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

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 2002, p. 1704-1713, Vol. 22, No. 6
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.6.1704-1713.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Endothelial Receptor Tyrosine Kinase Tie1 Activates Phosphatidylinositol 3-Kinase and Akt To Inhibit Apoptosis

Christopher D. Kontos,1,2* Eugene H. Cha,1 John D. York,2 and Kevin G. Peters3

Department of Medicine, Division of Cardiology,1 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710,2 Procter & Gamble Health Care Research Center, Mason, Ohio 45040-80063

Received 23 March 2001/ Returned for modification 5 June 2001/ Accepted 24 December 2001

Tie1 is an orphan receptor tyrosine kinase that is expressed almost exclusively in endothelial cells and that is required for normal embryonic vascular development. Genetic studies suggest that Tie1 promotes endothelial cell survival, but other studies have suggested that the Tie1 kinase has little to no activity, and Tie1-mediated signaling pathways are unknown. To begin to study Tie1 signaling, a recombinant glutathione S-transferase (GST)-Tie1 kinase fusion protein was produced in insect cells and found to be autophosphorylated in vitro. GST-Tie1 but not a kinase-inactive mutant associated with a recombinant p85 SH2 domain protein in vitro, suggesting that Tie1 might signal through phosphatidylinositol (PI) 3-kinase. To study Tie1 signaling in a cellular context, a c-fms-Tie1 chimeric receptor (fTie1) was expressed in NIH 3T3 cells. Ligand stimulation of fTie1 resulted in Tie1 autophosphorylation and downstream activation of PI 3-kinase and Akt. Stimulation of fTie1-expressing cells potently inhibited UV irradiation-induced apoptosis in a PI 3-kinase-dependent manner. Moreover, both Akt phosphorylation and inhibition of apoptosis were abrogated by mutation of tyrosine 1113 to phenylalanine, suggesting that this residue is an important PI 3-kinase binding site. These findings are the first biochemical demonstration of a signal transduction pathway and corresponding cellular function for Tie1, and the antiapoptotic effect of Tie1 is consistent with the results of previous genetic studies.


* Corresponding author. Mailing address: Box 3629, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-2119. Fax: (919) 684-8591. E-mail: cdkontos{at}duke.edu.


Molecular and Cellular Biology, March 2002, p. 1704-1713, Vol. 22, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.6.1704-1713.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.




This article has been cited by other articles:

  • Yuan, H. T., Venkatesha, S., Chan, B., Deutsch, U., Mammoto, T., Sukhatme, V. P., Woolf, A. S., Karumanchi, S. A. (2007). Activation of the orphan endothelial receptor Tie1 modifies Tie2-mediated intracellular signaling and cell survival. FASEB J. 21: 3171-3183 [Abstract] [Full Text]  
  • Liu, D., Si, H., Reynolds, K. A., Zhen, W., Jia, Z., Dillon, J. S. (2007). Dehydroepiandrosterone Protects Vascular Endothelial Cells against Apoptosis through a G{alpha}i Protein-Dependent Activation of Phosphatidylinositol 3-Kinase/Akt and Regulation of Antiapoptotic Bcl-2 Expression. Endocrinology 148: 3068-3076 [Abstract] [Full Text]  
  • Harfouche, R., Hussain, S. N. A. (2006). Signaling and regulation of endothelial cell survival by angiopoietin-2. Am. J. Physiol. Heart Circ. Physiol. 291: H1635-H1645 [Abstract] [Full Text]  
  • Macdonald, P. R., Progias, P., Ciani, B., Patel, S., Mayer, U., Steinmetz, M. O., Kammerer, R. A. (2006). Structure of the Extracellular Domain of Tie Receptor Tyrosine Kinases and Localization of the Angiopoietin-binding Epitope. J. Biol. Chem. 281: 28408-28414 [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]  
  • Saharinen, P., Kerkela, K., Ekman, N., Marron, M., Brindle, N., Lee, G. M., Augustin, H., Koh, G. Y., Alitalo, K. (2005). Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. JCB 169: 239-243 [Abstract] [Full Text]  
  • Yang, W. J., Yang, D. D., Na, S., Sandusky, G. E., Zhang, Q., Zhao, G. (2005). Dicer Is Required for Embryonic Angiogenesis during Mouse Development. J. Biol. Chem. 280: 9330-9335 [Abstract] [Full Text]  
  • Huang, J., Niu, X.-L., Pippen, A. M., Annex, B. H., Kontos, C. D. (2005). Adenovirus-Mediated Intraarterial Delivery of PTEN Inhibits Neointimal Hyperplasia. Arterioscler. Thromb. Vasc. Bio. 25: 354-358 [Abstract] [Full Text]  
  • Porat, R. M., Grunewald, M., Globerman, A., Itin, A., Barshtein, G., Alhonen, L., Alitalo, K., Keshet, E. (2004). Specific Induction of tie1 Promoter by Disturbed Flow in Atherosclerosis-Prone Vascular Niches and Flow-Obstructing Pathologies. Circ. Res. 94: 394-401 [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]  
  • Niu, X.-L., Peters, K. G., Kontos, C. D. (2002). Deletion of the Carboxyl Terminus of Tie2 Enhances Kinase Activity, Signaling, and Function. EVIDENCE FOR AN AUTOINHIBITORY MECHANISM. J. Biol. Chem. 277: 31768-31773 [Abstract] [Full Text]