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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 (DeltaC), 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 DeltaC-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.
Highlights
Protein tyrosine phosphorylation is a powerful signal that regulates cell proliferation, cell invasion, and cell migration
The control A431D cells, EPHA2 receptor levels and induces mislocalization of EPHA2 in which do not express E-cadherin, exhibited loose association and both tumor cells and mouse embryonic stem cells
Cells, we studied the effects stimulation of ephrin-A1 resulted in cell-cell dissociation of overexpression of EPHA2 receptor tyrosine kinase in the in MCF-10A spheroids
Summary
Protein tyrosine phosphorylation is a powerful signal that regulates cell proliferation, cell invasion, and cell migration. Specific tyrosine kinase inhibitors, such as inhibitors of the Her-2/Neu receptor and EGFR, have been developed for cancer therapeutics with varying degrees of success. Exciting in their clinical effectiveness, these inhibitors are only suitable for treating a small subset of cancer types. A new family of receptor tyrosine kinases, the Eph family, plays a critical role in cancer. The level of EPHA2 receptor expressed on tumor cells correlates with the degree of tumor malignancy (Kinch and CarlesKinch, 2003). Overexpression of the EPHA2 receptor in MCF-10A cells is associated with increased cell growth in soft agar and increased tumor growth when these cells were implanted into nude mice (Zelinski et al, 2001). Despite the strong correlation of EPHA2 receptor expression with malignant phenotypes, the mechanisms by which EPHA2 contributes to tumor cell malignancy are not completely understood
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