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  • It has previously been established

    2019-07-11

    It has previously been established that DDRs play an important role in collagen regulation in at least two distinct ways: (1) activation of DDRs by collagen results in up-regulation of the matrix metalloproteinases, which results in cleavage and degradation of the ECM20., 21., [22] and (2) BCTC structure of DDRs is found to regulate the expression of α1 chains of fibrillar collagens type 1 and 3., We have now established a novel and third mechanism of collagen regulation by DDR2, namely that binding of DDR2 to collagen can directly modulate fibrillogenesis of collagen fibrils and fibers. Our results suggest that even the expression of kinase-dead isoforms of DDR2 may be significant for collagen regulation if they contain the DDR2 ECD. It is interesting to note that for DDR1 there are at least two naturally occurring isoforms (obtained by alternate splicing), which lack the DDR1 kinase domain but harbor the DDR1 ECD. Further, the DDR1 ECD is known to be shed as a soluble protein in almost all cell lines. Although, much less is known about DDR2 isoforms, which comprise of only an ECD, there is convincing evidence that the DDR2 gene also undergoes alternative splicing. This is demonstrated by the multiple DDR2 mRNA species observed in several cell lines using Northern blot analysis.,, In addition, several protein species (130, 90, 50 and 45 kDa) have been found in Western blots of cultured human smooth muscle cells when probed with a DDR2 antibody recognizing an epitope within the DDR2 ECD. Collagen regulation and collagen fibrillogenesis in vivo are complex processes where a wide range of interactions of collagen especially with other collagen binding proteins are present along with cleavage of collagen fibers by MMPs. It remains to be examined how the effect of DDR2 on collagen fibrillogenesis is affected by these in vivo factors (and vice versa). Further work is in progress by us to investigate how DDR2 regulates collagen fibrillogenesis in vivo. Our ongoing work also aims to characterize the occurrence of kinase-dead isoforms of DDR2, the mechanism(s) of DDR2 oligomerization and their effect on collagen fibrillogenesis. Our observations that DDR2 delays and disrupts the formation of native banded collagen fibrils may provide new insights into collagen deposition and regulation especially in diseases where DDR2 is up-regulated. Indeed the DDR2–collagen receptor–ligand pair exhibits a unique feature whereby receptor binding itself is functionally significant as it can modify or modulate the state of the ligand.
    Materials and Methods
    Acknowledgements