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© The Rockefeller University Press, 0021-9525/1999/9/1147/ $5.00
The Journal of Cell Biology, Volume 146, Number 5, September 6, 1999 1147-1160

Protein Kinase C–dependent Mobilization of the {alpha}6ß4 Integrin from Hemidesmosomes and Its Association with Actin-rich Cell Protrusions Drive the Chemotactic Migration of Carcinoma Cells

Isaac Rabinovitza, Alex Tokerb, and Arthur M. Mercurioa
a Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215
b Boston Biomedical Research Institute, Boston, Massachusetts 02114

Correspondence to: Arthur M. Mercurio, Beth Israel Deaconess Medical Center-Dana 601, 330 Brookline Ave., Boston, MA 02215. Tel:(617) 667-7714 Fax:(617) 975-5531 E-mail:amercuri{at}bidmc.harvard.edu.

We explored the hypothesis that the chemotactic migration of carcinoma cells that assemble hemidesmosomes involves the activation of a signaling pathway that releases the {alpha}6ß4 integrin from these stable adhesion complexes and promotes its association with F-actin in cell protrusions enabling it to function in migration. Squamous carcinoma-derived A431 cells were used because they express {alpha}6ß4 and migrate in response to EGF stimulation. Using function-blocking antibodies, we show that the {alpha}6ß4 integrin participates in EGF-stimulated chemotaxis and is required for lamellae formation on laminin-1. At concentrations of EGF that stimulate A431 chemotaxis (~1 ng/ml), the {alpha}6ß4 integrin is mobilized from hemidesmosomes as evidenced by indirect immunofluorescence microscopy using mAbs specific for this integrin and hemidesmosomal components and its loss from a cytokeratin fraction obtained by detergent extraction. EGF stimulation also increased the formation of lamellipodia and membrane ruffles that contained {alpha}6ß4 in association with F-actin. Importantly, we demonstrate that this mobilization of {alpha}6ß4 from hemidesmosomes and its redistribution to cell protrusions occurs by a mechanism that involves activation of protein kinase C-{alpha} and that it is associated with the phosphorylation of the ß4 integrin subunit on serine residues. Thus, the chemotactic migration of A431 cells on laminin-1 requires not only the formation of F-actin–rich cell protrusions that mediate {alpha}6ß4-dependent cell movement but also the disruption of {alpha}6ß4-containing hemidesmosomes by protein kinase C.

Key Words: integrins, cell movement, PKC, hemidesmosomes, cytoskeleton


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