The fully linked HTML version of this article has now been published.
JCS ePress
online publication date 30 Mar 2004
doi: 10.1242/jcs.01061
Research Article
EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation
Dana M. Brantley-Sieders,
Justin Caughron,
Donna Hicks,
Ambra Pozzi,
Joseph C. Ruiz,
and
Jin Chen*
* Author for correspondence (e-mail: jin.chen{at}vanderbilt.edu)
Angiogenesis is critical for vascular remodeling during development and contributes to the pathogenesis of diseases such as cancer. Targeted disruption of several EphB class receptor tyrosine kinases results in vascular remodeling defects during embryogenesis. The role of EphA class receptors in vascular remodeling, however, is not well-characterized. We recently demonstrated that global inhibition of EphA receptors disrupts endothelial migration induced by ephrin, VEGF or tumor-derived signals, though the specific target remained undefined. Here, we report that EphA2 regulates endothelial cell assembly and migration through phosphoinositide (PI) 3-kinase-mediated activation of Rac1 GTPase in two model systems: primary bovine and murine pulmonary microvascular endothelial cells. EphA2-deficient endothelial cells fail to undergo vascular assembly and migration in response to ephrin-A1 in vitro. Ephrin-A1 stimulation induces PI3-kinase-dependent activation of Rac1 in wild-type endothelial cells, whereas EphA2-deficient cells fail to activate Rac1 upon stimulation. Expression of dominant negative PI3-kinase or Rac1 inhibits ephrin-A1-induced endothelial cell migration. Consistent with in vitro data, EphA2-deficient mice show a diminished angiogenic response to ephrin-A1 in vivo. Moreover, EphA2-deficient endothelial cells fail to assemble in vivo when transplanted into recipient mice. These data suggest that EphA2 is an essential regulator of post-natal angiogenesis.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
M. A. Cercone, W. Schroeder, S. Schomberg, and T. C. Carpenter
EphA2 receptor mediates increased vascular permeability in lung injury due to viral infection and hypoxia
Am J Physiol Lung Cell Mol Physiol,
November 1, 2009;
297(5):
L856 - L863.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Okazaki, A. Ni, P. Baluk, O. A. Ayeni, J. Kearley, A. J. Coyle, A. Humbles, and D. M. McDonald
Capillary Defects and Exaggerated Inflammatory Response in the Airways of EphA2-Deficient Mice
Am. J. Pathol.,
June 1, 2009;
174(6):
2388 - 2399.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Vaught, J. Chen, and D. M. Brantley-Sieders
Regulation of Mammary Gland Branching Morphogenesis by EphA2 Receptor Tyrosine Kinase
Mol. Biol. Cell,
May 15, 2009;
20(10):
2572 - 2581.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Brantley-Sieders, G. Zhuang, D. Vaught, T. Freeman, Y. Hwang, D. Hicks, and J. Chen
Host Deficiency in Vav2/3 Guanine Nucleotide Exchange Factors Impairs Tumor Growth, Survival, and Angiogenesis In vivo
Mol. Cancer Res.,
May 1, 2009;
7(5):
615 - 623.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Wykosky and W. Debinski
The EphA2 Receptor and EphrinA1 Ligand in Solid Tumors: Function and Therapeutic Targeting
Mol. Cancer Res.,
December 1, 2008;
6(12):
1795 - 1806.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Huang, D. Wu, H. Jin, D. Stupack, and J. Y.J. Wang
Induction of cell retraction by the combined actions of Abl-CrkII and Rho-ROCK1 signaling
J. Cell Biol.,
November 17, 2008;
183(4):
711 - 723.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Noberini, M. Koolpe, S. Peddibhotla, R. Dahl, Y. Su, N. D. P. Cosford, G. P. Roth, and E. B. Pasquale
Small Molecules Can Selectively Inhibit Ephrin Binding to the EphA4 and EphA2 Receptors
J. Biol. Chem.,
October 24, 2008;
283(43):
29461 - 29472.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. B. Fang, D. M. Brantley-Sieders, Y. Hwang, A.-J. L. Ham, and J. Chen
Identification and Functional Analysis of Phosphorylated Tyrosine Residues within EphA2 Receptor Tyrosine Kinase
J. Biol. Chem.,
June 6, 2008;
283(23):
16017 - 16026.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Lackmann and A. W. Boyd
Eph, a Protein Family Coming of Age: More Confusion, Insight, or Complexity?
Sci. Signal.,
April 15, 2008;
1(15):
re2 - re2.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. B. Fang, R. C. Ireton, G. Zhuang, T. Takahashi, A. Reynolds, and J. Chen
Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism
J. Cell Sci.,
February 1, 2008;
121(3):
358 - 368.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. B. Larsen, M. W. Pedersen, M.-T. Stockhausen, M. V. Grandal, B. v. Deurs, and H. S. Poulsen
Activation of the EGFR Gene Target EphA2 Inhibits Epidermal Growth Factor-Induced Cancer Cell Motility
Mol. Cancer Res.,
March 1, 2007;
5(3):
283 - 293.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Zhuang, S. Hunter, Y. Hwang, and J. Chen
Regulation of EphA2 Receptor Endocytosis by SHIP2 Lipid Phosphatase via Phosphatidylinositol 3-Kinase-dependent Rac1 Activation
J. Biol. Chem.,
January 26, 2007;
282(4):
2683 - 2694.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Brantley-Sieders, W. B. Fang, Y. Hwang, D. Hicks, and J. Chen
Ephrin-A1 Facilitates Mammary Tumor Metastasis through an Angiogenesis-Dependent Mechanism Mediated by EphA Receptor and Vascular Endothelial Growth Factor in Mice
Cancer Res.,
November 1, 2006;
66(21):
10315 - 10324.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Salvucci, M. de la Luz Sierra, J. A. Martina, P. J. McCormick, and G. Tosato
EphB2 and EphB4 receptors forward signaling promotes SDF-1-induced endothelial cell chemotaxis and branching remodeling
Blood,
November 1, 2006;
108(9):
2914 - 2922.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N.-Y. Yang, E. B. Pasquale, L. B. Owen, and I. M. Ethell
The EphB4 Receptor-tyrosine Kinase Promotes the Migration of Melanoma Cells through Rho-mediated Actin Cytoskeleton Reorganization
J. Biol. Chem.,
October 27, 2006;
281(43):
32574 - 32586.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Guo, H. Miao, L. Gerber, J. Singh, M. F. Denning, A. C. Gilliam, and B. Wang
Disruption of EphA2 Receptor Tyrosine Kinase Leads to Increased Susceptibility to Carcinogenesis in Mouse Skin.
Cancer Res.,
July 15, 2006;
66(14):
7050 - 7058.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. G. Hunter, G. Zhuang, D. Brantley-Sieders, W. Swat, C. W. Cowan, and J. Chen
Essential Role of Vav Family Guanine Nucleotide Exchange Factors in EphA Receptor-Mediated Angiogenesis.
Mol. Cell. Biol.,
July 1, 2006;
26(13):
4830 - 4842.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ojima, H. Takagi, K. Suzuma, H. Oh, I. Suzuma, H. Ohashi, D. Watanabe, E. Suganami, T. Murakami, M. Kurimoto, et al.
EphrinA1 Inhibits Vascular Endothelial Growth Factor-Induced Intracellular Signaling and Suppresses Retinal Neovascularization and Blood-Retinal Barrier Breakdown
Am. J. Pathol.,
January 1, 2006;
168(1):
331 - 339.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Mulero-Navarro, E. Pozo-Guisado, P. A. Perez-Mancera, A. Alvarez-Barrientos, I. Catalina-Fernandez, E. Hernandez-Nieto, J. Saenz-Santamaria, N. Martinez, J. M. Rojas, I. Sanchez-Garcia, et al.
Immortalized Mouse Mammary Fibroblasts Lacking Dioxin Receptor Have Impaired Tumorigenicity in a Subcutaneous Mouse Xenograft Model
J. Biol. Chem.,
August 5, 2005;
280(31):
28731 - 28741.
[Abstract]
[Full Text]
[PDF]
|
|
|
© The Company of Biologists Ltd 2004
