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 fu nction, is disturbed in invasive cancer. The HAV (histidine alanine valine) sequence in the first extracellular domain of E-cadherin is crucial for he mophilic interactions between cadherins, We report that specific peptides c ontaining an HAV sequence interfere with the functions of the E-cadherin/ca tenin complex. Cells either expressing specific cadherins or not were chall enged with both cadherin and noncadherin peptides comprising a central HAV sequence, Specific E-cadherin peptides inhibited cell aggregation, disturbe d the epithelial morphotype and were able to stimulate invasion of cells ex pressing 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 E-cadherin function s are inhibited by homologous proteolytic HAV-containing fragments that are released in an autocrine manner and subsequently inhibit the E- cadherin/c atenin complex. In this way such cadherin fragments may induce and support cancer invasion.