Eph-receptor tyrosine kinases (Eph-RTKs) and their membrane-bound receptor-like
ligands, the
ephrins, represent a cell-cell signaling system that directs cellular migration during development. Differential expression in
cancer suggests similar roles in
tumor progression. We have previously shown that
ephrin-B2 mRNA is overexpressed in advanced
malignant melanomas (MM). In this study, immunohistochemistry revealed a most prominent expression of
ephrin-B2 in the invasive front of advanced MM. Therefore, we addressed the question of whether
ephrin-B2 signaling modulates MM cell migration and matrix interaction. Using a wild-type ephrin-B2-negative B16 mouse MM subclone we show that overexpression of
ephrin-B2 leads to the formation of multiple lamellipodia, enhanced polymerisation of actin fibers, and induction of focal adhesion complexes with constitutive activation of
focal adhesion kinase. Consequently, ephrin-B2-overexpressing B16 cells display a significant increase of beta1-integrin-mediated attachment to matrix components, preferentially
laminin and
fibronectin. As a further effect of
ephrin-B2 overexpression, we observed an accelerated migration in both Boyden chamber invasion experiments as well as in in vitro scratch-
wound assays. We conclude that
ephrin-B2 can act as a major modulator of cell migration and matrix interactions of MM cells, which possibly contributes to the expansion and metastatic spread of MM in vivo.