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Molecular and Cellular Biology, April 2009, p. 2011-2022, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01472-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Angiopoietin 2 Is a Partial Agonist/Antagonist of Tie2 Signaling in the Endothelium {triangledown} ,{dagger}

Hai Tao Yuan,* Eliyahu V. Khankin, S. Ananth Karumanchi, and Samir M. Parikh

Division of Molecular and Vascular Medicine, Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215

Received 19 September 2008/ Returned for modification 16 December 2008/ Accepted 3 February 2009

Angiopoietin 2 (Ang2) was originally shown to be a competitive antagonist for Ang1 of the receptor tyrosine kinase Tie2 in endothelial cells (ECs). Since then, reports have conflicted on whether Ang2 is an agonist or antagonist of Tie2. Here we show that Ang2 functions as an agonist when Ang1 is absent but as a dose-dependent antagonist when Ang1 is present. Exogenous Ang2 activates Tie2 and the promigratory, prosurvival PI3K/Akt pathway in ECs but with less potency and lower affinity than exogenous Ang1. ECs produce Ang2 but not Ang1. This endogenous Ang2 maintains Tie2, phosphatidylinositol 3-kinase, and Akt activities, and it promotes EC survival, migration, and tube formation. However, when ECs are stimulated with Ang1 and Ang2, Ang2 dose-dependently inhibits Ang1-induced Tie2 phosphorylation, Akt activation, and EC survival. We conclude that Ang2 is both an agonist and an antagonist of Tie2. Although Ang2 is a weaker agonist than Ang1, endogenous Ang2 maintains a level of Tie2 activation that is critical to a spectrum of EC functions. These findings may reconcile disparate reports of Ang2's effect on Tie2, impact our understanding of endogenous receptor tyrosine kinase signal transduction mechanisms, and affect how Ang2 and Tie2 are targeted under conditions such as sepsis and cancer.

* Corresponding author. Mailing address: Molecular and Vascular Medicine, Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, RN-380G, Boston, MA 02215. Phone: (617) 667-2208. Fax: (617) 667-2913. E-mail: hyuan{at}bidmc.harvard.edu

{triangledown} Published ahead of print on 17 February 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2009, p. 2011-2022, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01472-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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