title: Common and specific effects of TIE2 mutations causing venous malformations.
abstract: Venous malformations (VMs) are localized defects in vascular morphogenesis frequently caused by mutations in the gene for the endothelial tyrosine kinase receptor TIE2. Here, we report the analysis of a comprehensive collection of 22 TIE2 mutations identified in patients with VM, either as single amino acid substitutions or as double-mutations on the same allele. Using endothelial cell (EC) cultures, mouse models and ultrastructural analysis of tissue biopsies from patients, we demonstrate common as well as mutation-specific cellular and molecular features, on the basis of which mutations cluster into categories that correlate with data from genetic studies. Comparisons of double-mutants with their constituent single-mutant forms identified the pathogenic contributions of individual changes, and their compound effects. We find that defective receptor trafficking and subcellular localization of different TIE2 mutant forms occur via a variety of mechanisms, resulting in attenuated response to ligand. We also demonstrate, for the first time, that TIE2 mutations cause chronic activation of the MAPK pathway resulting in loss of normal EC monolayer due to extracellular matrix (ECM) fibronectin deficiency and leading to upregulation of plasminogen/plasmin proteolytic pathway. Corresponding EC and ECM irregularities are observed in affected tissues from mouse models and patients. Importantly, an imbalance between plasminogen activators versus inhibitors would also account for high d-dimer levels, a major feature of unknown cause that distinguishes VMs from other vascular anomalies.
authors: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors: Marjut
authors: M
authors: Nätynki
authors: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors: Jaakko
authors: J
authors: Kangas
authors: Biocenter Oulu, University of Oulu, Oulu, Finland.
authors: Ilkka
authors: I
authors: Miinalainen
authors: Biocenter Oulu, University of Oulu, Oulu, Finland, Department of Pathology and Oulu University Hospital, University of Oulu, Oulu, Finland.
authors: Raija
authors: R
authors: Sormunen
authors: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors: Riikka
authors: R
authors: Pietilä
authors: Human Molecular Genetics, de Duve Institute, and.
authors: Julie
authors: J
authors: Soblet
authors: Human Molecular Genetics, de Duve Institute, and Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
authors: Laurence M
authors: LM
authors: Boon
authors: Human Molecular Genetics, de Duve Institute, and.
authors: Miikka
authors: M
authors: Vikkula
authors: Human Molecular Genetics, de Duve Institute, and.
authors: Nisha
authors: N
authors: Limaye
authors: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland, lauri.eklund@oulu.fi.
authors: Lauri
authors: L
authors: Eklund
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D010766:Phosphorylation; D042787:Receptor, TIE-2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D054079:Vascular Malformations / Q000201:enzymology / Q000235:genetics*
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D008024:Ligands; C036309:fibrin fragment D; D042787:Receptor, TIE-2