Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor.
GAS6, the product of a growth arrest specific (GAS) gene, is the ligand of the tyrosine kinase receptor Axl. GAS6 and Axl are both expressed in endothelial cells, where they are involved in many processes such as leukocyte transmigration through capillaries and neointima formation in injured vessels. Here, we show that Axl stimulation by GAS6 results in inhibition of the ligand-dependent activation of vascular endothelial growth factor (VEGF) receptor 2 and the consequent activation of an angiogenic program in vascular endothelial cells. GAS6 inhibits chemotaxis of endothelial cells stimulated by VEGF-A isoforms, but not that triggered by fibroblast growth factor-2 or hepatocyte growth factor. Furthermore, it inhibits endothelial cell morphogenesis on Matrigel and VEGF-A-dependent vascularization of chick chorion allantoid membrane. GAS6 activates the tyrosine phosphatase SHP-2 (SH2 domain-containing tyrosine phosphatase 2), which is instrumental in the negative feedback exerted by Axl on VEGF-A activities. A dominant-negative SHP-2 mutant, in which Cys 459 is substituted by Ser, reverted the effect of GAS6 on stimulation of VEGF receptor 2 and endothelial chemotaxis triggered by VEGF-A. These studies provide the first demonstration of a cross talk between Axl and VEGF receptor 2 and add new information on the regulation of VEGF-A activities during tissue vascularization.
Gallicchio
Margherita
M
Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, C. so Massimo D'azeglio 52, 10100 Torino, Italy. margherita.gallicchio@unito.it
Mitola
Stefania
S
Valdembri
Donatella
D
Fantozzi
Roberto
R
Varnum
Brian
B
Avanzi
Gian Carlo
GC
Bussolino
Federico
F
D000818:Animals; D002633:Chemotaxis; D002642:Chick Embryo; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology; D025461:Feedback, Physiological; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D018919:Neovascularization, Physiologic; D015513:Oncogene Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D020239:Receptor Cross-Talk; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000722289:AXL protein, human