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J Biol Chem. 2013 May 3;288(18):12469-77. doi: 10.1074/jbc.M112.433979. Epub 2013 Mar 15.

Ligand-independent Tie2 dimers mediate kinase activity stimulated by high dose angiopoietin-1.

Author information

1
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita-shi, Osaka 565-0871, Japan.

Abstract

Tie2 is a receptor tyrosine kinase expressed on vascular endothelial cells (ECs). It has dual roles in promoting angiogenesis and stabilizing blood vessels, and it has been suggested that Tie2 forms dimers and/or oligomers in the absence of angiopoietin-1 (Ang1); however, the mechanism of ligand-independent dimerization of Tie2 and its biological significance have not been clarified. Using a bimolecular fluorescence complementation assay and a kinase-inactive Tie2 mutant, we show here that ligand-independent Tie2 dimerization is induced without Tie2 phosphorylation. Moreover, based on the fact that Tie1 never forms heterodimers with Tie2 in the absence of Ang1 despite having high amino acid sequence homology with Tie2, we searched for ligand-independent dimerization domains of Tie2 by reference to the difference with Tie1. We found that the YIA sequence of the intracellular domain of Tie2 corresponding to the LAS sequence in Tie1 is essential for this dimerization. When the YIA sequence was replaced by LAS in Tie2 (Tie2YIA/LAS), ligand-independent dimer was not formed in the absence of Ang1. When activation of Tie2YIA/LAS was induced by a high dose of Ang1, phosphorylation of Tie2 was limited compared with wild-type Tie2, resulting in retardation of activation of Erk downstream of Tie2. Therefore, these data suggest that ligand-independent dimerization of Tie2 is essential for a strong response upon stimulation with high dose Ang1.

KEYWORDS:

Angiogenesis; Angiopoietin; Endothelial Cell; Imaging; Tyrosine Protein Kinase (Tyrosine Kinase); Vascular Biology

PMID:
23504320
PMCID:
PMC3642295
DOI:
10.1074/jbc.M112.433979
[Indexed for MEDLINE]
Free PMC Article

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