br Conclusions Overexpression of DDR might contribute to tum

Conclusions Overexpression of DDR2 might contribute to tumor progression in lung SQCC, and the T681I mutation we found in this work is an inactivating mutation. There is a possibility that not only activating mutation but also overexpression of DDR2 might be a molecular target for treatment of lung SQCC, and assessing that is a subject for future research.
Conflict of interest statement
In a recent issue of Journal of Molecular and Cellular Cardiology, George et al. [] examined the regulation of discoidin domain receptor 2 (DDR2) ubenimex in cardiac fibroblasts by angiotensin II (Ang II) and its functional link with fibroblast collagen production. Myocardial fibrosis is an underlying pathological feature in common with the development of irreversible heart failure due to several pathological etiologies. Clinically, fibrosis is characterized by the accumulation of extracellular matrix (ECM) proteins leading to a stiffening of the left ventricle (LV) and subsequent decrease in LV function , , , . In the non-diseased myocardium, ECM deposition surrounds the myocytes and provides structural integrity. In response to pathology, ECM production robustly increases , . Although fibrosis is linked to the development of heart failure, its relation to the pathophysiology of chronic pressure overload is not fully understood. Recent evidence has implicated the renin–angiotensin system in the progression of myocardial fibrosis as elevated levels of Ang II are associated with myocardial fibrosis in patients and animal models of atherosclerosis, hypertension, cardiac hypertrophy, and heart failure , , , . DDR2 is a tyrosine kinase collagen receptor expressed by multiple cell types (e.g. smooth muscle cells, osteoblasts, and fibroblasts) and is associated with pathological scarring of multiple organs, including the liver, lung, and pancreas , , . Nevertheless, the functional role of DDR2 in the myocardium remains unclear. George et al. present evidence that Ang II acts via protein kinase C to trigger p38 mitogen activated protein kinase (p38 MAPK)-mediated activation of nuclear factor-κB (NF-κB) leading to enhanced DDR2 transcription and collagen production in cardiac fibroblasts . The authors do a wonderful job determining the mechanism behind Ang II induced upregulation of DDR2 in cardiac fibroblasts. In addition, their result indicates that DDR2 acts as a positive modulator of collagen production highlighting a need to understand DDR2 in the progression of cardiac fibrosis in order to identify appropriate prognostic and therapeutic targets along the fibrosis continuum. DDR2 regulation of cardiac fibrosis The study by George et al. is notable for several reasons. One important outcome of this study was the demonstration of a relationship between DDR2 and collagen production in cardiac fibroblasts exposed to Ang II. The authors revealed that DDR2 and collagen production are locked in a cycle of mutual regulation through mechanisms that remain to be fully understood. DDR2 is activated by triple-helix collagen types I and III, resulting in an increase in matrix metalloproteinases (MMPs) (Fig. 1) [15], [16], [17], [18], [19], [20]. MMPs are key enzymes that regulate LV remodeling through proteolysis of multiple ECM proteins including collagens I and III. Fragments of these ECM proteins, termed matricryptins, regulate fibroblast migration and increase deposition of new ECM proteins including collagen [21], [22], [23]. In addition, transforming growth factor (Tgf)β activation is dependent on MMP cleavage of the carboxyl-terminal pro-region of Tgfβ thus facilitating a positive feed-back loop by amplifying collagen levels accessible to DDR2 [24], [25]. Future studies elucidating the mutual regulation of DDR2 and collagen will aid in a deeper understanding of DDR2 signaling in Ang II induced cardiac fibrosis. The stimulatory effect of Ang II on DDR2 expression was transient, as DDR2 levels returned to baseline after 12h of Ang II exposure. Interestingly, collagen also followed this pattern of transient expression, further demonstrating the positive regulatory relationship between DDR2 and collagen. The short-term effect of Ang II may be due to DDR2 turnover and may serve to prevent excessive collagen production. While there is no direct evidence for DDR2 shedding in vivo, stimulation of osteoblasts with the soluble ectodomain of DDR2 inhibits collagen deposition in vitro suggesting that ectodomain shedding may be one mechanism of DDR2 regulation [26], [27]. Additional experiments focusing on the mechanisms of DDR2 removal, whether through ectodomain shedding or some other mechanism, are necessary to better comprehend the Ang II induced cardiac fibrosis pathway.