title: The intracellular juxtamembrane domain of discoidin domain receptor 2 (DDR2) is essential for receptor activation and DDR2-mediated cancer progression.
abstract: Discoidin domain receptors (DDRs) are unusual receptor tyrosine kinases (RTKs) that are activated by fibrillar collagens instead of soluble growth factors. DDRs play an important role in various cellular functions and disease processes, including malignant progression. Compared to other RTKs, DDRs have relatively long juxtamembrane domains, which are believed to contribute to receptor function. Despite this possibility, the function and mechanism of the juxtamembrane domain of DDRs have not yet been fully elucidated. In this study, we found that the cytoplasmic juxtamembrane 2 (JM2) region of DDR2 contributed to receptor dimerization, which is critical for receptor activation in response to collagen stimulation. A collagen-binding assay showed that JM2 was required for efficient binding of collagen to the discoidin (DS) domain. Immunohistochemical analysis of DDR2 expression using a tissue microarray demonstrated that DDR2 was overexpressed in several carcinoma tissues, including bladder, testis, lung, kidney, prostate and stomach. In H1299 cells, inhibition of DDR2 activity by overexpressing the juxtamembrane domain containing JM2 suppressed collagen-induced colony formation, cell proliferation and invasion via the inhibition of matrix metalloproteinase-2 and matrix metalloproteinase-9. Taken together, our results suggest that JM2-mediated dimerization is likely to be essential for DDR2 activation and cancer progression. Thus, inhibition of DDR2 function using a JM2-containing peptide might be a useful strategy for the treatment of DDR2-positive cancers.
authors.affiliation: Department of Life Science, Chung-Ang University, Seoul, Korea.
authors.forename: Daehwan
authors.initials: D
authors.lastname: Kim
authors.forename: Panseon
authors.initials: P
authors.lastname: Ko
authors.forename: Eunae
authors.initials: E
authors.lastname: You
authors.forename: Sangmyung
authors.initials: S
authors.lastname: Rhee
mesh_terms: D001665:Binding Sites; D015153:Blotting, Western; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D000070818:Discoidin Domain Receptors; D018450:Disease Progression; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D003432:Cross-Linking Reagents; D011975:Receptors, Mitogen; D003094:Collagen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases
keywords: cancer cell proliferation; colony formation; dimerization; discoidin domain receptor 2; intracellular juxtamembrane region; invasion; matrix metalloproteinases