Expression of the
alpha6beta4 integrin is associated with poor patient prognosis and reduced survival in a variety of human
cancers. In recent years, a limited number of in vivo studies have examined the contribution of this
integrin receptor to
cancer progression and they have revealed that the
alpha6beta4 integrin plays a multifaceted role in regulating
tumor development and progression. In the current study, we investigated the mechanism by which one
tyrosine residue in the beta4 subunit cytoplasmic domain, Y1494, contributes to the
tumor-promoting functions of the
alpha6beta4 integrin in vivo. We show that Y1494 participates in the stimulation of diverse signaling pathways that promote alpha6beta4-dependent
tumor growth and invasion. Mutation of Y1494 inhibits the ability of the
alpha6beta4 integrin to support anchorage-independent growth in vitro and
tumor development and angiogenesis in vivo, a result that mimics the loss of total expression of the beta4 subunit. Our results support the hypothesis that Y1494 regulates alpha6beta4-dependent anchorage-independent growth through activation of the
extracellular signal-regulated kinase 1/2 signaling pathway, and invasion through the combined activation of
phosphatidylinositol 3-kinase and Src. Collectively, our results identify Y1494 as a major regulatory site for signaling from the
alpha6beta4 integrin to promote
tumor development and progression.