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Vol. 20, Issue 13, 3012-3024, July 1, 2009

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Clustering of Syndecan-4 and Integrin β1 by Laminin 3 Chain–derived Peptide Promotes Keratinocyte Migration

Eri Araki^*, Yutaka Momota, Takeshi Togo, Miki Tanioka^*, Kentaro Hozumi, Motoyoshi Nomizu, Yoshiki Miyachi^*, and Atsushi Utani^*

*Departments of Dermatology, and Plastic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Department of Veterinary Internal Medicine, Faculty of Agriculture, Iwate University, Iwate 020-8550, Japan; and School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan

Submitted September 25, 2008; Revised April 2, 2009; Accepted April 22, 2009
Monitoring Editor: M. Bishr Omary

Syndecans function as receptors for extracellular matrix (ECM) with integrins in cell spreading. However, the molecular mechanism of their specific involvement in cell migration or in wound healing has not been elucidated yet. Here, we report that a synthetic peptide, PEP75, which contains the syndecan-binding sequence of the laminin 3LG4 module, induces keratinocyte migration in in vitro and in vivo. Soluble PEP75 induced the clustering of syndecan-4 and conformation-modified integrin β1 colocalized with syndecan-4 in soluble PEP75-induced clusters. Treatment of cells in solution with PEP75 resulted in the exposure of the P4G11 antibody epitope of integrin β1 in immunostaining as well as in flow cytometry and augmented integrin β1–dependent cell adhesion to ECM. Pulldown assays demonstrated that PEP75 bound to syndecan-4, but not to integrin β1. A siRNA study revealed a role for syndecan-4 in PEP75-induced up-regulation of P4G11 antibody binding and migration of HaCaT cells. We conclude that binding of soluble PEP75 to syndecan-4 induces the coupling of integrin β1, which is associated with integrin β1-conformational changes and activation, and leads to keratinocyte migration. To activate integrin function through syndecans could be a novel therapeutic approach for chronic wound.

Address correspondence to: Atsushi Utani (utani{at}kuhp.kyoto-u.ac.jp)

Abbreviations used: ECM, extracellular matrix.

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