br Signaling of DDR receptor and its regulation
Signaling of DDR2 receptor and its regulation Being the tyrosine kinase receptor, downstream signaling of DDR2 receptor is initiated by phosphorylation of cytoplasmic tyrosine residue upon ligand binding (Type II collagen) but the authentic facts or detail information of tyrosine phosphorylation upon the binding of collagen protein is not still clear to the researcher. A recent study on the phosphoproteomic showed that the collagen provoked DDR2 auto-phosphorylation were identified at two sites of the kinase domain (tyr684and tyr813) in the DDR2 signaling pathway . Additionally, an intriguing fact came in light about the site of JM domains (tyr481) that was found to be phosphorylated constitutively  but phosphorylation of tyr471, which was reported to be the docking site for adaptor shcA. Further Tyr471was not recognized utilizing anti-phosphotyrosine immune-precipitation and peptide identification following the protein STI571 . The expression of DDR2 receptor in various systems is different and implicates the involvements with several transcription factor/complexes. The ATF4-C/Ebb transcription factor is responsible for DDR2 expression in osteogenic differentiation system . In case of rat VSM cells, hypoxia or hyperbaric oxygen responsible for the enhanced My-Max binding activity of DDR2 promoter region lead to the increased expression of DDR2 receptor . However, the signaling and regulatory mechanism of DDR2 receptor is quite different depending upon the site of expression and types of molecules being sensed. In case of osteoarthritis, cartilage produces type II collagen in major amount which binds to DDR2 receptor provoking the activation of metalloproteinases (MMPs) for degradation of cartilage and DDR2 itself being activated in this cascade. Therefore, either inactivation or proper antagonist binding into DDR2 active site in OA induced mice model may stop the extent of disintegration of cartilage and the severity of diseases.
DDR2 receptor in cross talking mechanism at joints Cross talking pathway provides us a better understanding of the chondrocytes behavior as chondrocytes expressed several receptors that get activated by components of an extracellular matrix upon damage in articular cartilage. DDR2 receptor in OA chondrocytes has been highly expressed representing the key events in the progression of OA . The binding of type II collagen protein of cartilage preferentially induces DDR2 expression in chondrocytes but this interaction is also prevented by intact /uninjured proteoglycan of extracellular matrix (ECM). The cross taking pathway in intact ECM supports receptor to enable the cell polarity, differentiation and survival which are important for the normal cell functioning. The ECM of articular cartilage is disrupted in OA resulting in the production of collagen type II protein, aggrecan etc. which allows it to interact with the DDR2 receptor or any other unknown receptor. DDR2 receptor in chondrocytes further induces the expression of MMP-13 via up-regulation of TNF-α and IL-1β that contributes to the degeneration of articular cartilage pre-dominantly [4,33] as depicted in Fig. 2, Fig. 3. This is considered to be one of the key mechanisms in chondrocytes at the early stage of progression of osteoarthritis. Other findings again have strengthened the contribution of DDR2 receptor activation in the progression of OA as DDR2 appears to mediate collagen type II dependent release of catabolic cytokine IL-6 in primary human chondrocytes [4,24]. In integration to it, in-vitro studies have demonstrated that the DDR2 receptor activation is responsible for osteoblasts differentiation and chondrocytes maturation via RUNX2 (Runt-related transcription factor-2) activation pathway . This all information fortifies the paramount role of chondrocytes extracellular matrix in maintaining the cartilage integrity and highlights the conception of early structural alteration of ECM by the involution of DDR2 receptor in persuading the mechanism of OA progression.