A team effort in our lab led to the elucidation of the mechanism by which α6β4 mediates signal transduction. Fabrizio Mainiero discovered that ligand binding to α6β4 elicits tyrosine phosphorylation of the β4 cytoplasmic domain, recruitment of Shc, and activation of Ras to ERK signaling. Agnese Mariotti and Laurent Gagnoux-Palacios identified the SFKs Fyn and Yes as integrin-associated tyrosine kinases. Mike Dans mapped the four major tyrosine phosphorylation sites and defined the mechanism of recruitment of Shc. Fabrizio Mainiero and Agnese Mariotti demonstrated that the EGF-R combines with α6β4 and - through the integrin-associated SFK - induces phosphorylation of β4, causing disruption of hemidesmosomes and increased epithelial cell migration and proliferation. These results indicate that tyrosine phosphorylation of β4 promotes signaling but antagonizes assembly of hemidesmosomes, suggesting that these two functions may be mutually exclusive. Chiara Murgia and Pamela Blaikie generated mice carrying two distinct targeted deletions of the cytoplasmic domain of β4 and demonstrated that the β4 cytoplasmic tail is necessary for stable epidermal adhesion and proliferation in vivo. These mouse models inform our understanding of the physiological function of α6β4 and the pathogenesis of a class of human blistering skin diseases, PA-JEB, which are caused by mutations in the genes encoding α6, β4, or laminin-5.
