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E-Cadherin Regulates the Function of the EphA2 Receptor Tyrosine Kinase¹

Department of Basic Medical Sciences and Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907 [N. D. Z., M. A., M. S. K.]; Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati, Cincinnati, Ohio 45267 [M-F. C.]; and Department of Medicine, Rammelkamp Center for Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109 [B. W.]

EphA2 is a member of the Eph family of receptor tyrosine kinases, which are increasingly understood to play critical roles in disease and development. We report here the regulation of EphA2 by E-cadherin. In nonneoplastic epithelia, EphA2 was tyrosine-phosphorylated and localized to sites of cell-cell contact. These properties required the proper expression and functioning of E-cadherin. In breast cancer cells that lack E-cadherin, the phosphotyrosine content of EphA2 was decreased, and EphA2 was redistributed into membrane ruffles. Expression of E-cadherin in metastatic cells restored a more normal pattern of EphA2 phosphorylation and localization. Activation of EphA2, either by E-cadherin expression or antibody-mediated aggregation, decreased cell-extracellular matrix adhesion and cell growth. Altogether, this demonstrates that EphA2 function is dependent on E-cadherin and suggests that loss of E-cadherin function may alter neoplastic cell growth and adhesion via effects on EphA2.

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