and TIE2
Hannes C. A. Drexler, Matthias Vockel, Christian Polaschegg, Maike Frye, Kevin Peters, Dietmar Vestweber
Molecular & Cellular Proteomics October 1, 2019, First published on August 19, 2019, 18 (10) 2058-2077; DOI: 10.1074/mcp.RA119.001716

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Vascular Endothelial Receptor Tyrosine Phosphatase: Identification of Novel Substrates Related to Junctions and a Ternary Complex with EPHB4 and TIE2
Hannes C. A. Drexler, Matthias Vockel, Christian Polaschegg, Maike Frye, Kevin Peters, Dietmar Vestweber
Molecular & Cellular Proteomics October 1, 2019, First published on August 19, 2019, 18 (10) 2058-2077; DOI: 10.1074/mcp.RA119.001716
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Molecular & Cellular Proteomics: 18 (10)
Molecular & Cellular Proteomics
Vol. 18, Issue 10
1 Oct 2019
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