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

Endothelial receptor tyrosine kinases (RTKs) and their signaling mechanisms are of interest because they may control tumor angiogenesis and thereby tu mor growth, In this report we have examined activation of the signal transd ucers and activators of transcription (STATs) by the three known vascular e ndothelial growth factor receptors (VEGFR1-3), as well as by the endothelia l 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 ov erexpressed in 293T cells, MTie-2 activated STAT1 while the other endotheli al RTKs failed to do so, In contrast, the three VEGFRs were strong activato rs 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 STAXs correlated with their ability to activate transcription as judged by lucife rase 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, Inte restingly, co-expression of the Tie-2 receptors with STAT1 resulted in appe arance of a novel, p21 related transcript. Taken together, these findings i dentify STAT proteins as novel targets for signal transduction by the endot helial RTKs, suggesting that they may be involved in the regulation of endo thelial function.