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Blood, 1 March 2005, Vol. 105, No. 5, pp. 1970-1976. Prepublished online as a Blood First Edition Paper on October 26, 2004; DOI 10.1182/blood-2004-04-1469. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-04-1469v1 105/5/1970    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gallicchio, M. Articles by Bussolino, F. Search for Related Content PubMed PubMed Citation Articles by Gallicchio, M. Articles by Bussolino, F. Related Collections Hemostasis, Thrombosis, and Vascular Biology Cell Adhesion and Motility Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Inhibition of vascular endothelial growth factor receptor 2–mediated endothelial cell activation by Axl tyrosine kinase receptor Margherita Gallicchio, Stefania Mitola, Donatella Valdembri, Roberto Fantozzi, Brian Varnum, Gian Carlo Avanzi, and Federico Bussolino From the Department of Anatomy, Pharmacology, and Forensic Medicine, University of Turin, Torino, Italy; the Division of Molecular Angiogenesis, Institute for Cancer Research and Treatment (IRCC), School of Medicine, University of Turin, Candiolo, Italy; the Department of Oncological Science, University of Turin, Torino, Italy; Amgen Inc, Amgen Center, Thousand Oaks, California; and the Department of Medical Science, University "Amedeo Avogadro," Novara, Italy. 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Sinha, P. K. Vohra, R. Bhattacharya, S. Dutta, S. Sinha, and D. Mukhopadhyay Dopamine regulates phosphorylation of VEGF receptor 2 by engaging Src-homology-2-domain-containing protein tyrosine phosphatase 2 J. Cell Sci., September 15, 2009; 122(18): 3385 - 3392. [Abstract] [Full Text] [PDF] S. Scutera, T. Fraone, T. Musso, P. Cappello, S. Rossi, D. Pierobon, Z. Orinska, R. Paus, S. Bulfone-Paus, and M. Giovarelli Survival and Migration of Human Dendritic Cells Are Regulated by an IFN-{alpha}-Inducible Axl/Gas6 Pathway J. Immunol., September 1, 2009; 183(5): 3004 - 3013. [Abstract] [Full Text] [PDF] A. Gustafsson, D. Martuszewska, M. Johansson, C. Ekman, S. Hafizi, B. Ljungberg, and B. Dahlback Differential Expression of Axl and Gas6 in Renal Cell Carcinoma Reflecting Tumor Advancement and Survival Clin. Cancer Res., July 15, 2009; 15(14): 4742 - 4749. [Abstract] [Full Text] [PDF] L. Jiang, C. Y. Liu, Q. F. Yang, P. Wang, and W. Zhang Plasma Level of Growth Arrest-Specific 6 (GAS6) Protein and Genetic Variations in the GAS6 Gene in Patients With Acute Coronary Syndrome Am J Clin Pathol, May 1, 2009; 131(5): 738 - 743. [Abstract] [Full Text] [PDF] N. Tiffin, I. Okpechi, C. Perez-Iratxeta, M. A. Andrade-Navarro, and R. Ramesar Prioritization of candidate disease genes for metabolic syndrome by computational analysis of its defining phenotypes Physiol Genomics, September 17, 2008; 35(1): 55 - 64. [Abstract] [Full Text] [PDF] M. E. Cavet, E. M. Smolock, O. H. Ozturk, C. World, J. Pang, A. Konishi, and B. C. Berk Gas6-Axl Receptor Signaling Is Regulated by Glucose in Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 886 - 891. [Abstract] [Full Text] [PDF] M. Tjwa, L. Bellido-Martin, Y. Lin, E. Lutgens, S. Plaisance, F. Bono, N. Delesque-Touchard, C. Herve, R. Moura, A. D. Billiau, et al. Gas6 promotes inflammation by enhancing interactions between endothelial cells, platelets, and leukocytes Blood, April 15, 2008; 111(8): 4096 - 4105. [Abstract] [Full Text] [PDF] J.-D. Lay, C.-C. Hong, J.-S. Huang, Y.-Y. Yang, C.-Y. Pao, C.-H. Liu, Y.-P. Lai, G.-M. Lai, A.-L. Cheng, I.-J. Su, et al. Sulfasalazine Suppresses Drug Resistance and Invasiveness of Lung Adenocarcinoma Cells Expressing AXL Cancer Res., April 15, 2007; 67(8): 3878 - 3887. [Abstract] [Full Text] [PDF] G. D.M. Collett, A. P. Sage, J. P. Kirton, M. Y. Alexander, A. P. Gilmore, and A. E. Canfield Axl/Phosphatidylinositol 3-Kinase Signaling Inhibits Mineral Deposition by Vascular Smooth Muscle Cells Circ. Res., March 2, 2007; 100(4): 502 - 509. [Abstract] [Full Text] [PDF] P. Vajkoczy, P. Knyazev, A. Kunkel, H.-H. Capelle, S. Behrndt, H. von Tengg-Kobligk, F. Kiessling, U. Eichelsbacher, M. Essig, T.-A. Read, et al. Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival PNAS, April 11, 2006; 103(15): 5799 - 5804. [Abstract] [Full Text] [PDF] S. Mitola, B. Brenchio, M. Piccinini, L. Tertoolen, L. Zammataro, G. Breier, M. T. Rinaudo, J. den Hertog, M. Arese, and F. Bussolino Type I Collagen Limits VEGFR-2 Signaling by a SHP2 Protein-Tyrosine Phosphatase-Dependent Mechanism 1 Circ. Res., January 6, 2006; 98(1): 45 - 54. [Abstract] [Full Text] [PDF] S. J. Holland, M. J. Powell, C. Franci, E. W. Chan, A. M. Friera, R. E. Atchison, J. McLaughlin, S. E. Swift, E. S. Pali, G. Yam, et al. Multiple Roles for the Receptor Tyrosine Kinase Axl in Tumor Formation Cancer Res., October 15, 2005; 65(20): 9294 - 9303. [Abstract] [Full Text] [PDF] I. Balogh, S. Hafizi, J. Stenhoff, K. Hansson, and B. Dahlback Analysis of Gas6 in Human Platelets and Plasma Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1280 - 1286. [Abstract] [Full Text] [PDF]

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