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

A critical role for Tiel , 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 Tiel. We report here that Angl induces Tiel phosphorylation in endothelial cells. Tiel phosphorylation was, however, Tie2 dependent because 1 ) Angl failed to induce Tiel phosphorylation when Tie2 was down‐regulated in endothelial cells;2) Tiel phosphorylation was induced in the absence of Angl by either a constitutively active form of Tie2 or a Tie2 agonistic antibody; 3 ) in HEK 293 cells Angl phosphorylated a form of Tiel without kinase activity when coexpressed with Tie2, and Angl failed to phos‐phorylate Tiel when coexpressed with kinase‐defective Tie2. Angl‐mediated AKT and 42/44MAPK phosphor‐ylation is predominantly Tie2 mediated, and Tiel down‐regulates this pathway. Finally, based on a battery of in vitro and in vivo data, we show that a main role for Tiel 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 Tiel 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.—Yuan, H. T., Venkatesha, S., Chan, B., Deutsch, U., Mam‐moto, T., Sukhatme, V. P., Woolf, A. S., Karumanchi, S. A. Activation of the orphan endothelial receptor Tiel modifies Tie2‐mediated intracellular signaling and cell survival. FASEB J. 2l, 3l7l–3l83 (2007)