Activation of the orphan endothelial receptor Tie1 modifies Tie2-mediated intracellular signaling and cell survival

Yuan, Hai Tao; Venkatesha, Shivalingappa; Chan, Barden; Deutsch, Urban; Mammoto, Tadanori; Sukhatme, Vikas P; Woolf, Adrian S; Karumanchi, S Ananth (2007). Activation of the orphan endothelial receptor Tie1 modifies Tie2-mediated intracellular signaling and cell survival. FASEB journal, 21(12), pp. 3171-83. Bethesda, Md.: Federation of American Societies for Experimental Biology 10.1096/fj.07-8487com

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Deutsch, Urban

ISSN:

0892-6638

ISBN:

17504972

Publisher:

Federation of American Societies for Experimental Biology

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:52

Last Modified:

04 May 2014 23:15

Publisher DOI:

10.1096/fj.07-8487com

PubMed ID:

17504972

Web of Science ID:

000249781600018

URI:

https://boris.unibe.ch/id/eprint/22209 (FactScience: 32272)

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