Disease relevance of DDR2

• Using the doxycycline-inducible repression system (tet-off), we generated human fibrosarcoma and mouse fibroblast cell lines over-expressing DDR1 or DDR2 [1].
• We are interested in the interaction of DDR2 with collagen I because of its potential role in liver fibrosis [2].
• Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis [3].
• Furthermore, cirrhotic livers of patients with other diseases, including alcoholic liver disease and chronic hepatitis C, DDR2 transcripts were noted only within fibrotic lesions and the degree of intensity was much lower than in PBC and PSC [3].
• Here we provide evidence for a direct inhibitory effect of fibrillar collagen on proliferation of human melanoma and fibrosarcoma cells that involves activation of the tyrosine kinase discoidin domain receptor 2 and is independent of effects on cell spreading [4].

High impact information on DDR2

• Two mammalian receptor tyrosine kinases (DDR1 and DDR2) have extracellular domains closely related to a D. discoideum lectin, discoidin, required for cell aggregation [5].
• Activation of DDR2 by collagen results in the up-regulation of matrix metalloproteinase-1 expression [5].
• Receptor tyrosine kinases of the discoidin domain family, DDR1 and DDR2, are activated by different types of collagen and play important roles in cell adhesion, migration, proliferation, and matrix remodeling [6].
• These findings suggest that tyrosine 740 inhibits DDR2 autophosphorylation [7].
• Our data suggest that the defect in the cartilage matrix of mice that are heterozygous for a type XI collagen mutation (cho/+) permits activation and up-regulation of DDR2 in chondrocytes [8].

Biological context of DDR2

• The D2 period of collagen II contains a specific binding site for the human discoidin domain receptor, DDR2 [9].
• The DDR2 binding site on collagen II was further defined by recombinant collagen II-like proteins consisting predominantly of tandem repeats of the D2 or D4 period [9].
• We examined signal transduction pathways of DDR2 [10].
• Discoidin domain receptor 2 mediates tumor cell cycle arrest induced by fibrillar collagen [4].
• Tyrosine 740 phosphorylation of discoidin domain receptor 2 by Src stimulates intramolecular autophosphorylation and Shc signaling complex formation [7].

Anatomical context of DDR2

• Taken together, these data provide evidence for the potential roles of DDR1 and DDR2 in the regulation of collagen turnover mediated by SMCs in obstructive diseases of blood vessels and the lung [11].
• Stimulation of collagen II could make NIH-3T3 cells (as control) produce MMP-1, which could be inhibited by soluble extracellular part of DDR2 [12].
• Functional analysis of discoidin domain receptor 2 in synovial fibroblasts in rheumatoid arthritis [12].
• Expression of DDR2 in the epiphyseal plate was confirmed by RT-PCR and immunohistochemistry [13].
• Therefore, unusually high DDR2 expression in the bile ducts of PBC patients could contribute to duct injury by altering local cytokine levels and thereby increasing immune-mediated damage [3].

Associations of DDR2 with chemical compounds

• A common event downstream of DDR1 and DDR2 in human and mouse cells was the up-regulation of P-selectin glycoprotein ligand [1].
• We expressed glutathione S-transferase fusion proteins containing the discoidin and extracellular domains of DDR1 and DDR2 in insect cells and subjected them to a solid-phase collagen-binding assay [14].
• However treatment with the tyrosine kinase inhibitor genistein, down-regulation of discoidin domain receptor 2, or collagen deglycosylation that prevents discoidin domain receptor 2 activation allowed cells to enter the cell cycle in the presence of fibrillar collagen without a requirement for spreading and actin organization [4].

Regulatory relationships of DDR2

• Our data showed that transcript and protein of DDR2 were expressed constitutively in immature DCs and upregulated in TNF-alpha-stimulated mature DCs [15].
• Regular expression of discoidin domain receptor 2 in the improved adjuvant-induced animal model for rheumatoid arthritis [16].

Other interactions of DDR2

• Moreover, DDR2 overexpression increases SMC-mediated collagen and elastin degradation in vitro [11].
• ColI treatment induced DDR2 phosphorylation and subsequently induced the upregulation of IL-12 production, CD86 expression, and antigen uptake activity by immature DCs [15].
• CONCLUSIONS: DDR2, a TK that is stimulated by fibrillar collagens that accumulate in cirrhotic livers, is present at elevated levels in the small bile ducts of PBC patients [3].
• The widely expressed mammalian discoidin domain receptors (DDRs), DDR1 and DDR2, are unique among receptor tyrosine kinases in that they are activated by the extracellular matrix protein collagen [17].
• V-FGR, RET and DDR2 were also expressed [18].

Analytical, diagnostic and therapeutic context of DDR2

• DDR1 and DDR2 mRNAs were detected by RT-PCR [19].
• Atomic force microscopy of soluble collagen revealed that a predominately monomeric state of collagen was present with DDR2, while control solutions had an abundance of polymeric collagen [20].
• Transmission electron microscopy of collagen fibers, showed that the native periodic banded structure of collagen fibers was weakened and nearly absent in the presence of DDR2 [20].
• Binding of DDR2 complexes to collagen I coated on plastic plates was established by a microplate-based assay using Eu(3+)-labeled proteins and time-resolved fluorometry [2].
• Furthermore, in situ hybridization of PBC livers revealed that DDR2 is expressed in the small bile duct epithelial regions as well as in fibroblasts/stromal cells of fibrotic regions [3].

References