Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2.
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.
Saharinen
Pipsa
P
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, University of Helsinki, Finland.
Kerkelä
Katja
K
Ekman
Niklas
N
Marron
Marie
M
Brindle
Nicholas
N
Lee
Gyun Min
GM
Augustin
Hellmut
H
Koh
Gou Young
GY
Alitalo
Kari
K
D042682:Angiopoietins / Q000235:genetics / Q000494:pharmacology*; D002460:Cell Line; D042783:Endothelial Cells / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects*; D015870:Gene Expression; D006801:Humans; D010766:Phosphorylation; D042810:Receptor, TIE-1 / Q000235:genetics / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
D042682:Angiopoietins; D011993:Recombinant Fusion Proteins; D042810:Receptor, TIE-1; D042787:Receptor, TIE-2