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

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 ␣-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.

Stimulation of Proliferation of Rat Hepatic Stellate Cells by Galectin-1 and Galectin-3 through Different Intracellular Signaling Pathways

“…Activation of Eph family receptors by their cell-surface ligands was also reported to require at least 1 h for maximum receptor phosphorylation (69). In addition, tyrosine phosphorylation of discoidin domain receptor-2 caused by type I collagen was reported to take place at 30 min after stimulation and to last for 120 min (70,71), showing a time course very similar to that for our present observations. Thus, the time course of signal activation seems to be varied among the combination of ligands and their receptors, although the precise molecular mechanism for this variation is not known.…”

Wound angiogenesis as a function of tissue oxygen tension: A mathematical model

“…It was assumed that the buildup of ECM depends on fibroblast function (45,46) in the same manner that capillary sprout motion depends on the motion of the capillary tips; that is, the velocity v of the ECM density is given by…”

Rho Guanine Nucleotide Exchange Factor 5 Increases Lung Cancer Cell Tumorigenesis via MMP-2 and Cyclin D1 Upregulation

“…Furthermore, previous studies have shown a significant prognostic value for MMP-2 in NSCLC (41). Interestingly, expression and activation of MMP-2 and MMP-9 are complexly controlled by upstream signaling pathways, such as MAPKs (42), integrin (43), and discoidin domain receptor 2 (44). The transcription of MMP-2 and MMP-9 genes is regulated by upstream regulatory sequences, including NFkB-, AP-1-, and Ets-1-binding sites (9).…”