Release of cAMP gating by the alpha6beta4 integrin stimulates lamellae formation and the chemotactic migration of invasive carcinoma cells
UMass Chan Affiliations
Department of Cancer BiologyDocument Type
Journal ArticlePublication Date
1998-12-16Keywords
1-Methyl-3-isobutylxanthine1-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
Cancer Biology
Neoplasms
Metadata
Show full item recordAbstract
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.Source
J Cell Biol. 1998 Dec 14;143(6):1749-60. Link to article on publisher's websiteDOI
10.1083/jcb.143.6.1749Permanent Link to this Item
http://hdl.handle.net/20.500.14038/26236PubMed ID
9852165Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1083/jcb.143.6.1749