Tie2-R849W mutant in venous malformations chronically activates a functional STAT1 to modulate gene expression

Hsiao Tang Hu, Yi Hsien Huang, Yi Ann Chang, Chien Kuo Lee, Meei Jyh Jiang, Li Wha Wu

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Tie2 is an endothelial receptor tyrosine kinase. An amino-acid substitution of tryptophan for arginine at residue 849 (Tie2-R849W) leads to a ligand-independent activation of its kinase activity. This mutation has been associated with familial venous malformations (VMs), manifested by variable thickness or lack of smooth-muscle cells in the veins of patient lesions. The underlying mechanism for Tie2-R849W action in endothelial cells remains elusive. In this study, we used adenoviral infection to differentiate the effects of ectopic Tie2 (wild type, kinase-dead K855A, or constitutively active R849W) expression on endothelial cellular behaviors and Tie2-mediated downstream targets. Ectopic Tie2 reduced endothelial cell proliferation and serum withdrawal-induced apoptosis, while stimulating migration. When comparing R849W with K855A and its wild-type counterpart, a functional tyrosine kinase activity was required only for migration, and constitutively active Tie2-R849W conferred highest resistance to serum-induced apoptosis, but lowest ability to maintain tube-like structures formed on Matrigel. We further demonstrated that Tie2-R849W chronically induced STAT1 tyrosine phosphorylation and the promoter activity of STAT1-responsive IFN-regulatory factor 1 (IRF1). Although STAT1 phosphorylation required JNK and p38MAPK activation, only JNK activation was essential for IRF1 promoter activation by Tie2-R849W. Additional studies are needed to study the role of STAT1 activation in VMs.

Original languageEnglish
Pages (from-to)2325-2333
Number of pages9
JournalJournal of Investigative Dermatology
Volume128
Issue number9
DOIs
Publication statusPublished - 2008 Sep

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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