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  • br Roles of DDR in epithelial cell differentiation br


    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 dnmt 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
    Introduction Collagen is the most abundant protein in the extracellular matrix. Collagen not only provides structural support for cells, tissues, and organs, but also mediates many important biological processes via its interactions with a diverse array of binding partners [[1], [2], [3], [4], [5], [6], [7]]. Dysregulation of these interactions can lead to significant disease pathology. For example, the interaction between discoidin domain receptor 2 (DDR2) and collagen is aberrantly elevated in osteoarthritis, resulting in induction of matrix metalloproteinase 13 and leading to degradation of articular cartilage [8,9]. A molecular-level understanding of DDR–collagen interactions and how they lead to DDR activation would provide the critical information needed to design selective antagonists for basic biomedical research and potential therapeutics. Herein we review the current efforts of using synthetic peptides and recombinant collagen to study these important interactions.
    DDR and collagen
    Use of synthetic peptides to study DDR–collagen interactions Designing synthetic peptides to dnmt mimic the collagen triple helix has been a rapidly developing field of research over the past few decades. Synthetic collagen-like peptides have been used to study the structure, the stability, and the biological function of collagen. The earliest works focused on synthesizing simple triple-helical tripeptide repeats such as (PPG) [77] and (POG) [78]. As more techniques to prepare collagen-like peptides and methods to characterize triple helices are being developed, our understanding of collagen and its interactions with other proteins has grown dramatically.
    Use of recombinant collagen to study DDR–collagen interactions Synthetic peptides have proven highly valuable in replicating the characteristics of collagen and in defining the sites on collagen essential for binding and studying protein–collagen interactions. There are, however, disadvantages to synthetic collagen-like peptides. First, the thermal stability of the Toolkit peptides (Collagen Toolkit II: Tm = 30–49 °C [102]; Collagen Toolkit III: Tm = 33–61 °C [103]) and other synthetic collagen-like peptides can be much higher than that of animal collagen (Tm ~37 °C), which can affect binding. Second, peptide impurity can lead to imperfect and less stable triple helices [114]. Third, cysteines in terminal triplets like those in the N- and C- terminal GPC triplets of Collagen Toolkit peptides may oxidize and lead to crosslinking and aggregation [115]. One plausible alternative to synthetic collagen-like peptides is recombinant collagen. Recombinant Escherichia coli system has been used to generate bacterial collagen-like constructs to study collagen interactions [[116], [117], [118], [119], [120]].