discoidin domain receptor
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Author(s):  
Charles Saby ◽  
Erik Maquoi ◽  
Frédéric Saltel ◽  
Hamid Morjani

Type I collagen, the major components of breast interstitial stroma, is able to regulate breast carcinoma cell behavior. Discoidin domain receptor 1 (DDR1) is a type I collagen receptor playing a key role in this process. In fact, collagen/DDR1 axis is able to trigger the downregulation of cell proliferation and the activation of BIK-mediated apoptosis pathway. The aim of this review is to discuss the role of two important factors that regulate these processes. The first factor is the level of DDR1 expression. DDR1 is highly expressed in epithelial-like breast carcinoma cells, but poorly in basal-like ones. Moreover, DDR1 undergoes cleavage by MT1-MMP, which is highly expressed in basal-like breast carcinoma cells. The second factor is type I collagen remodeling since DDR1 activation depends on its fibrillar organization. Collagen remodeling is involved in the regulation of cell proliferation and apoptosis through age- and proteolysis-related modifications.


2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yun-Sen Zhu ◽  
Jiang-Nan Zhang ◽  
Ting-Ting Mo ◽  
Chang Jiang ◽  
Ru-Chao Ma ◽  
...  

Abstract Objective The present study aimed to determine the role of the discoidin domain receptor 2 (DDR2) in the osteonectin (ON) regulation of osteoblast mineralization through the activation of p38 mitogen-activated protein kinase (MAPK). Methods Four groups were established: the ON group, the inhibitor group, the Ddr2-small interfering ribonucleic acid (siRNA) group, and the control group. Osteoblasts from the parietal bones of neonatal Sprague–Dawley rats were isolated and cultured. In the ON group, 1 µg/mL ON was added to the osteoblasts. The gene expressions of collagen 1 (Col 1) and Ddr2 were detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In the inhibitor group, the osteoblasts were added to WRG-28 (a specific DDR2 inhibitor), and in the Ddr2-siRNA group, the osteoblasts were transfected with Ddr2-siRNA. The gene and protein expressions of DDR2, bone sialoprotein, osteocalcin, osteopontin, and p38 MAPK were determined using RT-qPCR and western blot analysis. Alizarin red staining and transmission electron microscopy were used to detect mineralization. Results The results showed that ON enhanced the osteoblast Col 1 and Ddr2 gene expressions, while the use of a Ddr2-siRNA/DDR2-blocker decreased the OPN, BSP, OCN, and P38 gene and protein expressions and reduced osteoblast cellular activity and mineralized nodules. Conclusion The present study demonstrated that DDR2 activation of p38 MAPK is an important approach to ON-regulating osteoblast mineralization.


Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1671
Author(s):  
William A. Denny ◽  
Jack U. Flanagan

The discoidin domain receptor tyrosine kinases DDR1 and DDR2 are distinguished from other kinase enzymes by their extracellular domains, which interact with collagen rather than with peptidic growth factors, before initiating signaling via tyrosine phosphorylation. They share significant sequence and structural homology with both the c-Kit and Bcr-Abl kinases, and so many inhibitors of those kinases are also effective. Nevertheless, there has been an extensive research effort to develop potent and specific DDR inhibitors. A key interaction for many of these compounds is H-bonding to Met-704 in a hydrophobic pocket of the DDR enzyme. The most widespread use of DDR inhibitors has been for cancer therapy, but they have also shown effectiveness in animal models of inflammatory conditions such as Alzheimer’s and Parkinson’s diseases, and in chronic renal failure and glomerulonephritis.


Author(s):  
Li Chen ◽  
Xiangyi Kong ◽  
Yi Fang ◽  
Shishir Paunikar ◽  
Xiangyu Wang ◽  
...  

Discoidin domain receptor tyrosine kinases (DDRs) are a class of receptor tyrosine kinases (RTKs), and their dysregulation is associated with multiple diseases (including cancer, chronic inflammatory conditions, and fibrosis). The DDR family members (DDR1a-e and DDR2) are widely expressed, with predominant expression of DDR1 in epithelial cells and DDR2 in mesenchymal cells. Structurally, DDRs consist of three regions (an extracellular ligand binding domain, a transmembrane domain, and an intracellular region containing a kinase domain), with their kinase activity induced by receptor-specific ligand binding. Collagen binding to DDRs stimulates DDR phosphorylation activating kinase activity, signaling to MAPK, integrin, TGF-β, insulin receptor, and Notch signaling pathways. Abnormal DDR expression is detected in a range of solid tumors (including breast, ovarian, cervical liver, gastric, colorectal, lung, and brain). During tumorigenesis, abnormal activation of DDRs leads to invasion and metastasis, via dysregulation of cell adhesion, migration, proliferation, secretion of cytokines, and extracellular matrix remodeling. Differential expression or mutation of DDRs correlates with pathological classification, clinical characteristics, treatment response, and prognosis. Here, we discuss the discovery, structural characteristics, organizational distribution, and DDR-dependent signaling. Importantly, we highlight the key role of DDRs in the development and progression of breast and ovarian cancer.


Author(s):  
Xiaoyu Yang ◽  
Jing Li ◽  
Liting Zhao ◽  
Yazhuo Chen ◽  
Zhijun Cui ◽  
...  

AbstractObesity is closely associated with low-bone-mass disorder. Discoidin domain receptor 2 (DDR2) plays essential roles in skeletal metabolism, and is probably involved in fat metabolism. To test the potential role of DDR2 in fat and fat-bone crosstalk, Ddr2 conditional knockout mice (Ddr2Adipo) were generated in which Ddr2 gene is exclusively deleted in adipocytes by Adipoq Cre. We found that Ddr2Adipo mice are protected from fat gain on high-fat diet, with significantly decreased adipocyte size. Ddr2Adipo mice exhibit significantly increased bone mass and mechanical properties, with enhanced osteoblastogenesis and osteoclastogenesis. Marrow adipocyte is diminished in the bone marrow of Ddr2Adipo mice, due to activation of lipolysis. Fatty acid in the bone marrow was reduced in Ddr2Adipo mice. RNA-Seq analysis identified adenylate cyclase 5 (Adcy5) as downstream molecule of Ddr2. Mechanically, adipocytic Ddr2 modulates Adcy5-cAMP-PKA signaling, and Ddr2 deficiency stimulates lipolysis and supplies fatty acid for oxidation in osteoblasts, leading to the enhanced osteoblast differentiation and bone mass. Treatment of Adcy5 specific inhibitor abolishes the increased bone mass gain in Ddr2Adipo mice. These observations establish, for the first time, that Ddr2 plays an essential role in the crosstalk between fat and bone. Targeting adipocytic Ddr2 may be a potential strategy for treating obesity and pathological bone loss simultaneously.


2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Ria Aryani Hayuningtyas ◽  
Myeonggil Han ◽  
Seoyeon Choi ◽  
Man Sup Kwak ◽  
In Ho Park ◽  
...  

Abstract Background C1q has been reported to reveal complement-independent roles in immune and non-immune cells. C1q binds to its specific receptors to regulate distinct functions that rely on the environment and cell types. Discoidin domain receptor 2 (DDR2) is activated by collagen and functions in wound healing by controlling matrix metalloproteinase (MMP) expression. Since C1q exhibits a collagen-like structure, we hypothesized that C1q might engage DDR2 to regulate wound healing and extracellular matrix (ECM) remodeling. Methods Cell-based assay, proximity ligation assay, ELISA, and surface plasmon analysis were utilized to investigate DDR2 and C1q binding. We also investigate the C1q-mediated in vitro wound healing ability using the human fibrosarcoma cell line, HT1080. Results C1q induced the phosphorylation of DDR2, p38 kinase, and ERK1/2. C1q and DDR2 binding improved cell migration and induced MMP2 and MMP9 expression. DDR2-specific shRNA reduced C1q-mediated cell migration for wound healing. Conclusions C1q is a new DDR2 ligand that promotes wound healing. These findings have therapeutic implications in wound healing-related diseases.


2021 ◽  
Author(s):  
Megan M. Corty ◽  
Alexandria P. Lassetter ◽  
Jo Q. Hill ◽  
Amy E. Sheehan ◽  
F. Javier Bernardo-Garcia ◽  
...  

Invertebrate axons and small caliber axons in mammalian peripheral nerves are unmyelinated but still ensheathed by glia. How this type of ensheathment is controlled and its roles in supporting neuronal function remain unclear. We performed an in vivo RNAi screen in Drosophila to identify glial genes required for axon ensheathment and identified the conserved receptor tyrosine kinase Discoidin domain receptor (Ddr). In larval peripheral nerves, loss of Ddr resulted in incomplete ensheathment of axons. We found a strong dominant genetic interaction between Ddr and the fly type XV/XVIII collagen Multiplexin (Mp), suggesting Ddr functions a collagen receptor to drive wrapping of axons during development. Surprisingly, while ablation of glia that wrap axons severely impaired larval motor behavior, incomplete wrapping in Ddr mutants was sufficient to support basic circuit function. In adult nerves, loss of Ddr from glia decreased long-term survival of sensory neurons and significantly reduced axon caliber without overtly affecting ensheathment. Our data establish a crucial role for non-myelinating glia in peripheral nerve development and function across the lifespan, and identify Ddr as a key regulator of axon-glia interactions during ensheathment.


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