A receptor for vascular endothelial growth factor that stimulates endothelial apoptosis.
Vascular endothelial growth factor (VEGF) is a dimeric angiogenic factor that is overexpressed by many tumors and stimulates tumor angiogenesis. VEGF initiates signaling by dimerizing the receptors VEGFR-1 and VEGFR-2. The Fas receptor stimulates apoptosis, and artificial dimerization of the Fas cytoplasmic domain has been shown to induce apoptosis. We constructed a chimeric receptor (VEGFR2Fas) combining the extracellular and transmembrane domains of VEGFR-2 with the cytoplasmic domain of Fas receptor. When VEGFR2Fas was stably expressed in endothelial cells in vitro, treatment with VEGF rapidly induced cell death with features characteristic of Fas-mediated apoptosis. These findings demonstrate that VEGFR2Fas functions as a VEGF-triggered death receptor and raise the possibility that introduction of VEGFR2Fas into tumor endothelium or tumor cells in vivo may convert tumor-derived VEGF from an angiogenic factor into an antiangiogenesis agent.
Quinn
T P
TP
Cardiovascular Research Institute, University of California San Francisco, San Francisco, California 94143, USA. tpquinn@itsa.ucsf.edu
Soifer
S J
SJ
Ramer
K
K
Williams
L T
LT
Nakamura
M C
MC
D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D020740:Chimerin Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D019281:Dimerization; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D013552:Swine; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D020740:Chimerin Proteins; D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019014:fas Receptor; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor