Discoidin domain receptors regulate the migration of primary human lung fibroblasts through collagen matrices

Transwell migration experiments showed that normal human lung fibroblast (NHLF) transmigration through collagen I-coated inserts is mediated by DDR2 and the DDR2-associated signaling kinases JAK2 and ERK1/2, but not DDR1. Additionally, experiments with specific small interfering (si)RNAs revealed that collagen I-induced expression of MMP-10 and MMP-2 is DDR2 but not DDR1 dependent in NHLFs. Our data showed that collagen I increases NHLF migration through collagen IV, the main component of basement membranes. Furthermore, basal and collagen I-induced NHLF migration through collagen IV-coated inserts was both DDR2 and DDR1 dependent. Finally, DDR2, but not DDR1 was shown to be involved in fibroblast proliferation.Our results suggest a mechanism by which the presence of collagen I in situations of excessive matrix deposition could induce fibroblast migration through basement membranes through DDR2 activation and subsequent DDR1 and MMP-2 gene expression. This work provides new insights into the role of DDRs in fibroblast function.Discoidin domain receptors (DDRs) are non-integrin collagen receptors that belong to the receptor tyrosine kinase family [1]. There are two related DDRs, DDR1 and DDR2. DDR1 is mainly expressed in epithelial cells, particularly of the lung, kidney, mammary gland and gastrointestinal tract, whereas DDR2 is primarily found in cells of mesenchymal origin, such as fibroblasts and smooth muscle cells [1,2]. DDR1 can be activated by most collagens including collagen I to IV and VIII, while DDR2 responds to collagen I and to a lesser extent to collagen II, III and V, but does not recognize collagen IV [3]. Collagen I is the most abundant protein of interstitial connective tissue, whereas the more flexible, network-forming collagen IV is the most important structural component of basement membranes [4].Studies with knockout mice and human carcinoma cells have shown that DDR1 and DDR2 play important roles in the expression of proinflammatory and profib