The hepatocyte growth factor/scatter factor (HGF/SF) receptor c-Met and variants of the CD44 family of surface adhesion molecules, including CD44v6, have been implicated in cancer progression and metastasis. CD44 isoforms bearing heparin sulfate chains can bind to HGF/SF and facilitate its presentation to c-Met. Here, we demonstrate that HGF/SF-Met binding up-regulates the expression of CD44v6 in murine melanoma cells, serving to compensate for loss by internalization. c-Met-mediated CD44v6 up-regulation was achieved through transcriptional activation of the immediate early gene egr-1. Enhanced egr-1 expression was apparent at the level of RNA 40 min after exposure to HGF/SF, and Egr-1 protein was detectable between 1 and 2 h post-treatment. CD44v6 RNA levels were correspondingly elevated 2 h after HGF/SF exposure. HGF/SF induced egr-1 activation via the Ras>Erk1/2 pathway but not through either phosphatidylinositol 3′-kinase or protein kinase C. Binding of NK2, a naturally occurring splice variant of HGF/SF, to c-Met failed to induce either Egr-1 or CD44v6, accounting at least in part for its antagonistic behavior. We also identified an Egr-1-binding site in the mouse CD44 gene promoter that accounts for its responsiveness to HGF/SF in melanoma cells. The compensatory up-regulation of both c-Met and CD44v6 in response to HGF/SF has important implications with respect to strategies used by cancer cells to sustain stimulation of growth- and metastasis-promoting pathways associated with tumor progression.