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First published online 2 March 2004
doi: 10.1242/jcs.01003
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Research Article |
Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109 and the Department of Pathobiology, University of Washington, Seattle, Washington 98195, USA
* Author for correspondence (e-mail: difrank{at}fhcrc.org)
Accepted 21 November 2003
Repair of wounded epidermis requires both keratinocyte migration and deposition of laminin 5 over exposed dermal collagen. To understand the coupling between leading cell migration and laminin 5 deposition, we developed a novel migration assay using time-lapse microscopy. We demonstrate that in migrating, human keratinocytes the deposition of laminin 5 promoted `processive migration', characterized by stable cell polarization that was tightly coupled to persistent, linear migration in the absence of a chemotactic gradient. Processive migration required deposition of laminin 5, which was restricted to the rear of the polar cell. Integrin 
3ß1 interacted with these laminin 5 deposits at contact sites that did not require actin-dependent cross-linking. Further, we show that the migrating cells switched adhesion by integrin 2ß1 on collagen at the front of the cell to integrin 3ß1 on exogenous laminin 5 at the rear of the cell. Along with this switch of integrin usage was the removal of collagen from sites under the cell that precisely correlated with deposition of laminin 5. Processive migration was blocked with suppressors of microtubule dynamics (nocodazole and taxol) or rottlerin, a PKC-
inhibitor. These drugs were also shown to block deposition of laminin 5 but, surprisingly, constitutive secretion was unimpaired, suggesting deposition was a regulated event. Thus, at the front of the cell, the leading lamellipodium was stabilized through integrin interactions in focal complexes with the exogenous substratum. However, at the rear of the cell, stable cell polarization and linear migration was promoted by laminin 5 deposits and integrin 3ß1.
Key words: Integrins, Keratinocytes, Cell migration, Cell adhesion, Extracellular matrix
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