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  • There are two types of


    There are two types of DDRs, DDR1 and DDR2, which are type I transmembrane RTKs characterized by an N-terminal extracellular discoidin domain containing a collagen binding site [8]. DDR1 expression is somewhat restricted to epithelial cells, while DDR2 is often expressed in cells of mesenchymal origin. A recent study in ovarian cancer found that DDR1 is associated with an epithelial phenotype of ovarian cancer cells, with DDR1 displaying higher expression in the epithelial-like cells than in the mesenchymal-like cells. Interestingly, an opposing trend was observed in the expression of DDR2. This DDR switching phenomenon may be induced by certain EMT transcription factors such as Slug, as well as epigenetic mechanisms [77,78]. Although the function of each DDR is still not well-defined, the phenotype-specific expression of the receptors indicates that they might have specific functions in the context of EMT. The ECM and stroma of tumors undergoes constant remodeling. Consistent with this, collagen is dynamically degraded, deposited, cross-linked, and stiffened, resulting in an increased deposition of collagen as a tumor progresses [70]. DDR1 and DDR2 recognize the GVMGFO (Gly-Val-Met-Gly-Phe-Hyp) motif within fibrillar collagens I–III and V [8]. DDR1 is also bound and activated by collagen IV while DDR2 also interacts with collagen X. Since DDR mineralocorticoid receptor antagonists on collagens are distinct from integrin binding sites, the simultaneous activation of DDRs and integrins is possible, and actually DDRs and integrins together can contribute to the elevation of N-cadherin in pancreatic cancer [11]. DDR1 consists of an extracellular discoidin domain, followed by an extracellular juxtamembrane region, a single transmembrane domain, then an unusually large cytosolic juxtamembrane domain which contains phosphorylatable tyrosines that may serve as docking sites for many other proteins, and a catalytic kinase domain near the C-terminus (Fig. 2). There are five different isoforms of DDR1 (a–e) generated through alternative splicing. Of all the isoforms, DDR1a and DDR1b are the most widely distributed, while the others are less common or lack kinase activity. The only difference between DDR1a and DDR1b is that DDR1a lacks a 37-residue segment present in the cytosolic juxtamembrane region. This segment contains two important phosphorylation sites, Y513 and Y520. After phosphorylation, Y513 and Y520 are reported to bind to Src homology and collagen homology 1 (Shc1) and c-src tyrosine kinase (Csk), respectively [[79], [80], [81]]. Compared to DDR1, the intracellular signaling pathway of DDR2 is poorly defined, although several potential downstream effectors of DDR2 signaling have been identified through phosphoproteomic analysis, such as SHP-2, NCK1, the SRC family kinase LYN, phospholipase C-like 2 (PLCL2), and phosphatidylinositol-4-phosphate 3-kinase (PIK3C2A) [82].
    Induction of cadherin switching by DDRs Understanding cellular changes caused by collagen is important, since many diseases, including tumors such as pancreatic cancer, are characterized by extensive deposition of collagen. Many cell types can undergo EMT in response to collagen. Studies in Ras-transformed MDCK cells demonstrate that fibronectin and laminin 1 inhibit cell migration by establishing E-cadherin-mediated cell-cell adhesion, while collagen prevents the formation of E-cadherin adhesions [83]. This indicates that collagen signaling is distinct from other ECM signaling pathways in the regulation of cadherin switching. Different mechanisms of cadherin switching induced by collagen have been reported. For example, collagen induces activation of FAK and recruitment to the E-cadherin-catenin complex [84]. As a result, FAK-dependent phosphorylation of β-catenin is increased. This leads to the nuclear translocation of β-catenin and the expression of β-catenin target genes which may drive the cadherin switching event. Moreover, stimulation with collagen can also activate integrin-linked kinase (ILK), thus increasing the phosphorylation of IκB and subsequent nuclear translocation of active NF-κB [85]. ILK also causes inhibitory phosphorylation of GSK-3β, which, together with activated NF-κB, leads to a functional increase of Snail and LEF-1 expression. As a result, the expression of E-cadherin is reduced. In addition, collagen induces the secretion of TGFβ in some cells, and cause cadherin switching in a canonical TGFβ signaling-dependent manner [86].