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Adhesion-Independent 6ß4 Integrin Clustering Is Mediated by Phosphatidylinositol 3-Kinase

Department of Pathology, M. D. Anderson Cancer Center, Houston, Texas

Clustering of cell-surface integrins is known to augment integrin-mediated signal transduction, but mechanisms of integrin clustering are poorly understood. Here we report that adhesion-independent clustering of 6ß4 integrin, known to be important in mediating tumor cell motility, is driven by phosphatidylinositol 3-kinase (PI3K) but does not require activation of the PI3K-Akt pathway. We observed clustering of 6ß4 in breast carcinoma cells after adhesion-independent cross-linking of the ß4 integrin subunit. Clustering was significantly blocked when cross-linking was performed in the presence of PI3K inhibitors LY294002 and wortmannin. In contrast, no significant inhibition of clustering was observed with protein kinase C inhibitor GF109203X, rapamycin, or heparin. Although 6ß4 clustering was blocked by PI3K inhibitors, clustering was not associated with increased PI3K lipid kinase activity or increased phosphorylation of Akt. A novel role for PI3K in 6ß4 integrin clustering is proposed.

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