Discoidin domain receptor 2 regulates fibroblast proliferation and migration through the extracellular matrix in association with transcriptional activation of matrix metalloproteinase-2.
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.
Olaso
Elvira
E
Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Labrador
Juan-Pablo
JP
Wang
LiHsien
L
Ikeda
Kazuo
K
Eng
Francis J
FJ
Klein
Rudiger
R
Lovett
David H
DH
Lin
Hsin Chieh
HC
Friedman
Scott L
SL
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D000070818:Discoidin Domain Receptors; D005109:Extracellular Matrix / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology*; D017930:Genes, Reporter; D007700:Kinetics; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011975:Receptors, Mitogen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000166:cytology; D015533:Transcriptional Activation
D024042:Collagen Type I; D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D020778:Matrix Metalloproteinase 2