Dynamic Functions of the α6β4 Integrin in Carcinoma

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Abstract

The α6β4 integrin plays pivotal but distinct roles in the biology of epithelial and carcinoma cells. In healthy epithelia, its major function is to anchor the epithelium to the basement membrane as a component of either Type I or Type II hemidesmosomes. The signaling capacity of this integrin in the hemidesmosome appears to be minimal. Epithelial wounds or, more importantly, factors linked to malignant transformation and progression can induce dramatic changes in the function of α6β4. In fact, a scenario is emerging of how the function of α6β4 is altered in carcinoma. Factors in the host-tumor microenvironment have the potential to mobilize α6β4 from hemidesmosomes and promote its association with F-actin. This association with F-actin enables this integrin to function in cell migration and to harness traction forces on laminin-containing matrices such as basement membranes, a process that could contribute to the remodeling of basement membranes during tumor invasion. Importantly, this altered localization of α6β4 appears to be coupled to an activation of its signaling potential. The primal signaling event triggered by α6β4 appears to be activation of PI3-K. Although the mechanism by which this occurs needs to be deciphered in more detail, especially with respect to the involvement of growth factor receptors, α6β4-mediated activation of PI3-K and its effectors such as Akt, mTOR and Rac has profound consequences on the biology of carcinoma cells. Arguably, the ability of α6β4 to stimulate the translation of VEGF and possibly other growth factors may be the most significant contribution of this integrin to cancer because of the potential autocrine and paracrine effects of these factors.