A signaling adapter function for α6β4 integrin in the control of HGF-dependent invasive growth

alpha6 beta4 integrin and the Met receptor for HGF have been shown independently to promote invasive growth. We demonstrate here that Met selectively associates with alpha6 beta4. In carcinoma cells expressing Met alone, HGF does not exert significant biological effects. Ectopic expression of alpha6 beta4 restores HGF-regulated processes. Following Met activation, alpha6 beta4 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 alpha6 beta4 mutant defective for Shc recruitment, Met cannot sustain HGF-mediated responses. Surprisingly, a truncated beta4 unable to bind laminins retains the activity of wild-type alpha6 beta4. Such findings invoke an unexpected role for alpha6 beta4 in cancer invasion as a functional amplifier of biochemical outputs rather than a mechanical adhesive device.