Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts.
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.
Saharinen
Pipsa
P
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, P.O.B. 63, 00014 Helsinki, Finland.
Eklund
Lauri
L
Miettinen
Juho
J
Wirkkala
Riikka
R
Anisimov
Andrey
A
Winderlich
Mark
M
Nottebaum
Astrid
A
Vestweber
Dietmar
D
Deutsch
Urban
U
Koh
Gou Young
GY
Olsen
Bjorn R
BR
Alitalo
Kari
K
D042683:Angiopoietin-1 / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D008168:Lung / Q000166:cytology; D042810:Receptor, TIE-1 / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D011993:Recombinant Fusion Proteins; D042810:Receptor, TIE-1; D042787:Receptor, TIE-2