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Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP.

Publication ,  Journal Article
Souma, T; Thomson, BR; Heinen, S; Carota, IA; Yamaguchi, S; Onay, T; Liu, P; Ghosh, AK; Li, C; Eremina, V; Hong, Y-K; Economides, AN; Jin, J ...
Published in: Proc Natl Acad Sci U S A
February 6, 2018

The angiopoietin (ANGPT)-TIE2/TEK signaling pathway is essential for blood and lymphatic vascular homeostasis. ANGPT1 is a potent TIE2 activator, whereas ANGPT2 functions as a context-dependent agonist/antagonist. In disease, ANGPT2-mediated inhibition of TIE2 in blood vessels is linked to vascular leak, inflammation, and metastasis. Using conditional knockout studies in mice, we show TIE2 is predominantly activated by ANGPT1 in the cardiovascular system and by ANGPT2 in the lymphatic vasculature. Mechanisms underlying opposing actions of ANGPT2 in blood vs. lymphatic endothelium are poorly understood. Here we show the endothelial-specific phosphatase VEPTP (vascular endothelial protein tyrosine phosphatase) determines TIE2 response to ANGPT2. VEPTP is absent from lymphatic endothelium in mouse in vivo, permitting ANGPT2/TIE2-mediated lymphangiogenesis. Inhibition of VEPTP converts ANGPT2 into a potent TIE2 activator in blood endothelium. Our data support a model whereby VEPTP functions as a rheostat to modulate ANGPT2 ligand effect on TIE2.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

February 6, 2018

Volume

115

Issue

6

Start / End Page

1298 / 1303

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3
  • Receptor, TIE-2
  • Mice, Transgenic
  • Mice, Knockout
  • Humans
  • HEK293 Cells
  • Endothelium, Vascular
  • Endothelium, Lymphatic
  • Animals
 

Citation

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Souma, T., Thomson, B. R., Heinen, S., Carota, I. A., Yamaguchi, S., Onay, T., … Quaggin, S. E. (2018). Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. Proc Natl Acad Sci U S A, 115(6), 1298–1303. https://doi.org/10.1073/pnas.1714446115
Souma, Tomokazu, Benjamin R. Thomson, Stefan Heinen, Isabel Anna Carota, Shinji Yamaguchi, Tuncer Onay, Pan Liu, et al. “Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP.Proc Natl Acad Sci U S A 115, no. 6 (February 6, 2018): 1298–1303. https://doi.org/10.1073/pnas.1714446115.
Souma T, Thomson BR, Heinen S, Carota IA, Yamaguchi S, Onay T, et al. Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):1298–303.
Souma, Tomokazu, et al. “Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP.Proc Natl Acad Sci U S A, vol. 115, no. 6, Feb. 2018, pp. 1298–303. Pubmed, doi:10.1073/pnas.1714446115.
Souma T, Thomson BR, Heinen S, Carota IA, Yamaguchi S, Onay T, Liu P, Ghosh AK, Li C, Eremina V, Hong Y-K, Economides AN, Vestweber D, Peters KG, Jin J, Quaggin SE. Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):1298–1303.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

February 6, 2018

Volume

115

Issue

6

Start / End Page

1298 / 1303

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3
  • Receptor, TIE-2
  • Mice, Transgenic
  • Mice, Knockout
  • Humans
  • HEK293 Cells
  • Endothelium, Vascular
  • Endothelium, Lymphatic
  • Animals