Characterization and regulation of the receptor tyrosine kinase Tie-1 in platelets

The receptor tyrosine kinase Tie-1 is expressed predominantly on endothelia l cells where it has an essential role in blood vessel formation. Targeted disruption of the Tie-1 gene results in a lethal phenotype with severe disr uption to the normal integrity of the vasculature. In an examination of Tie -1 in vivo, we observed a significant pool of the receptor present in the c irculation associated with the platelet fraction. Western blotting reveals the platelet form of Tie-1 to be a protein of approximately 110 kDa, this c ontrasts with the 135/125-kDa doublet found in endothelial cells. Platelet activation results in increased surface expression of Tie-1. The closely re lated receptor tyrosine kinase Tie-2/Tek is not present in platelets. Endot helial Tie-1 undergoes metalloprotease-mediated ectodomain cleavage in resp onse to phorbol ester and other agonists. Tie-1 cleavage leads to release o f the extracellular domain and generation of a cell-associated intracellula r domain with signalling capacity. The potential for cleavage was investiga ted in platelets. In contrast to endothelial Tie-1, phorbol ester does not stimulate truncation of the platelet receptor, suggesting these cells lack one or more components of the regulated metalloprotease system controlling Tie-1. These data demonstrate the Tie-1 receptor tyrosine kinase is present on platelets and its surface expression is regulated. Furthermore, platele t Tie-1 differs significantly from the endothelial receptor. Platelet Tie-1 has the potential to modulate endothelial function by competing for any Ti e ligands and may have signalling roles important in controlling aspects of platelet behaviour. Copyright (C) 2000 S. Karger AG. Basel.