Release of cAMP Gating by the {alpha}6{beta}4 Integrin Stimulates Lamellae Formation and the Chemotactic Migration of Invasive Carcinoma Cells

doi:10.1083/jcb.143.6.1749

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© The Rockefeller University Press, 0021-9525/1998//1749 $5.00
The Journal of Cell Biology, Volume 143, Number 6, , 1998 1749-1760

Article

Release of cAMP Gating by the ${alpha}$ 6β4 Integrin Stimulates Lamellae Formation and the Chemotactic Migration of Invasive Carcinoma Cells

Kathleen L. O'Connor, Leslie M. Shaw, and Arthur M. Mercurio

Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

The ${alpha}$ 6β4 integrin promotes carcinoma in-vasion by its activationof 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 ${alpha}$ 6β4 stimulates chemotactic migration, a key component of invasion, but that it has noinfluence on haptotaxis. Stimulation of chemotaxis by ${alpha}$ 6β4expression was observed in response to either lysophosphatidicacid (LPA) or fibroblast conditioned medium. Moreover, theLPA-dependent formation of lamellae in these cells is dependentupon ${alpha}$ 6β4 expression. Both lamellae formation and chemotacticmigration are inhibited or "gated" by cAMP and our results reveal that a critical function of ${alpha}$ 6β4 is to suppress the intracellular cAMP concentration by increasing the activityof a rolipram-sensitive, cAMP-specific phosphodiesterase (PDE).This PDE activity is essential for lamellae formation, chemotacticmigration and invasion based on data obtained with PDE inhibitors.Although PI3-K and cAMP-specific PDE activities are both requiredto promote lamellae formation and chemotactic migration, ourdata indicate that they are components of distinct signalingpathways. The essence of our findings is that ${alpha}$ 6β4 stimulatesthe chemotactic migration of carcinoma cells through its abilityto influence key signaling events that underlie this criticalcomponent of carcinoma invasion.

Key Words: integrin • migration • cyclic AMP • phosphodiesterase • cytoskeleton

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.

We would also like to thank M. Conti and S. Iona (Stanford University, Stanford, CA) for their generous contribution of the PDE 4antibodies, as well as S. Akiyama for the β1 integrinantibody. We also thank R. Falcioni, (Regina Elena Cancer Institute,Rome, Italy), R. Bachelder, I. Rabinovitz, and D. Senger (allthree from Beth Israel Deaconess Medical Center, Boston, MA)for their comments and discussions regarding the manuscript.

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