title: The discoidin domain receptor DDR2 is a receptor for type X collagen.
abstract: During endochondral ossification, collagen X is deposited in the hypertrophic zone of the growth plate. Our previous results have shown that collagen X is capable of interacting directly with chondrocytes, primarily via integrin alpha2beta1. In this study, we determined whether collagen X could also interact with the non-integrin collagen receptors, discoidin domain receptors (DDRs), DDR1 or DDR2. The widely expressed DDRs are receptor tyrosine kinases that are activated by a number of different collagen types. Collagen X was found to be a much better ligand for DDR2 than for DDR1. Collagen X bound to the DDR2 extracellular domain with high affinity and stimulated DDR2 autophosphorylation, the first step in transmembrane signalling. Expression of DDR2 in the epiphyseal plate was confirmed by RT-PCR and immunohistochemistry. The spatial expression of DDR2 in the hypertrophic zone of the growth plate is consistent with a physiological interaction of DDR2 with collagen X. Surprisingly, the discoidin domain of DDR2, which fully contains the binding sites for the fibrillar collagens I and II, was not sufficient for collagen X binding. The nature of the DDR2 binding site(s) within collagen X was further analysed. In addition to a collagenous domain, collagen X contains a C-terminal NC1 domain. DDR2 was found to recognise the triple-helical region of collagen X as well as the NC1 domain. Binding to the collagenous region was dependent on the triple-helical conformation. DDR2 autophosphorylation was induced by the collagen X triple-helical region but not the NC1 domain, indicating that the triple-helical region of collagen X contains a specific DDR2 binding site that is capable of receptor activation. Our study is the first to describe a non-fibrillar collagen ligand for DDR2 and will form the basis for further studies into the biological function of collagen X during endochondral ossification.
authors.affiliation: Division of Biomedical Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. b.leitinger@imperial.ac.uk
authors.forename: Birgit
authors.initials: B
authors.lastname: Leitinger
authors.forename: Alvin P L
authors.initials: AP
authors.lastname: Kwan
mesh_terms: D000818:Animals; D002356:Cartilage / Q000378:metabolism; D002642:Chick Embryo; D019902:Chondrocytes / Q000378:metabolism; D003094:Collagen / Q000737:chemistry; D024121:Collagen Type X / Q000737:chemistry* / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011975:Receptors, Mitogen / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D024121:Collagen Type X; D011975:Receptors, Mitogen; D011994:Recombinant Proteins; D003094:Collagen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases