Article abstract
Nature Cell Biology 10, 527 - 537 (2008)
Published online: 20 April 2008 | doi:10.1038/ncb1715
Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell–cell and cell–matrix contacts
Pipsa Saharinen1,7, Lauri Eklund2,6,7, Juho Miettinen1, Riikka Wirkkala2, Andrey Anisimov1, Mark Winderlich3, Astrid Nottebaum3, Dietmar Vestweber3, Urban Deutsch4, Gou Young Koh5, Bjorn R. Olsen6 & Kari Alitalo1
Abstract
The receptor tyrosine kinase Tie2, and its activating ligand Angiopoietin-1 (Ang1), are required for vascular remodelling and vessel integrity, whereas Ang2 may counteract these functions. However, it is not known how Tie2 transduces these different signals. Here, we show that Ang1 induces unique Tie2 complexes in mobile and confluent endothelial cells. Matrix-bound Ang1 induced cell adhesion, motility and Tie2 activation in cell–matrix contacts that became translocated to the trailing edge in migrating endothelial cells. In contrast, in contacting cells Ang1 induced Tie2 translocation to cell–cell contacts and the formation of homotypic Tie2–Tie2 trans-associated complexes that included the vascular endothelial phosphotyrosine phosphatase, leading to inhibition of paracellular permeability. Distinct signalling proteins were preferentially activated by Tie2 in the cell–matrix and cell–cell contacts, where Ang2 inhibited Ang1-induced Tie2 activation. This novel type of cellular microenvironment-dependent receptor tyrosine kinase activation may explain some of the effects of angiopoietins in angiogenesis and vessel stabilization.
- Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, P.O.B. 63, 00014 Helsinki, Finland.
- Oulu Centre for Cell-Matrix Research, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, University of Oulu, P.O.B. 5000, 90014 University of Oulu, Finland.
- Max-Planck-Institute of Molecular Biomedicine, Roentgenstr, D-48149 Muenster, Germany.
- Theodor Kocher Institute, University of Berne, Freiestrasse 1, CH-3012 Bern, Switzerland.
- National Research Laboratory of Vascular Biology and Biomedical Center and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1, Guseong-dong, Daejeon 305-701, Republic of Korea.
- Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA.
- These authors contributed equally to this work.
Correspondence to: Kari Alitalo1 e-mail: Kari.Alitalo@Helsinki.fi
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