ACTIVATION OF PHOSPHOINOSITIDE 3-OH KINASE BY THE ALPHA-6-BETA-4 INTEGRIN PROMOTES CARCINOMA INVASION

We demonstrate that the alpha 6 beta 4 integrin promotes carcinoma inv asion through a preferential and localized targeting of phosphoinositi de-3 OH kinase (PI3K) activity. Stable expression of alpha 6 beta 4 in creased carcinoma invasion in a PI3K-dependent manner, and transient e xpression of a constitutively active PI3K increased invasion in the ab sence of alpha 6 beta 4. Ligation of alpha 6 beta 4 stimulated signifi cantly more PI3K activity than ligation of beta 1 integrins, establish ing specificity among integrins for PI3K activation. alpha 6 beta 4-re gutated PI3K activity was required for the formation of lamellae, dyna mic sites of motility, in carcinoma cells. The small G protein Rac is required downstream of PI3K for invasion. These studies define a mecha nism by which the alpha 6 beta 4 integrin promotes carcinoma invasion and invoke a novel function for PI3K signaling.