Activation of the orphan endothelial receptor Tie1 modifies Tie2-mediated intracellular signaling and cell survival. FASEB J 2007 Oct;21(12):3171-83
Date
05/17/2007Pubmed ID
17504972DOI
10.1096/fj.07-8487comScopus ID
2-s2.0-35248867961 (requires institutional sign-in at Scopus site) 89 CitationsAbstract
A critical role for Tie1, an orphan endothelial receptor, in blood vessel morphogenesis has emerged from mutant mouse studies. Moreover, it was recently demonstrated that certain angiopoietin (Ang) family members can activate Tie1. We report here that Ang1 induces Tie1 phosphorylation in endothelial cells. Tie1 phosphorylation was, however, Tie2 dependent because 1) Ang1 failed to induce Tie1 phosphorylation when Tie2 was down-regulated in endothelial cells; 2) Tie1 phosphorylation was induced in the absence of Ang1 by either a constitutively active form of Tie2 or a Tie2 agonistic antibody; 3) in HEK 293 cells Ang1 phosphorylated a form of Tie1 without kinase activity when coexpressed with Tie2, and Ang1 failed to phosphorylate Tie1 when coexpressed with kinase-defective Tie2. Ang1-mediated AKT and 42/44MAPK phosphorylation is predominantly Tie2 mediated, and Tie1 down-regulates this pathway. Finally, based on a battery of in vitro and in vivo data, we show that a main role for Tie1 is to modulate blood vessel morphogenesis by virtue of its ability to down-regulate Tie2-driven signaling and endothelial survival. Our new observations help to explain why Tie1 null embryos have increased capillary densities in several organ systems. The experiments also constitute a paradigm for how endothelial integrity is fine-tuned by the interplay between closely related receptors by a single growth factor.
Author List
Yuan HT, Venkatesha S, Chan B, Deutsch U, Mammoto T, Sukhatme VP, Woolf AS, Karumanchi SAAuthor
Tadanori Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Angiopoietin-1Animals
Apoptosis
Blood Vessels
Caspase 3
Cell Line
Cell Survival
Embryo, Mammalian
Endothelial Cells
Enzyme Activation
Female
Humans
In Situ Nick-End Labeling
Male
Mice
Neovascularization, Physiologic
Phosphorylation
Proto-Oncogene Proteins c-akt
RNA, Small Interfering
Receptor, TIE-1
Receptor, TIE-2
Signal Transduction
Tissue Culture Techniques
