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Title: Regulation and physiological role of the proteolytic cleavage of the endothelial receptor tyrosine kinsae TIE-1 in vessel destabilisation prior to angiogenesis
Authors: Tsiamis, Achilleas C.
First Published: 2004
Award date: 2004
Abstract: The receptor tyrosine kinase Tie-1 is a novel endothelial cell membrane receptor, with still unknown ligand, which seems to play an important role in vessel maturation. In our study, we show that VEGF regulates the proteolytic cleavage of the Tie-1 extracellular domain resulting to the release of an extracellular fragment and the production of an intracellular fragment with potential downstream signalling functions. This is mediated by a metalloprotease, involving phosphorylation of tyrosine kinases. Nitric oxide, thrombin, angioprotein II, Bradykinin and bFGF were not found to regulate proteolytic cleavage of the Tie-1 receptor's extracellular domain. Cell survival and cell proliferation experiments confirmed that the Tie-1 ectodomain cleavage leads to enhanced endothelial cell survival and proliferation. In order to examine the physiological role of Tie-1 cleavage we attempted to specifically inhibit truncation by synthesising a peptide corresponding to the truncation site and raising a monoclonal antibody against it. The in-vivo angiogenesis model of the chick chorioallantoic membrane (CAM) model was used. Tie-1 was identified in the developing CAM existing in both its truncated and full-length form. Treatment of the mature CAM with VEGF results to ectodomain cleavage of Tie-1. treatment of the CAM with monoclonal antibodies recognising the extracellular epitope of the receptor results to interstitial oedema suggesting a role for the receptor in vessel stabilisation. Tie-1 was also identified in platelets where it is present in a different, non-cleavable isoform suggesting that proteolytic cleavage of the Tie-1 receptor's extracellular domain is endothelial cell specific phenomenon.
Type: Thesis
Rights: Copyright © the author. All rights reserved.
Appears in Collections:Theses, College of Medicine, Biological Sciences and Psychology
Leicester Theses

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