Abstract
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.
Highlights
§ Present address: Dept. of Cellular Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, 48940-Vizcaya, Spain
To determine whether a similar response is elicited by Discoidin domain receptor 2 (DDR2) in skin fibroblasts, soluble type I collagen was added to DDR2ϩ/Ϫ fibroblast for up to 16 h (Fig. 1)
DDR2 was immunoprecipitated from skin fibroblast lysates using polyclonal antibody R2-JM, and phosphorylated DDR2 was detected by immunoblotting with anti-phosphotyrosine antibody 4G10
Summary
Vol 277, No 5, Issue of February 1, pp. 3606 –3613, 2002 Printed in U.S.A. Discoidin Domain Receptor 2 Regulates Fibroblast Proliferation and Migration through the Extracellular Matrix in Association with Transcriptional Activation of Matrix Metalloproteinase-2*. 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. Interstitial matrices typical of healing wounds, which are rich in type I and III collagens, preserve fibroblasts in a synthetic phenotype, whereas matrices containing basement membrane components slow cell growth and matrix production [7] and receptor expression [8]. We explore the role of DDR2 signaling in fibroblast function
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