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J. Biol. Chem., Vol. 281, Issue 38, 28408-28414, September 22, 2006

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Structure of the Extracellular Domain of Tie Receptor Tyrosine Kinases and Localization of the Angiopoietin-binding Epitope^*

Philip R. Macdonald¹, Pavlos Progias¹, Barbara Ciani¹, Sanjai Patel, Ulrike Mayer, Michel O. Steinmetz^¶, and Richard A. Kammerer²

From the Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom, Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich NR14 7TJ, United Kingdom, and ^¶Biomolecular Research, Structural Biology, Paul Scherrer Insititut, CH-5232 Villigen PSI, Switzerland

Angiogenesis is essential for tissue repair and regeneration during wound healing but also plays important roles in many pathological processes including tumor growth and metastasis. The receptor protein tyrosine kinase Tie2 and its ligands, the angiopoietins, have important functions in the regulation of angiogenesis. Here, we report a detailed structural and functional characterization of the extracellular region of Tie2. Sequence analysis of the extracellular domain revealed an additional immunoglobulin-like domain resulting in a tandem repeat of immunoglobulin-like domains at the N terminus of the protein. The same domain organization was also found for the Tie1 receptor that shares a high degree of homology with Tie2. Based on structural similarities to other receptor tyrosine kinases and cell adhesion molecules, we demonstrate that the N-terminal two immunoglobulin-like domains of Tie2 harbor the angiopoietin-binding site. Using transmission electron microscopy we furthermore show that the extracellular domain of Tie receptors consists of a globular head domain and a short rod-like stalk that probably forms a spacer between the cell surface and the angiopoietin-binding site. Mutational analysis demonstrated that the head domain consists of the three immunoglobulin-like domains and the three epidermal growth factor-like modules and that the stalk is formed by the three fibronectin type III repeats. These findings might be of particular interest for drug development because Tie receptors are potential targets for treatment of angiogenesis-associated diseases.

Received for publication, May 31, 2006 , and in revised form, July 18, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² A Wellcome Trust senior research fellow. To whom correspondence should be addressed: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Bldg., Oxford Rd., Manchester M13 9PT, United Kingdom. Tel.: 44-161-275-1504; Fax: 44-161-275-1505; E-mail: richard.kammerer{at}manchester.ac.uk.

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