br Conflict statement br Discoidin domain receptor

Conflict statement
Discoidin domain receptor (DDR)1 belongs, together with its close analog DDR2, to a unique family of receptor tyrosine kinases (RTKs) containing a discoidin homology domain in their extracellular region []. DDRs are expressed during early embryonic development in different tissues: DDR2 mainly in POM 1 of mesenchymal origin, DDR1 mainly in epithelia. DDRs were initially discovered by homology cloning based on their catalytic kinase domains and were considered orphan receptors until 1997 when two independent research groups discovered that several different types of collagens are functional ligands [,] for DDRs. Though belonging to the larger family of collagen receptors including integrins α(x)β1 [,], platelet glycoprotein VI [,], leukocyte-associated immunoglobulin-like receptor 1 [], osteoclast-associated immunoglobulin-like receptor [] and G-protein-coupled receptor 56 (gene name ) [], DDRs are the only collagen-activated RTKs. Additionally, both DDR1 and DDR2, upon collagen binding, undergo autophosphorylation with very slow kinetics followed by a sustained response [,], drastically different from other RTKs that are activated in the course of minutes by soluble peptide-like growth factors. This uniquely slow activation kinetic is suggestive of a key role in long lasting and probably energy-voracious responses, rather than rapid responses to acute stimuli. As for other RTKs, DDR1 shows ectodomain (ECD) shedding in both constitutive [] and collagen-induced circumstances [,]. Shedding has been shown to be mediated by proteolytic activity of the membrane-anchored collagenases, membrane-type (MT) 1-, MT2- and MT3-matrix metalloproteinases (MMP) []. The shedding process is not well understood and its significance is unknown [], but it certainly is an inherent part of DDR1 mode of action (MoA). The molecular basis of the DDR-collagen interaction at the level of the isolated ligand-binding domain is well understood, however, the biochemical and cellular mechanisms that control receptor de-activation and internalization, as well as the downstream molecular MoA, remain undefined. Though the DDR1 molecular MoA remains mysterious, the availability of a DDR1 deficient mouse [] allowed the scientific community to explore the role and relevance of DDR1 in multiple diseases including fibrosis [,,], cancer [] and atherosclerosis []. This review article focuses on the role of DDR1 in fibrosis. DDR1 distribution in healthy, fibrotic and inflamed tissues Whereas we can easily mine publicly available databases to infer DDR1 expression profile in different tissues (as reported in Fig. 1), fine comprehension of DDR1 biology has been hampered by the absence of a commercially available specific anti-human DDR1 antibody. For that reason, co-authors of the present review (S.M., M.P.) have devoted quite some time to clone and characterize (using both DDR1 and DDR2 overexpressing cell lines as well as naturally overexpressing cancer cell lines) [19] a highly selective anti-human DDR1. The coherent picture emerging for the expression of DDR1 in the skin, liver, kidney and lung is summarized in Fig. 2. In normal skin, DDR1 is expressed in keratinocytes and in epithelial cells of glands whereas dermal fibroblasts do not express DDR1. In hypertrophic scars, DDR1 retains the same expression patterns in epithelial cells whereas no DDR1 was observed in myofibroblasts or in vascular smooth muscle cells. In normal liver, DDR1 is expressed in bile duct epithelial cells and at the periphery of hepatocytes, especially at the portal parenchymal interface. Portal fibroblasts do not express DDR1. In cholangiocarcinoma, DDR1 is expressed in proliferating tumoral epithelial cells but not in myofibroblasts. In normal kidney, DDR1 is expressed in the distal tubular cells and in the parietal epithelial cells of the Bowman capsule. In chronic kidney disease such as diabetic nephropathy, DDR1 retains the same expression patterns in tubular epithelial cells whereas no DDR1 expression is observed in myofibroblasts. In normal lung, DDR1 is expressed in bronchiolar epithelial cells as well as in type 1 and 2 alveolar pneumocytes. In IPF, DDR1 retains the same expression patterns in bronchiolar and alveolar epithelia whereas no positivity is observed in myofibroblasts.