Discoidin domain receptor 2 is associated with the increased expression of matrix metalloproteinase-13 in synovial fibroblasts of rheumatoid arthritis

Su, Jin; Yu, Jiangtian; Ren, Tingting; Zhang, Wei; Zhang, Yuanqiang; Liu, Xinping; Sun, Tiezheng; Lü, Hou-shan; Miyazawa, Keiji; Yao, Libo

doi:10.1007/s11010-009-0127-0

Cited by 49 publications

(58 citation statements)

References 35 publications

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“…Previously, we and others demonstrated that collagen II-DDR2-MMP-13 axis may contribute to articular cartilage destruction in arthritis [14,21]. These observations collectively suggest that Cbl-b abundance may impact DDR2-related pathogenesis.…”

Section: Discussionsupporting

confidence: 55%

Ubiquitin ligase Cbl‐b acts as a negative regulator in discoidin domain receptor 2 signaling via modulation of its stability

Zhao

Zhang

et al. 2014

FEBS Letters

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a b s t r a c tDiscoidin domain receptor 2 (DDR2), a collagen receptor tyrosine kinase, initiates signal transduction upon collagen binding, but little is known as to how DDR2 signaling is negatively regulated. Herein we demonstrate that Cbl family member Cbl-b predominantly promotes the ubiquitination of DDR2 upon collagen II stimulation. Cbl-b-mediated ubiquitination accelerates the degradation of activated DDR2. Finally, the production of MMP-13, a downstream target of DDR2, is enhanced in Cbl-b-knocked down MC3T3-E1 cells and Cbl-b-deficient mouse primary synovial fibroblasts. Thus, Cbl-b, by promoting the ubiquitination and degradation of DDR2, functions as a negative regulator in the DDR2 signaling pathway. Structured summary of protein interactions:DDR2 physically interacts with Cbl-b by anti tag coimmunoprecipitation (View interaction)

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Section: Discussionsupporting

confidence: 55%

Ubiquitin ligase Cbl‐b acts as a negative regulator in discoidin domain receptor 2 signaling via modulation of its stability

Zhao

Zhang

et al. 2014

FEBS Letters

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“…Over the past decade, different groups have identified several target genes downstream of DDR2 activation in various types of cells, including distinct MMPs, interlukin 6 (IL-6), and IL-12. (22,25,(27)(28)(29)(30)54,55) However, the detailed signaling pathways mediating DDR2 regulation of target-gene transcription remain ill-understood. Our study on DDR2 modulation of osteoblastic and chondroblastic gene expression enriches the target-gene list of DDR2.…”

Section: Discussionmentioning

confidence: 99%

“…The constitutively activated Ddr2 plasmid pSecTag2B-FcDDR2 was described previously. (30) The pCMV5-Runx2 was provided by professor Gerard Karsenty (Baylor University Medical School, Waco, TX, USA). Runx2 S301, 319E and Runx2 S301, 319A mutants were generated by polymerase chain reaction (PCR) and inserted into pcDNA3.1 vector (Invitrogen, Carlsbad, CA, USA).…”

Section: Plasmidsmentioning

confidence: 99%

“…In contrast, DDR2 is expressed specifically in stromal cells and regulates cell proliferation and controls remodeling of the ECM by influencing the expression and activity of several matrix metalloproteinases (MMPs). (23)(24)(25)(26)(27)(28)(29)(30) Mice lacking DDR1 or DDR2 are both smaller than their wild-type littermates, (31)(32)(33) but the defective organs seem to be different in the two genetic models. The majority of Ddr1 knockout females show multiple reproductive defects, whereas Ddr2 knockout mice exhibit shortening of long bones and irregular growth of flat bones, which have been attributed previously to reduced chondrocyte and fibroblast proliferation.…”

Section: Introductionmentioning

confidence: 99%

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An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation

Zhang

et al. 2010

Journal of Bone and Mineral Research

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Discoidin domain receptor 2 (DDR2) belongs to receptor tyrosine kinase (RTK) family and is activated by collagen binding. Although the bone defects in Ddr2 null mice have been reported for a decade, the molecular mechanism remains unclear. This study sought to investigate the function and detailed mechanism of DDR2 in osteogenic and chondrogenic differentiation. Herein we found that in preosteoblastic cells, DDR2 activation was enhanced by osteogenic induction but was not paralleled with the alteration of DDR2 expression. Under differentiated condition, downregulation of endogenous DDR2 through specific shRNA dramatically repressed osteoblastic marker gene expression and osteogenic differentiation. Enforced expression of constitutively activated DDR2 increased the expression of bone markers in both undifferentiated and differentiated osteoblasts. Importantly, molecular evidence showed that DDR2 regulated the transactivity of Runx2, a master transcription factor involved in skeletal development, by modulating its phosphorylation. Analysis of candidate protein kinases indicated that extracellular signal-regulated kinase (ERK) activation is responsive to DDR2 signaling and involved in DDR2 regulation of Runx2 phosphorylation and transcriptional activity. Notably, a gain-of-function mutant of Runx2 with enhanced ERK-independent phosphorylation rescued the impaired osteogenic phenotypes observed in Ddr2-silenced cells, whereas a Runx2 mutant devoid of phosphorylation regulation by ERK inhibited DDR2 induction of osteogenesis. In addition, DDR2 facilitated Runx2 transactivation and type X collagen expression in hypertrophic chondrocytes. Thus this study reveals for the first time that DDR2 plays an essential role in osteoblast and chondrocyte differentiation. The mechanism disclosure may provide therapeutic targets for human genetic disorders caused by DDR2 deficiency. ß

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“…Thus, DDR1 has been proposed to interact with several cofactors, including ShcA, Nck2, and Shp-2 (14,15), and STAT5, NF-B, and p38 MAPK (5,16,17). DDR2 appears to require the recruitment of Src for complete phosphorylation (5,18,19) and has been shown to signal through the ERK1/2 MAPK and activator protein (AP)-1 (20,21). However, detailed studies on the pathways activated by DDR 1 and 2 in different cell types and their transcriptional targets have not yet been described.…”

Section: Discoidin Domain Receptors (Ddrs)mentioning

confidence: 99%

Collagen I Induces Discoidin Domain Receptor (DDR) 1 Expression through DDR2 and a JAK2-ERK1/2-mediated Mechanism in Primary Human Lung Fibroblasts

Ruiz

Járai

2011

Journal of Biological Chemistry

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Discoidin domain receptors (DDRs) DDR1 and DDR2 are receptor tyrosine kinases with the unique ability among receptor tyrosine kinases to respond to collagen. Several signaling molecules have been implicated in DDR signaling, including Shp-2, Src, and MAPK pathways, but a detailed understanding of these pathways and their transcriptional targets is still lacking. Similarly, the regulation of the expression of DDRs is poorly characterized with only a few inflammatory mediators, such as lipopolysaccharide and interleukin-1␤ identified as playing a role in DDR1 expression. DDRs have been reported to induce the expression of various genes including matrix metalloproteinases and bone morphogenetic proteins, but the regulatory mechanisms underlying DDR-induced gene expression remain to be determined. The aim of the present work was to elucidate the molecular mechanisms implicated in the expression of DDRs and to identify DDR-induced signaling pathways and target genes. Our data show that collagen I induces the expression of DDR1 in a dose-and time-dependent manner in primary human lung fibroblasts. Furthermore, activation of DDR2, JAK2, and ERK1/2 MAPK signaling pathways was essential for collagen I-induced DDR1 and matrix metalloproteinase 10 expression. Finally, inhibition of the ERK1/2 pathway abrogated DDR1 expression by blocking the recruitment of the transcription factor polyoma enhancer A-binding protein 3 to the DDR1 promoter. Our data provide new insights into the molecular mechanisms of collagen I-induced DDR1 expression and demonstrate an important role for ERK1/2 activation and the recruitment of polyoma enhancer-A binding protein 3 to the DDR1 promoter. Discoidin domain receptors (DDRs)2 are non-integrin collagen receptors and constitute a unique subfamily of receptor tyrosine kinases containing a discoidin homology region in their extracellular domain (1). There are two related DDRs: DDR1 and DDR2. DDR1 is mainly expressed in epithelial cells, particularly of the lung, kidney, mammary gland, and gastrointestinal tract, whereas DDR2 is primarily found in cells of mesenchymal origin, such as fibroblasts and smooth muscle cells (1, 2). DDR1 is primarily activated by collagens I-IV and VIII, whereas DDR2 responds to collagen I and to a lesser extent to collagens II, III, and V but does not interact with collagen IV (3, 4). DDR2 has one isoform, whereas five DDR1 isoforms are generated by alternative splicing: DDR1a, b, c, d, and e. DDRs have been implicated in the expression of pro-inflammatory mediators and matrix-degrading enzymes and play an important role in processes such as migration, proliferation, extracellular matrix (ECM) remodeling and wound repair (2, 5-7). Moreover, studies in vivo and in vitro have implicated DDRs in various fibrotic and fibroproliferative conditions such as cancer, atherosclerosis, inflammation, arthritis, and fibrosis of the kidney, liver, skin, and lung (1, 2, 8 -13).The wide range of processes regulated upon DDR stimulation suggests that DDRs may exert their effects via mult...

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Discoidin domain receptor 2 is associated with the increased expression of matrix metalloproteinase-13 in synovial fibroblasts of rheumatoid arthritis

Cited by 49 publications

References 35 publications

Ubiquitin ligase Cbl‐b acts as a negative regulator in discoidin domain receptor 2 signaling via modulation of its stability

Ubiquitin ligase Cbl‐b acts as a negative regulator in discoidin domain receptor 2 signaling via modulation of its stability

An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation

Collagen I Induces Discoidin Domain Receptor (DDR) 1 Expression through DDR2 and a JAK2-ERK1/2-mediated Mechanism in Primary Human Lung Fibroblasts

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