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

Tomokazu Souma, Benjamin R. Thomson, Stefan Heinen, Isabel Anna Carota, Shinji Yamaguchi, Tuncer Onay, Pan Liu, Asish K. Ghosh, Chengjin Li, Vera Eremina, Young Kwon Hong, Aris N. Economides, Dietmar Vestweber, Kevin G. Peters, Jing Jin, Susan E. Quaggina*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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 modelwhereby VEPTP functions as a rheostat to modulate ANGPT2 ligand effect on TIE2.

Original languageEnglish (US)
Pages (from-to)1298-1303
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number6
DOIs
StatePublished - Feb 6 2018

Fingerprint

Class 3 Receptor-Like Protein Tyrosine Phosphatases
Angiopoietin-2
Phosphoric Monoester Hydrolases
Lymphatic Endothelium
Blood Vessels
Angiopoietins
Lymphangiogenesis
Cardiovascular System
Endothelium
Homeostasis
Neoplasm Metastasis
Ligands
Inflammation

Keywords

  • Angiogenesis
  • Angiopoietin-TIE2 pathway
  • Lymphangiogenesis
  • Tyrosine kinase
  • VEPTP

ASJC Scopus subject areas

  • General

Cite this

Souma, Tomokazu ; Thomson, Benjamin R. ; Heinen, Stefan ; Carota, Isabel Anna ; Yamaguchi, Shinji ; Onay, Tuncer ; Liu, Pan ; Ghosh, Asish K. ; Li, Chengjin ; Eremina, Vera ; Hong, Young Kwon ; Economides, Aris N. ; Vestweber, Dietmar ; Peters, Kevin G. ; Jin, Jing ; Quaggina, Susan E. / Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 6. pp. 1298-1303.
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abstract = "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 modelwhereby VEPTP functions as a rheostat to modulate ANGPT2 ligand effect on TIE2.",
keywords = "Angiogenesis, Angiopoietin-TIE2 pathway, Lymphangiogenesis, Tyrosine kinase, VEPTP",
author = "Tomokazu Souma and Thomson, {Benjamin R.} and Stefan Heinen and Carota, {Isabel Anna} and Shinji Yamaguchi and Tuncer Onay and Pan Liu and Ghosh, {Asish K.} and Chengjin Li and Vera Eremina and Hong, {Young Kwon} and Economides, {Aris N.} and Dietmar Vestweber and Peters, {Kevin G.} and Jing Jin and Quaggina, {Susan E.}",
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doi = "10.1073/pnas.1714446115",
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Souma, T, Thomson, BR, Heinen, S, Carota, IA, Yamaguchi, S, Onay, T, Liu, P, Ghosh, AK, Li, C, Eremina, V, Hong, YK, Economides, AN, Vestweber, D, Peters, KG, Jin, J & Quaggina, SE 2018, 'Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 6, pp. 1298-1303. https://doi.org/10.1073/pnas.1714446115

Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. / Souma, Tomokazu; Thomson, Benjamin R.; Heinen, Stefan; Carota, Isabel Anna; Yamaguchi, Shinji; Onay, Tuncer; Liu, Pan; Ghosh, Asish K.; Li, Chengjin; Eremina, Vera; Hong, Young Kwon; Economides, Aris N.; Vestweber, Dietmar; Peters, Kevin G.; Jin, Jing; Quaggina, Susan E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 6, 06.02.2018, p. 1298-1303.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP

AU - Souma, Tomokazu

AU - Thomson, Benjamin R.

AU - Heinen, Stefan

AU - Carota, Isabel Anna

AU - Yamaguchi, Shinji

AU - Onay, Tuncer

AU - Liu, Pan

AU - Ghosh, Asish K.

AU - Li, Chengjin

AU - Eremina, Vera

AU - Hong, Young Kwon

AU - Economides, Aris N.

AU - Vestweber, Dietmar

AU - Peters, Kevin G.

AU - Jin, Jing

AU - Quaggina, Susan E.

PY - 2018/2/6

Y1 - 2018/2/6

N2 - 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 modelwhereby VEPTP functions as a rheostat to modulate ANGPT2 ligand effect on TIE2.

AB - 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 modelwhereby VEPTP functions as a rheostat to modulate ANGPT2 ligand effect on TIE2.

KW - Angiogenesis

KW - Angiopoietin-TIE2 pathway

KW - Lymphangiogenesis

KW - Tyrosine kinase

KW - VEPTP

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U2 - 10.1073/pnas.1714446115

DO - 10.1073/pnas.1714446115

M3 - Article

VL - 115

SP - 1298

EP - 1303

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 6

ER -