Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

J. Cell Sci. 121 (3): 358-368


Research Article

Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism

Wei Bin Fang1, Reneé C. Ireton1, Guanglei Zhuang1, Takamune Takahashi2, Al Reynolds1,3, and Jin Chen1,3,4,5,*

1 Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
2 Department of Medicine, Division of Nephrology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
3 Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
4 Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
5 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

* Author for correspondence (e-mail: jin.chen{at}vanderbilt.edu)

Accepted for publication 4 November 2007.

Abstract: EPHA2 receptor tyrosine kinase is overexpressed in several human cancer types and promotes malignancy. However, the mechanisms by which EPHA2 promotes tumor progression are not completely understood. Here we report that overexpression of a wild-type EPHA2, but not a signaling-defective cytoplasmic truncation mutant ({Delta}C), in human mammary epithelial cells weakens E-cadherin-mediated cell-cell adhesion. Interestingly, the total level of cadherins and the composition of the adherens junction complexes were not affected, nor was the tyrosine phosphorylation of the cadherin complex components changed. By contrast, RhoA GTPase activity was significantly affected by modulating the EPHA2 activity in MCF-10A cells. Treatment with a ROCK kinase inhibitor rescued cell-cell adhesion defects in EPHA2-overexpressing cells, whereas expression of constitutively activated Rho disrupted adherens junctions in {Delta}C-expressing cells. EPHA2-dependent Rho activation and destabilization of adherens junctions appeared to be regulated via a signaling pathway involving Src kinase, low molecular weight phosphotyrosine phosphatase (LMW-PTP) and p190 RhoGAP. EPHA2 interacted with both Src and LMW-PTP, and the interactions increased in EPHA2-overexpressing cells. In addition, LMW-PTP phosphatase activity was elevated, and this elevation was accompanied by a decrease in tyrosine phosphorylation of p190 RhoGAP and destabilization of cell-cell adhesion. Expression of either a dominant negative LMW-PTP mutant, C12S, or a wild-type p190 RhoGAP rescued adhesion defects in EPHA2-overexpressing cells. Together, these data suggest that EPHA2 promotes tumor malignancy through a mechanism involving RhoA-dependent destabilization of adherens junctions.

Key Words: EPHA2 • RhoA • Adherens junction


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Characterization of Low Molecular Weight Protein Tyrosine Phosphatase Isoforms in Human Breast Cancer Epithelial Cell Lines.
I. ALHO, L. COSTA, M. BICHO, and C. COELHO (2013)
Anticancer Res 33, 1983-1987
   Abstract »    Full Text »    PDF »
EphA2 Activation Promotes the Endothelial Cell Inflammatory Response: A Potential Role in Atherosclerosis.
S. D. Funk, A. Yurdagul Jr, P. Albert, J. G. Traylor Jr, L. Jin, J. Chen, and A. W. Orr (2012)
Arterioscler Thromb Vasc Biol 32, 686-695
   Abstract »    Full Text »    PDF »
The Receptor Tyrosine Kinase EphA2 Is a Direct Target Gene of Hypermethylated in Cancer 1 (HIC1).
B. Foveau, G. Boulay, S. Pinte, C. Van Rechem, B. R. Rood, and D. Leprince (2012)
J. Biol. Chem. 287, 5366-5378
   Abstract »    Full Text »    PDF »
Ligand Targeting of EphA2 Enhances Keratinocyte Adhesion and Differentiation via Desmoglein 1.
S. Lin, K. Gordon, N. Kaplan, and S. Getsios (2010)
Mol. Biol. Cell 21, 3902-3914
   Abstract »    Full Text »    PDF »
Major Role of Epidermal Growth Factor Receptor and Src Kinases in Promoting Oxidative Stress-dependent Loss of Adhesion and Apoptosis in Epithelial Cells.
H.-L. Chan, H.-C. Chou, M. Duran, J. Gruenewald, M. D. Waterfield, A. Ridley, and J. F. Timms (2010)
J. Biol. Chem. 285, 4307-4318
   Abstract »    Full Text »    PDF »
Intercellular Junction Assembly, Dynamics, and Homeostasis.
K. J. Green, S. Getsios, S. Troyanovsky, and L.M. Godsel (2010)
Cold Spring Harb Perspect Biol 2, a000125
   Abstract »    Full Text »    PDF »
Myosin IXa Regulates Epithelial Differentiation and Its Deficiency Results in Hydrocephalus.
M. Abouhamed, K. Grobe, I. V. Leefa Chong San, S. Thelen, U. Honnert, M. S. Balda, K. Matter, and M. Bahler (2009)
Mol. Biol. Cell 20, 5074-5085
   Abstract »    Full Text »    PDF »
EphA2 in the Early Pathogenesis and Progression of Non-Small Cell Lung Cancer.
J. M. Brannan, B. Sen, B. Saigal, L. Prudkin, C. Behrens, L. Solis, W. Dong, B. N. Bekele, I. Wistuba, and F. M. Johnson (2009)
Cancer Prevention Research 2, 1039-1049
   Abstract »    Full Text »    PDF »
EphA2 receptor mediates increased vascular permeability in lung injury due to viral infection and hypoxia.
M. A. Cercone, W. Schroeder, S. Schomberg, and T. C. Carpenter (2009)
Am J Physiol Lung Cell Mol Physiol 297, L856-L863
   Abstract »    Full Text »    PDF »
Hsp90 Is an Essential Regulator of EphA2 Receptor Stability and Signaling: Implications for Cancer Cell Migration and Metastasis.
B. Annamalai, X. Liu, U. Gopal, and J. S. Isaacs (2009)
Mol. Cancer Res. 7, 1021-1032
   Abstract »    Full Text »    PDF »
Quantitative Phosphoproteomics Reveals a Cluster of Tyrosine Kinases That Mediates Src Invasive Activity in Advanced Colon Carcinoma Cells.
C. Leroy, C. Fialin, A. Sirvent, V. Simon, S. Urbach, J. Poncet, B. Robert, P. Jouin, and S. Roche (2009)
Cancer Res. 69, 2279-2286
   Abstract »    Full Text »    PDF »
Induction of cell retraction by the combined actions of Abl-CrkII and Rho-ROCK1 signaling.
X. Huang, D. Wu, H. Jin, D. Stupack, and J. Y.J. Wang (2008)
J. Cell Biol. 183, 711-723
   Abstract »    Full Text »    PDF »
Endothelial EphA receptor stimulation increases lung vascular permeability.
J. Larson, S. Schomberg, W. Schroeder, and T. C. Carpenter (2008)
Am J Physiol Lung Cell Mol Physiol 295, L431-L439
   Abstract »    Full Text »    PDF »
Identification and Functional Analysis of Phosphorylated Tyrosine Residues within EphA2 Receptor Tyrosine Kinase.
W. B. Fang, D. M. Brantley-Sieders, Y. Hwang, A.-J. L. Ham, and J. Chen (2008)
J. Biol. Chem. 283, 16017-16026
   Abstract »    Full Text »    PDF »
Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism.
W. B. Fang, R. C. Ireton, G. Zhuang, T. Takahashi, A. Reynolds, and J. Chen (2008)
Development 135, e1
   Full Text »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882