Vascular endothelial growth factor activates STAT proteins in aortic endothelial cells.
Vascular endothelial growth factor (VEGF) intracellular signaling in endothelial cells is initiated by the activation of distinct tyrosine kinase receptors, VEGFR1 (Flt-1) and VEGFR2 (Flk-1/KDR). Because the tyrosine kinase-dependent transcription factors known as STAT (signal transducers and activators of transcription) proteins are important modulators of cell growth responses induced by other growth factor receptors, we have determined the effects VEGF of on STAT activation in BAEC (bovine aortic endothelial cells). Here, we show that VEGF induces tyrosine phosphorylation and nuclear translocation of STAT1 and STAT6. VEGF also stimulates STAT3 tyrosine phosphorylation, but nuclear translocation does not occur. We found that placenta growth factor, which selectively activates VEGFR1, has no effect on the STATs. However, upon VEGF stimulation, STAT1 associates with the VEGFR2 in a tyrosine kinase-dependent manner, indicating that VEGF-induced STAT1 activation is mediated primarily by VEGFR2. Thus, our study shows for the first time that VEGF activates the STAT pathway through VEGFR2. Because the growth-promoting activity of VEGF depends upon VEGFR2 activation, these findings suggest a role for the STATs in the regulation of gene expression associated with the angiogenic effects of VEGF.
Bartoli
M
M
Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912-2500, USA.
Gu
X
X
Tsai
N T
NT
Venema
R C
RC
Brooks
S E
SE
Marrero
M B
MB
Caldwell
R B
RB
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D053613:Janus Kinase 1; D008222:Lymphokines / Q000494:pharmacology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D017978:Receptors, Growth Factor / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D053613:Janus Kinase 1