Activation of phosphoinositide 3-OH kinase by the α6β4 integrin promotes carcinoma invasion

We demonstrate that the alpha 6 beta 4 integrin promotes carcinoma invasion through a preferential and localized targeting of phosphoinositide-3 OH kinase (PI3K) activity. Stable expression of alpha 6 beta 4 increased carcinoma invasion in a PI3K-dependent manner, and transient expression of a constitutively active PI3K increased invasion in the absence of alpha 6 beta 4. Ligation of alpha 6 beta 4 stimulated significantly more PI3K activity than ligation of beta 1 integrins, establishing specificity among integrins for PI3K activation. alpha 6 beta 4-regutated PI3K activity was required for the formation of lamellae, dynamic sites of motility, in carcinoma cells. The small G protein Rac is required downstream of PI3K for invasion. These studies define a mechanism by which the alpha 6 beta 4 integrin promotes carcinoma invasion and invoke a novel function for PI3K signaling.