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Published 25 April 2005. doi:10.1083/jcb.200411105
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 169, Number 2, 239-243
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Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2



Pipsa Saharinen1, Katja Kerkelä1, Niklas Ekman1, Marie Marron2, Nicholas Brindle2, Gyun Min Lee3, Hellmut Augustin4, Gou Young Koh3, and Kari Alitalo1

1 Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland
2 Department of Cardiovascular Sciences, University of Leicester, Leicester LE2 7LX, UK
3 Department of Biological Sciences, Biomedical Center, Korea Advanced Institute of Science and Technology, Guseong-dong, Daejeon, 305-70, Republic of Korea
4 Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center Freiburg, D-79106 Freiburg, Germany

Correspondence to Kari Alitalo: Kari.Alitalo{at}Helsinki.fi


Abstract

The Tie1 receptor tyrosine kinase was isolated over a decade ago, but so far no ligand has been found to activate this receptor. Here, we have examined the potential of angiopoietins, ligands for the related Tie2 receptor, to mediate Tie1 activation. We show that a soluble Ang1 chimeric protein, COMP-Ang1, stimulates Tie1 phosphorylation in endothelial cells with similar kinetics and angiopoietin dose dependence when compared with Tie2. The phosphorylation of overexpressed Tie1 was weakly induced by COMP-Ang1 also in transfected cells that do not express Tie2. When cotransfected, Tie2 formed heteromeric complexes with Tie1, enhanced Tie1 activation, and induced phosphorylation of a kinase-inactive Tie1 in a ligand-dependent manner. Tie1 phosphorylation was also induced by native Ang1 and Ang4, although less efficiently than with COMP-Ang1. In conclusion, we show that Tie1 phosphorylation is induced by multiple angiopoietin proteins and that the activation is amplified via Tie2. These results should be important in dissecting the signal transduction pathways and biological functions of Tie1.

N. Ekman's present address is Cancer Cell Circuitry Laboratory, Department of Biomedicine/Biochemistry, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.

M. Marron's present address is Cardiovascular Research Group, Division of Clinical Sciences, Northern General Hospital, University of Sheffield, Sheffield S5 7AU, UK.

Abbreviations used in this paper: BEC, blood vascular endothelial cell; DTSSP, 3,3'-dithiobis[sulfosuccinimidylpropionate]; E, embryonic day; HUVEC, human umbilical vein endothelial cell; LEC, lymphatic endothelial cell.


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