Introduction Collagen deposition is a common feature

Introduction Collagen deposition is a common feature found in cancerous tissues and fibrotic organs/lesions. It is now well accepted that collagen deposition is not just a consequence of disease, but that it can also trigger a vicious cycle. Both chemical and physical signals elicited from collagen are involved in fibrotic disease progression (for concise reviews of this field: [[1], [2], [3]]). Therefore, how Viroptic transmit collagen signals and how these signals are regulated are critical issues in unveiling the underlying mechanism of disease progression. Integrins and discoidin domain receptors (DDRs) are the two most important and ubiquitously expressed collagen receptors. Four integrin heterodimers, including α1β1, α2β1, α10β1, and α11β1, show different binding affinities to different types of collagen, tissue-specific expression patterns, and different effects in development and disease progression [4,5]. Many emerging roles of DDRs in cell differentiation, development and disease progression have been discovered in this decade, and there are still many intriguing issues to be explored. Glycoprotein VI is another type of collagen receptor found in platelets, and it plays a critical role in collagen-induced platelet activation and aggregation [6,7]. This review focuses on the roles of DDRs.
Roles of DDR1 in epithelial cell differentiation
Roles of DDR1 in cell migration, and invasion
Dichotomous functions of DDR1 in disease progression
Conclusions and perspectives The switch in expression from DDR1 to DDR2 during EMT is another important issue. The DDRs may exert distinct or redundant functions. Further studies of the diverse signaling pathways mediated by the DDRs might provide new insight into the distinct functions of the DDRs. DDR1 down-regulation is not always observed during EMT, especially in cancerous tissues (Fig. 3). In fact, increased DDR1 expression is found in many malignant tumors. The dichotomous functions and dual faces of DDR1 lead to the issue of whether DDR1 is actually a suitable therapeutic target for cancer therapy. Another remaining issue is what causes the loss of sensitivity to the EMT-inducer that triggers DDR1 downregulation and in what types of cancer is this process relevant. Excessive collagen deposition and remodeling are regularly seen in fibrotic lesions and cancerous tissue. Increased collagen signaling not only impairs tissue architecture but also impacts tissues homeostasis, which can impair organ functions or accelerate cancer cell malignancy. Therefore, modulation of collagen signaling becomes a critical issue. The development of DDR inhibitors has shed some light on possible treatments for many diseases [107,[123], [124], [125], [126], [127], [128]]. However, many of these drugs can inhibit the kinase activities of both DDRs but not their kinase-independent functions. Drug discovery is still an important issue, and further assessment of the power of DDRs as therapeutic targets is need.
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 cells 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.