This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hunter, S. G.
Right arrow Articles by Chen, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hunter, S. G.
Right arrow Articles by Chen, J.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 2006, p. 4830-4842, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.02215-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Essential Role of Vav Family Guanine Nucleotide Exchange Factors in EphA Receptor-Mediated Angiogenesis

Sonja G. Hunter,1 Guanglei Zhuang,2 Dana Brantley-Sieders,1 Wojciech Swat,3 Christopher W. Cowan,4,{dagger} and Jin Chen1,2,5,6*

Department of Medicine, Division of Rheumatology and Immunology,1 Department of Cancer Biology,2 Department of Cell and Developmental Biology,5 Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,6 Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110,3 Neurobiology Program, Children's Hospital, and Departments of Neurology and Neurobiology, Harvard Medical School, Boston, Massachusetts 021154

Received 15 November 2005/ Returned for modification 29 December 2005/ Accepted 13 April 2006

Angiogenesis, the process by which new blood vessels are formed from preexisting vasculature, is critical for vascular remodeling during development and contributes to the pathogenesis of diseases such as cancer. Prior studies from our laboratory demonstrate that the EphA2 receptor tyrosine kinase is a key regulator of angiogenesis in vivo. The EphA receptor-mediated angiogenic response is dependent on activation of Rho family GTPase Rac1 and is regulated by phosphatidylinositol 3-kinase. Here we report the identification of Vav2 and Vav3 as guanine nucleotide exchange factors (GEFs) that link the EphA2 receptor to Rho family GTPase activation and angiogenesis. Ephrin-A1 stimulation recruits the binding of Vav proteins to the activated EphA2 receptor. The induced association of EphA receptor and Vav proteins modulates the activity of Vav GEFs, leading to activation of Rac1 GTPase. Overexpression of either Vav2 or Vav3 in primary microvascular endothelial cells promotes Rac1 activation, cell migration, and assembly in response to ephrin-A1 stimulation. Conversely, loss of Vav2 and Vav3 GEFs inhibits Rac1 activation and ephrin-A1-induced angiogenic responses both in vitro and in vivo. In addition, embryonic fibroblasts derived from Vav2–/– Vav3–/– mice fail to spread on an ephrin-A1-coated surface and exhibit a significant decrease in the formation of ephrin-A1-induced lamellipodia and filopodia. These findings suggest that Vav GEFs serve as a molecular link between EphA2 receptors and the actin cytoskeleton and provide an important mechanism for EphA2-mediated angiogenesis.

* Corresponding author. Mailing address: Vanderbilt University School of Medicine, A-4323 MCN, 1161 21st Avenue South, Nashville, TN 37232-2363. Phone: (615) 343-3819. Fax: (615) 343-7392. E-mail: jin.chen{at}vanderbilt.edu.

{dagger} Present address: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390.

Molecular and Cellular Biology, July 2006, p. 4830-4842, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.02215-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Saveliev, A., Vanes, L., Ksionda, O., Rapley, J., Smerdon, S. J., Rittinger, K., Tybulewicz, V. L. J. (2009). Function of the Nucleotide Exchange Activity of Vav1 in T Cell Development and Activation. Sci Signal 2: ra83-ra83 [Abstract] [Full Text]  
  • Vaught, D., Chen, J., Brantley-Sieders, D. M. (2009). Regulation of Mammary Gland Branching Morphogenesis by EphA2 Receptor Tyrosine Kinase. Mol. Biol. Cell 20: 2572-2581 [Abstract] [Full Text]  
  • Brantley-Sieders, D. M., Zhuang, G., Vaught, D., Freeman, T., Hwang, Y., Hicks, D., Chen, J. (2009). Host Deficiency in Vav2/3 Guanine Nucleotide Exchange Factors Impairs Tumor Growth, Survival, and Angiogenesis In vivo. Mol Cancer Res 7: 615-623 [Abstract] [Full Text]  
  • Wykosky, J., Debinski, W. (2008). The EphA2 Receptor and EphrinA1 Ligand in Solid Tumors: Function and Therapeutic Targeting. Mol Cancer Res 6: 1795-1806 [Abstract] [Full Text]  
  • Noberini, R., Koolpe, M., Peddibhotla, S., Dahl, R., Su, Y., Cosford, N. D. P., Roth, G. P., Pasquale, E. B. (2008). Small Molecules Can Selectively Inhibit Ephrin Binding to the EphA4 and EphA2 Receptors. J. Biol. Chem. 283: 29461-29472 [Abstract] [Full Text]  
  • Larson, J., Schomberg, S., Schroeder, W., Carpenter, T. C. (2008). Endothelial EphA receptor stimulation increases lung vascular permeability. Am. J. Physiol. Lung Cell. Mol. Physiol. 295: L431-L439 [Abstract] [Full Text]  
  • Liu, Y., Mo, J. Q., Hu, Q., Boivin, G., Levin, L., Lu, S., Yang, D., Dong, Z., Lu, S. (2008). Targeted Overexpression of Vav3 Oncogene in Prostatic Epithelium Induces Nonbacterial Prostatitis and Prostate Cancer. Cancer Res. 68: 6396-6406 [Abstract] [Full Text]  
  • Fang, W. B., Brantley-Sieders, D. M., Hwang, Y., Ham, A.-J. L., Chen, J. (2008). Identification and Functional Analysis of Phosphorylated Tyrosine Residues within EphA2 Receptor Tyrosine Kinase. J. Biol. Chem. 283: 16017-16026 [Abstract] [Full Text]  
  • Fang, W. B., Ireton, R. C., Zhuang, G., Takahashi, T., Reynolds, A., Chen, J. (2008). Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism. J. Cell Sci. 121: 358-368 [Abstract] [Full Text]  
  • Shin, J., Gu, C., Park, E., Park, S. (2007). Identification of Phosphotyrosine Binding Domain-Containing Proteins as Novel Downstream Targets of the EphA8 Signaling Function. Mol. Cell. Biol. 27: 8113-8126 [Abstract] [Full Text]  
  • Parri, M., Buricchi, F., Giannoni, E., Grimaldi, G., Mello, T., Raugei, G., Ramponi, G., Chiarugi, P. (2007). EphrinA1 Activates a Src/Focal Adhesion Kinase-mediated Motility Response Leading to Rho-dependent Actino/Myosin Contractility. J. Biol. Chem. 282: 19619-19628 [Abstract] [Full Text]  
  • Fitsialos, G., Chassot, A.-A., Turchi, L., Dayem, M. A., LeBrigand, K., Moreilhon, C., Meneguzzi, G., Busca, R., Mari, B., Barbry, P., Ponzio, G. (2007). Transcriptional Signature of Epidermal Keratinocytes Subjected to in Vitro Scratch Wounding Reveals Selective Roles for ERK1/2, p38, and Phosphatidylinositol 3-Kinase Signaling Pathways. J. Biol. Chem. 282: 15090-15102 [Abstract] [Full Text]  
  • Zhuang, G., Hunter, S., Hwang, Y., Chen, J. (2007). Regulation of EphA2 Receptor Endocytosis by SHIP2 Lipid Phosphatase via Phosphatidylinositol 3-Kinase-dependent Rac1 Activation. J. Biol. Chem. 282: 2683-2694 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»