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Originally published In Press as doi:10.1074/jbc.M107571200 on November 26, 2001

J. Biol. Chem., Vol. 277, Issue 5, 3606-3613, February 1, 2002
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Discoidin Domain Receptor 2 Regulates Fibroblast Proliferation and Migration through the Extracellular Matrix in Association with Transcriptional Activation of Matrix Metalloproteinase-2*

Elvira OlasoDagger §, Juan-Pablo Labrador||**, LiHsien WangDagger Dagger , Kazuo IkedaDagger , Francis J. EngDagger , Rudiger Klein, David H. Lovett§§, Hsin Chieh LinDagger Dagger , and Scott L. FriedmanDagger ¶¶

From the Dagger  Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, the  Developmental Biology Program, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany, the || Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid Campus de Cantoblanco E-28049, Madrid, Spain, Dagger Dagger  Regeneron Pharmaceuticals, Incorporated, Tarrytown, New York 10591, and the §§ Department of Medicine and the Veterans Affairs Medical Center, University of California, San Francisco, California 94121

Discoidin domain receptor 2 (DDR2) is a tyrosine kinase receptor expressed in mesenchymal tissues, the ligand of which is fibrillar collagen. We have compared DDR2 signaling in skin fibroblasts derived from DDR2-/- and DDR2+/- mice. Proliferation of DDR2-/- fibroblasts was significantly decreased compared with DDR2+/- cells. DDR2-/- fibroblasts exhibited markedly impaired capacity to migrate through a reconstituted basement membrane (Matrigel) in response to a chemotactic stimulus, which correlated with diminished matrix metalloproteinase-2 (MMP-2) activity by gelatin zymography and diminished MMP-2 transcription of a minimal MMP-2 promoter. In contrast, a lack of DDR2 had no effect on cell motility or alpha -smooth muscle actin or vinculin expression. Additionally, expression of type I collagen was greatly reduced in DDR2-/- cells. Stable reconstitution of either wild-type DDR2 or constitutively active chimeric DDR2 in DDR2-/- cells by retroviral infection restored cell proliferation, migration through a reconstituted basement membrane (Matrigel), and MMP-2 levels to those of DDR2+/- fibroblasts. These data establish a role for DDR2 in critical events during wound repair.

* This work was supported by Grants DK39776 (to D. H. L.) and DK56621 (to S. L. F.) from the National Institutes of Health and by a grant from the Basque Government (to E. O.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: Dept. of Cellular Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, 48940-Vizcaya, Spain.

** Present address: Dept. of Molecular and Cellular Biology, 519 LSA, University of California, Berkeley, CA 94720.

¶¶ To whom correspondence and reprint requests should be addressed: Mount Sinai School of Medicine, Rm. 1170F, 1425 Madison Ave., P. O. Box 1123, New York, NY 10029. Tel.: 212-659-9501; Fax: 212-849-2574; E-mail: frieds02@doc.mssm.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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