Venous malformation-causing TIE2-mutations lead to AKT-mediated downregulation of PDGFB
(2013) 13th Annual Meeting of the Belgian Society of Human Genetics — Location: Brussels, Belgium (15.March.2013)
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- Abstract
- Mutations in the endothelial-cell tyrosine kinase receptor TIE2 cause inherited and sporadic forms of venous malformation. The most recurrent somatic mutation, L914F, and the common germline mutation, R849W, have been shown to differ 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 stronger effect. Gene expression profiling of HUVECs overexpressing the mutant or wild-type forms of TIE2 indicates that L914F strongly dysregulates genes involved in vascular development and cell migration, while R849W has weak effects, making it indistinguishable from wild-type cells in global analyses. Interestingly, we show for the first time that VM-causative mutations inhibit the transcription factor FOXO1 in an AKT-dependent manner, resulting in deficient PDGFB-production. Lack of this mural cell attractant might explain the paucity of smooth muscle cells surrounding distended vascular channels in venous malformations.
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Uebelhoer, M., Nätynki, M., Kangas, J., Soblet, J., Mendola, A., & et al. (2013). Venous malformation-causing TIE2-mutations lead to AKT-mediated downregulation of PDGFB. 13th Annual Meeting of the Belgian Society of Human Genetics, Brussels, Belgium. https://hdl.handle.net/2078.5/84039