Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426041
Title: A study of a mutant form of receptor tyrosine kinase Tie-2 associated with venous malformations
Author: Morris, Paul Neville
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2005
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Abstract:
The receptor tyrosine kinase Tie-2 is expressed predominantly in endothelial cells and is involved in blood vessel formation and maintenance. A missense mutation resulting in an R849 to W substitution in the kinase domain of Tie-2 has been reported to co-segregate with an autosomal dominantly inherited form of venous malformation (VM). In this disorder focal masses arise comprising of numerous dilated vascular channels lined with endothelial cells but largely lacking mural cell support. The mechanism whereby R849W mutant Tie-2 results in VM is not known. The aim of this study was to determine the functional effects of this mutant form of Tie-2 in order to gain insight into the mechanism by which it results in VM. To do this, wild type and VM (R849W) mutant Tie-2 were subcloned into mammalian expression vector pCR3 and stably expressed in endothelial cells. the VM mutant form of Tie-2 exhibited elevated constitutive tyrosine phosphorylation compared with wild type receptor in endothelial cells. expression of VM mutant Tie-2 caused a dramatic increase in endothelial cell survival during serum starvation. Under basal conditions VM mutant Tie-2 was found to be associated with a number of tyrosine phosphorylated proteins including Shp-2 and the adapter protein Shc. Consistent with effects on cell survival, endothelial cells expressing VM mutant Tie-2 had constitutively activated Akt. These data suggest the mutant form of Tie-2 may act to prevent regression of mural cell poor vessels via ligand-independent Tie-2 activation of Akt and endothelial survival.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.426041  DOI: Not available
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