Release of cAMP gating by the alpha 6 beta 4 integrin stimulates lamellae formation and the chemotactic migration of invasive carcinoma cells

The alpha 6 beta 4 integrin promotes carcinoma invasion by its activation o f a phosphoinositide 3-OH (PI3-K) signaling pathway (Shaw, L.M., I. Rabinov itz, H.H.-F. Wang, A. Toker, and A.M. Mercurio. Cell. 91: 949-960). We demo nstrate here using MDA-MB-435 breast carcinoma cells that alpha 6 beta 4 st imulates chemotactic migration, a key component of invasion, but that it ha s no influence on haptotaxis, Stimulation of chemotaxis by alpha 6 beta 4 e xpression was observed in response to either lysophosphatidic acid (LPA) or fibroblast conditioned medium. Moreover, the LPA-dependent formation of la mellae in these cells is dependent upon alpha 6 beta 4 expression. Both lam ellae formation and chemotactic migration are inhibited or "gated" by cAMP and our results reveal that a critical function of alpha 6 beta 4 is to sup press the intracellular cAMP concentration by increasing the activity of a rolipram-sensitive, cAMP-specific phosphodiesterase (PDE). This PDE activit y is essential for lamellae formation, chemotactic migration and invasion b ased on data obtained with PDE inhibitors. Although PI3-K and cAMP-specific PDE activities are both required to promote lamellae formation and chemota ctic migration, our data indicate that they are components of distinct sign aling pathways. The essence of our findings is that alpha 6 beta 4 stimulat es the chemotactic migration of carcinoma cells through its ability to infl uence key signaling events that underlie this critical component of carcino ma invasion.