Inhibition of adhesion and induction of epithelial cell invasion by HAV- containing E-cadherin-specific peptides

The E-cadherin/catenin complex, an organizer of epithelial structure and function, is disturbed in invasive cancer. The HAV (histidine alanine valine) sequence in the first extracellular domain of E-cadherin is crucial for homophilic interactions between cadherins. We report that specific peptides containing an HAV sequence interfere with the functions of the E-cadherin/catenin complex. Cells either expressing specific cadherins or not were challenged with both cadherin and noncadherin peptides comprising a central HAV sequence. Specific E-cadherin peptides inhibited cell aggregation, disturbed the epithelial morphotype and were able to stimulate invasion of cells expressing E-cadherins. Conditioned medium, containing E-cadherin fragments, also stimulated invasion in contrast to conditioned medium from which the E-cadherin fragments were removed. Our studies show that Ecadherin functions are inhibited by homologous proteolytic HAV-containing fragments that are released in an autocrine manner and subsequently inhibit the Ecadherin/catenin complex. In this way such cadherin fragments may induce and support cancer invasion. SUMMARY