This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jones, N. Articles by Dumont, D. J. Search for Related Content PubMed PubMed Citation Articles by Jones, N. Articles by Dumont, D. J.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, April 2003, p. 2658-2668, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2658-2668.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Unique Autophosphorylation Site on Tie2/Tek Mediates Dok-R Phosphotyrosine Binding Domain Binding and Function

Nina Jones,^1, Stephen H. Chen,^1,2 Celina Sturk,^1,2 Zubin Master,^1,2 Jennifer Tran,^1,3 Robert S. Kerbel,^1,2,3 and Daniel J. Dumont^1,2,4*

Division of Molecular and Cellular Biology Research, Sunnybrook and Women's College Research Institute,¹ Toronto-Sunnybrook Regional Cancer Center, Toronto, Ontario M4N 3M5,⁴ Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9,² Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada³

Received 11 September 2002/ Returned for modification 29 October 2002/ Accepted 22 January 2003

Tie2/Tek is an endothelial cell receptor tyrosine kinase that induces signal transduction pathways involved in cell migration upon angiopoietin-1 (Ang1) stimulation. To address the importance of the various tyrosine residues of Tie2 in signal transduction, we generated a series of Tie2 mutants and examined their signaling properties. Using this approach in conjunction with a phosphorylation state-specific antibody, we identified tyrosine residue 1106 on Tie2 as an Ang1-dependent autophosphorylation site that mediates binding and phosphorylation of the downstream-of-kinase-related (Dok-R) docking protein. This tyrosine residue is contained within a unique interaction motif for the phosphotyrosine binding domain of Dok-R, and the pleckstrin homology domain of Dok-R further contributes to Tie2 binding in a phosphatidylinositol 3'-kinase-dependent manner. Introduction of a Tie2 mutant lacking tyrosine residue 1106 into endothelial cells interferes with Dok-R phosphorylation in response to Ang1. Furthermore, this mutant is unable to restore the migration potential of endothelial cells derived from mice lacking Tie2. Together, these findings demonstrate that tyrosine residue 1106 on Tie2 is critical for coupling downstream cell migration signal transduction pathways with Ang1 stimulation in endothelial cells.

Present address: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario M5G 1X5, Canada.

This article has been cited by other articles:

• Bogdanovic, E., Nguyen, V. P. K. H., Dumont, D. J. (2006). Activation of Tie2 by angiopoietin-1 and angiopoietin-2 results in their release and receptor internalization. J. Cell Sci. 119: 3551-3560 [Abstract] [Full Text]  
• Kim, Y. M., Kim, K. E., Koh, G. Y., Ho, Y.-S., Lee, K.-J. (2006). Hydrogen peroxide produced by angiopoietin-1 mediates angiogenesis.. Cancer Res. 66: 6167-6174 [Abstract] [Full Text]  
• Brindle, N. P.J., Saharinen, P., Alitalo, K. (2006). Signaling and Functions of Angiopoietin-1 in Vascular Protection. Circ. Res. 98: 1014-1023 [Abstract] [Full Text]  
• Boulay, I., Nemorin, J.-G., Duplay, P. (2005). Phosphotyrosine Binding-Mediated Oligomerization of Downstream of Tyrosine Kinase (Dok)-1 and Dok-2 Is Involved in CD2-Induced Dok Phosphorylation. J. Immunol. 175: 4483-4489 [Abstract] [Full Text]  
• Kanda, S., Miyata, Y., Mochizuki, Y., Matsuyama, T., Kanetake, H. (2005). Angiopoietin 1 Is Mitogenic for Cultured Endothelial Cells. Cancer Res. 65: 6820-6827 [Abstract] [Full Text]  
• Tachibana, K., Jones, N., Dumont, D. J., Puri, M. C., Bernstein, A. (2005). Selective Role of a Distinct Tyrosine Residue on Tie2 in Heart Development and Early Hematopoiesis. Mol. Cell. Biol. 25: 4693-4702 [Abstract] [Full Text]  
• Voskas, D., Jones, N., Van Slyke, P., Sturk, C., Chang, W., Haninec, A., Babichev, Y. O., Tran, J., Master, Z., Chen, S., Ward, N., Cruz, M., Jones, J., Kerbel, R. S., Jothy, S., Dagnino, L., Arbiser, J., Klement, G., Dumont, D. J. (2005). A Cyclosporine-Sensitive Psoriasis-Like Disease Produced in Tie2 Transgenic Mice. Am. J. Pathol. 166: 843-855 [Abstract] [Full Text]  
• Kappert, K., Peters, K. G., Bohmer, F. D., Ostman, A. (2005). Tyrosine phosphatases in vessel wall signaling. Cardiovasc Res 65: 587-598 [Abstract] [Full Text]  
• Kido, M., Du, L., Sullivan, C. C., Deutsch, R., Jamieson, S. W., Thistlethwaite, P. A. (2005). Gene transfer of a TIE2 receptor antagonist prevents pulmonary hypertension in rodents. J. Thorac. Cardiovasc. Surg. 129: 268-276 [Abstract] [Full Text]  
• Peters, K. G., Kontos, C. D., Lin, P. C., Wong, A. L., Rao, P., Huang, L., Dewhirst, M. W., Sankar, S. (2004). Functional Significance of Tie2 Signaling in the Adult Vasculature. Recent Prog Horm Res 59: 51-71 [Abstract] [Full Text]  
• Master, Z., Tran, J., Bishnoi, A., Chen, S. H., Ebos, J. M. L., Van Slyke, P., Kerbel, R. S., Dumont, D. J. (2003). Dok-R Binds c-Abl and Regulates Abl Kinase Activity and Mediates Cytoskeletal Reorganization. J. Biol. Chem. 278: 30170-30179 [Abstract] [Full Text]