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 journalArticlepeer-review

20 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • General

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