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Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response

Oncogene volume 18, pages 1–8 (1999)Cite this article

Abstract

Endothelial receptor tyrosine kinases (RTKs) and their signaling mechanisms are of interest because they may control tumor angiogenesis and thereby tumor growth. In this report we have examined activation of the signal transducers and activators of transcription (STATs) by the three known vascular endothelial growth factor receptors (VEGFR1-3), as well as by the endothelial Tie-1 and -2 receptors. We also studied signaling by the R849W mutant of Tie-2 (MTie-2), which has been shown to cause venous malformations. When overexpressed in 293T cells, MTie-2 activated STAT1 while the other endothelial RTKs failed to do so. In contrast, the three VEGFRs were strong activators of STAT3 and STAT5, suggesting that they activate only a specific subset of these signal transducers. STAT3 and STAT5 were also activated by Tie-2 and, more so, by MTie-2. Tyrosine phosphorylation and DNA binding of STATs correlated with their ability to activate transcription as judged by luciferase assays. When co-expressed with STAT5, VEGFR-1 as well as both the Tie-2 receptor forms increased expression of the cell cycle inhibitor p21. Interestingly, co-expression of the Tie-2 receptors with STAT1 resulted in appearance of a novel, p21 related transcript. Taken together, these findings identify STAT proteins as novel targets for signal transduction by the endothelial RTKs, suggesting that they may be involved in the regulation of endothelial function.

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Acknowledgements

We would like to thank Dr Olli Silvennoinen, Pipsa Saharinen and Kirsi Paukku for helpful discussions and Mari Helanterä and Paula Hyvärinen for excellent technical assistance. This study was supported by the Finnish Cancer Organizations, the Finnish Academy, the Sigrid Juselius Foundation, the State Technology Development Centre, the Helsinki University Hospital Research Funds and the European Union (PL 963380, BMH4-98-3380), and grants from the European Molecular Biology Organization and the Paulo Foundation.

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Authors and Affiliations

  1. Molecular/Cancer Biology Laboratory, Haartman Institute, University of Helsinki, Finland

    Eija I Korpelainen, Marika Kärkkäinen, Yuji Gunji & Kari Alitalo

  2. Laboratory of Human Molecular Genetics, Catholic University of Louvain and Christian de Duve Institute, Brussels, Belgium

    Miikka Vikkula

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Korpelainen, E., Kärkkäinen, M., Gunji, Y. et al. Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. Oncogene 18, 1–8 (1999). https://doi.org/10.1038/sj.onc.1202288

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