α6β4 integrin and the Met receptor for HGF have been shown independently to promote invasive growth. We demonstrate here that Met selectively associates with α6β4. In carcinoma cells expressing Met alone, HGF does not exert significant biological effects. Ectopic expression of α6β4 restores HGF-regulated processes. Following Met activation, α6β4 is tyrosine phosphorylated and combines with Shc and PI3K, generating an additional signaling platform that potentiates HGF-triggered activation of Ras- and PI3K-dependent pathways. In the presence of an α6β4 mutant defective for Shc recruitment, Met cannot sustain HGF-mediated responses. Surprisingly, a truncated β4 unable to bind laminins retains the activity of wild-type α6β4. Such findings invoke an unexpected role for α6β4 in cancer invasion as a functional amplifier of biochemical outputs rather than a mechanical adhesive device.