Abstract
The alpha6beta4 integrin promotes carcinoma in-vasion by its activation of a phosphoinositide 3-OH (PI3-K) signaling pathway (Shaw, L.M., I. Rabinovitz, H.H.-F. Wang, A. Toker, and A.M. Mercurio. Cell. 91: 949-960). We demonstrate here using MDA-MB-435 breast carcinoma cells that alpha6beta4 stimulates chemotactic migration, a key component of invasion, but that it has no influence on haptotaxis. Stimulation of chemotaxis by alpha6beta4 expression was observed in response to either lysophosphatidic acid (LPA) or fibroblast conditioned medium. Moreover, the LPA-dependent formation of lamellae in these cells is dependent upon alpha6beta4 expression. Both lamellae formation and chemotactic migration are inhibited or "gated" by cAMP and our results reveal that a critical function of alpha6beta4 is to suppress the intracellular cAMP concentration by increasing the activity of a rolipram-sensitive, cAMP-specific phosphodiesterase (PDE). This PDE activity is essential for lamellae formation, chemotactic migration and invasion based on data obtained with PDE inhibitors. Although PI3-K and cAMP-specific PDE activities are both required to promote lamellae formation and chemotactic migration, our data indicate that they are components of distinct signaling pathways. The essence of our findings is that alpha6beta4 stimulates the chemotactic migration of carcinoma cells through its ability to influence key signaling events that underlie this critical component of carcinoma invasion.
Highlights
The ␣64 integrin promotes carcinoma invasion by its activation of a phosphoinositide 3-OH (PI3-K) signaling pathway
We have established that the ability of ␣64 to stimulate carcinoma migration and invasion depends upon its preferential activation of a phosphoinositide 3-OH kinase (PI3-K)1/Rac signaling pathway that we [40] and Address correspondence to Arthur M
Abbreviations used in this paper: [cAMP]i, intracellular cyclic AMP concentration; DIC, differential–interference contrast; Gi, inhibitory type G protein; IBMX, isobutylmethylxanthine; LPA, lysophosphatidic acid; PDE; phosphodiesterase; PI3-K, phosphoinositide 3-OH kinase
Summary
The ␣64 integrin promotes carcinoma invasion by its activation of a phosphoinositide 3-OH (PI3-K) signaling pathway The LPA-dependent formation of lamellae in these cells is dependent upon ␣64 expression Both lamellae formation and chemotactic migration are inhibited or “gated” by cAMP and our results reveal that a critical function of ␣64 is to suppress the intracellular cAMP concentration by increasing the activity of a rolipram-sensitive, cAMP-specific phosphodiesterase (PDE). In contrast to its function in normal epithelia, ␣64 can stimulate carcinoma migration and invasion through its ability to interact with the actin cytoskeleton and mediate the formation and stabilization of lamellae [32] This dynamic function of ␣64 in enhancing the migration of invasive carcinoma cells is quite distinct from its role in maintaining stable adhesive contacts in normal epithelia by associating with intermediate filaments. Our studies have defined an integrin-mediated mechanism of carcinoma invasion that involves the stimulation of carcinoma migration by the dynamic association of ␣64 with F-actin and the activation of a specific signaling pathway by this integrin
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