Protein Kinase C-Dependent Mobilization of the {alpha}6{beta}4 Integrin from Hemidesmosomes and Its Association with Actin-Rich Cell Protrusions Drive the Chemotactic Migration of Carcinoma Cells

doi:10.1083/jcb.146.5.1147

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

Original Article

Protein Kinase C–Dependent Mobilization of the ${alpha}$ 6β4 Integrin from Hemidesmosomes and Its Association with Actin-Rich Cell Protrusions Drive the Chemotactic Migration of Carcinoma Cells

Isaac Rabinovitz^a, Alex Toker^b, and Arthur M. Mercurio^a

^a Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215
^b Boston Biomedical Research Institute, Boston, Massachusetts 02114
Beth Israel Deaconess Medical Center-Dana 601, 330 Brookline Ave., Boston, MA 02215.(617) 975-5531(617) 667-7714

amercuri{at}bidmc.harvard.edu

We explored the hypothesis that the chemotactic migration ofcarcinoma cells that assemble hemidesmosomes involves the activationof a signaling pathway that releases the ${alpha}$ 6β4 integrin fromthese stable adhesion complexes and promotes its associationwith F-actin in cell protrusions enabling it to function inmigration. Squamous carcinoma-derived A431 cells were used becausethey express ${alpha}$ 6β4 and migrate in response to EGF stimulation.Using function-blocking antibodies, we show that the ${alpha}$ 6β4integrin participates in EGF-stimulated chemotaxis and is requiredfor lamellae formation on laminin-1. At concentrations of EGFthat stimulate A431 chemotaxis ( $~$ 1 ng/ml), the ${alpha}$ 6β4 integrinis mobilized from hemidesmosomes as evidenced by indirect immunofluorescencemicroscopy using mAbs specific for this integrin and hemidesmosomalcomponents and its loss from a cytokeratin fraction obtainedby detergent extraction. EGF stimulation also increased theformation of lamellipodia and membrane ruffles that contained ${alpha}$ 6β4 in association with F-actin. Importantly, we demonstratethat this mobilization of ${alpha}$ 6β4 from hemidesmosomes and itsredistribution to cell protrusions occurs by a mechanism thatinvolves activation of protein kinase C- ${alpha}$ and that it is associatedwith the phosphorylation of the β4 integrin subunit onserine residues. Thus, the chemotactic migration of A431 cellson laminin-1 requires not only the formation of F-actin–richcell protrusions that mediate ${alpha}$ 6β4-dependent cell movementbut also the disruption of ${alpha}$ 6β4-containing hemidesmosomesby protein kinase C.

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

1.used in this paper: BPAG, bullous pemphigoid antigen; EGFR,EGF receptor; PKC, protein kinase C; PLC, phospholipase C; PI3K,phosphoinositide 3-OH kinase

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