Abstract
Germline substitutions in the endothelial cell tyrosine kinase receptor TIE2 (encoded by TEK) cause a rare, inherited form of venous anomaly known as a mucocutaneous venous malformation (VMCM; refs. 1, 2, 3 and V.W., N.L., M.U., A. Irrthum, L.M.B. et al., unpublished data). We identified a somatic 'second hit' causing loss of function of TIE2 in a resected VMCM and assessed whether such localized, tissue-specific events have a role in the etiology of sporadic venous malformations, which are far more common. We identified eight somatic TEK mutations in lesions from 28 of 57 individuals (49.1%) with sporadic venous malformations; the mutations were absent from the individuals' blood and control tissues. The somatic mutations included one causing a frequent L914F substitution and several double mutations in cis, all of which resulted in ligand-independent TIE2 hyperphosphorylation in vitro. When overexpressed in human umbilical vein endothelial cells, the L914F mutant was abnormally localized and responded to ligand, in contrast to wild-type TIE2 and the common, inherited R849W mutant, suggesting that the mutations have distinct effects. The presence of the same mutations in multifocal sporadic venous malformations in two individuals suggests a common origin for the abnormal endothelial cells at the distant sites. These data show that a sporadic disease may be explained by somatic changes in a gene causing rare, inherited forms and pinpoint TIE2 pathways as potential therapeutic targets for venous malformations.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
206,07 € per year
only 17,17 € per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Vikkula, M. et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87, 1181–1190 (1996).
Calvert, J.T. et al. Allelic and locus heterogeneity in inherited venous malformations. Hum. Mol. Genet. 8, 1279–1289 (1999).
Wouters, V., Boon, L.M., Mulliken, J.B. & Vikkula, M. in Inborn Errors of Development 2nd edn (eds. Epstein, C., Erickson, R.P. & Wynshaw-Boris, A.) (Oxford University Press, New York, 2007).
Dumont, D.J., Yamaguchi, T.P., Conlon, R.A., Rossant, J. & Breitman, M.L. tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors. Oncogene 7, 1471–1480 (1992).
Schnurch, H. & Risau, W. Expression of tie-2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage. Development 119, 957–968 (1993).
Sato, T.N., Qin, Y., Kozak, C.A. & Audus, K.L. Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc. Natl. Acad. Sci. USA 90, 9355–9358 (1993).
Dumont, D.J. et al. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 8, 1897–1909 (1994).
Dumont, D.J. et al. Vascularization of the mouse embryo: a study of flk-1, tek, tie, and vascular endothelial growth factor expression during development. Dev. Dyn. 203, 80–92 (1995).
Sato, T.N. et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70–74 (1995).
Suri, C. et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87, 1171–1180 (1996).
Partanen, J. & Dumont, D.J. Functions of Tie1 and Tie2 receptor tyrosine kinases in vascular development. Curr. Top. Microbiol. Immunol. 237, 159–172 (1999).
Jones, N., Iljin, K., Dumont, D.J. & Alitalo, K. Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat. Rev. Mol. Cell Biol. 2, 257–267 (2001).
Eklund, L. & Olsen, B.R. Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling. Exp. Cell Res. 312, 630–641 (2005).
Maisonpierre, P.C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997).
Loughna, S. & Sato, T.N. Angiopoietin and Tie signaling pathways in vascular development. Matrix Biol. 20, 319–325 (2001).
Nobuhara, Y. et al. TIE2 gain-of-function mutation in a patient with pancreatic lymphangioma associated with blue rubber-bleb nevus syndrome: report of a case. Surg. Today 36, 283–286 (2006).
Boon, L.M. et al. Assignment of a locus for dominantly inherited venous malformations to chromosome 9p. Hum. Mol. Genet. 3, 1583–1587 (1994).
Hebert, D.N. & Molinari, M. In and out of the ER: protein folding, quality control, degradation, and related human diseases. Physiol. Rev. 87, 1377–1408 (2007).
Boon, L.M., Mulliken, J.B., Enjolras, O. & Vikkula, M. Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities. Arch. Dermatol. 140, 971–976 (2004).
Chen, Z. et al. EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations: one-third of doublets occur at five pairs of amino acids. Oncogene 27, 4336–4343 (2008).
Colmone, A. & Sipkins, D.A. Beyond angiogenesis: the role of endothelium in the bone marrow vascular niche. Transl. Res. 151, 1–9 (2008).
Shewchuk, L.M. et al. Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail. Structure 8, 1105–1113 (2000).
Fukuhara, S. et al. Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat. Cell Biol. 10, 513–526 (2008).
Saharinen, P. et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat. Cell Biol. 10, 527–537 (2008).
Lievens, P.M., Mutinelli, C., Baynes, D. & Liboi, E. The kinase activity of fibroblast growth factor receptor 3 with activation loop mutations affects receptor trafficking and signaling. J. Biol. Chem. 279, 43254–43260 (2004).
Schmidt-Arras, D.E. et al. Tyrosine phosphorylation regulates maturation of receptor tyrosine kinases. Mol. Cell. Biol. 25, 3690–3703 (2005).
Tabone-Eglinger, S. et al. KIT mutations induce intracellular retention and activation of an immature form of the KIT protein in gastrointestinal stromal tumors. Clin. Cancer Res. 14, 2285–2294 (2008).
Acknowledgements
We thank the patients for their invaluable contributions; A. Mendola, A. Van Egeren and J. Träskelin for expert technical assistance; C. Godfraind for immunohistochemistry; and L. Niculescu for secretarial help. These studies were partially supported by the Interuniversity Attraction Poles initiated by the Belgian Federal Science Policy (network 5/25 and 6/05), Concerted Research Actions (ARC) Conventions no. 02/07/276 and 7/12-005 of the Belgian French Community Ministry, National Institutes of Health program project P01 AR048564-01A1, EU FW6 Integrated Project LYMPHANGIOGENOMICS (LSHG-CT-2004-503573), the Fonds national de la recherche scientifique (to M.V., a 'Maître de recherches du FNRS'); a fellowship from Fonds pour la formation à la recherche dans l'industrie et dans l'agriculture (to V.W.), the Patrimoine UCL and the Academy of Finland (116138 to L.E. and M.T.).
Author information
Authors and Affiliations
Contributions
L.E. and M.V. participated in experimental design, data analysis and writing; N.L., V.W. and L.E. participated in experimental design, data collection and analysis, writing and figure processing; M.U. contributed significantly to data collection and figure processing; M.T. contributed significantly to data collection, analysis, figure processing and writing and planning of experiments; R.W. contributed to data collection; and J.B.M. and L.M.B. provided clinical expertise, patient recruitment and detailed clinical descriptions. M.U. and M.T. contributed equally.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–5, Supplementary Tables 1–3 and Supplementary Methods (PDF 3249 kb)
Rights and permissions
About this article
Cite this article
Limaye, N., Wouters, V., Uebelhoer, M. et al. Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat Genet 41, 118–124 (2009). https://doi.org/10.1038/ng.272
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.272
