Mutations in the endothelial-cell tyrosine kinase receptor TIE2 cause inherited and sporadic forms of venous malformation. The most frequent somatic mutation, L914F, and the common germline mutation, R849W, have been shown to differ both in terms of phosphorylation-level, as well as sub-cellular localization and trafficking of the receptor. We now show that PI3K/AKT and STAT1 are chronically activated by both mutant forms, with L914F exerting a much stronger effect. Gene expression profiling of HUVECs overexpressing the mutant or wild-type forms of TIE2, indicates that L914F dysregulates multiple pathways, with more than 80 differentially expressed genes. By contrast, R849W has very weak effects, making it indistinguishable from wild-type cells in global analyses. The genes modulated by L914F-cells are predominantly involved in vascular development and cell migration, and provide us with insights into the mechanisms involved in lesion-formation.
Uebelhoer, Mélanie ; Nätynki, Marjut ; Kangas, Jaakko ; Soblet, Julie ; Mendola, Antonella ; et. al. L914F, the VM-causative TIE2 mutation, strongly dysregulates endothelial cell gene expression.12th Annual Meeting of the Belgian Society of Human Genetics (Liège, Belgium, 02/03/2012).
