UMMS Affiliation

Department of Cancer Biology

Publication Date

1998-12-16

Document Type

Article

Subjects

1-Methyl-3-isobutylxanthine; 1-Phosphatidylinositol 3-Kinase; 3',5'-Cyclic-AMP Phosphodiesterases; Antibodies; Antigens, Surface; Breast Neoplasms; Chemotaxis; Culture Media, Conditioned; Cyclic AMP; Female; Fibroblasts; Forskolin; Humans; Integrin alpha6beta4; Integrins; Kinetics; Lysophospholipids; Neoplasm Invasiveness; Phosphodiesterase Inhibitors; Pyrrolidinones; Rolipram; Signal Transduction; Tumor Cells, Cultured

Disciplines

Cancer Biology | Neoplasms

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.

DOI of Published Version

10.1083/jcb.143.6.1749

Source

J Cell Biol. 1998 Dec 14;143(6):1749-60. Link to article on publisher's website

Journal/Book/Conference Title

The Journal of cell biology

Related Resources

Link to Article in PubMed

PubMed ID

9852165

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