Discoidin Domain Receptor 2 Regulates Fibroblast Proliferation and Migration through the Extracellular Matrix in Association with Transcriptional Activation of Matrix Metalloproteinase-2

• Published in: The Journal of biological chemistry Vol. 277; no. 5; pp. 3606 - 3613
• Main Authors: Olaso, Elvira, Labrador, Juan-Pablo, Wang, LiHsien, Ikeda, Kazuo, Eng, Francis J., Klein, Rudiger, Lovett, David H., Lin, Hsin Chieh, Friedman, Scott L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2002; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Adhesion - physiology; Cell Differentiation - physiology; Cell Line; Cell Movement - physiology; Cells, Cultured; Collagen Type I - biosynthesis; Discoidin Domain Receptors; Extracellular Matrix - physiology; Fibroblasts - cytology; Genes, Reporter; Kinetics; Matrix Metalloproteinase 2 - genetics; Mice; Mice, Knockout; Phosphorylation; Receptor Protein-Tyrosine Kinases - deficiency; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, Mitogen - deficiency; Receptors, Mitogen - genetics; Receptors, Mitogen - metabolism; Skin - cytology; Transcriptional Activation; vinculin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M107571200

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 α-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.