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    • The binding of collagen X to DDR differs from

    2019-07-12

    The binding of collagen X to DDR2 differs from the binding of collagen X to α2β1 integrin in that the triple helical conformation is essential for DDR2 binding. We previously reported that heat denatured pepsinised collagen X supported cell adhesion via α2β1, indicating that the triple-helical conformation is not strictly required for α2β1 binding (Luckman et al., 2003). Although many previous studies have firmly established that collagen X is required for normal development of the growth plate (Warman et al., 1993, Wallis et al., 1994, Tselepis et al., 1996, Chan and Jacenko, 1998, Gress and Jacenko, 2000, Jacenko et al., 2002) the precise role of collagen X within the growth plate remains to be defined. Many of these studies favoured a structural role for the collagen X network in the hypertrophic zone. However, the interactions between the collagen X network and hypertrophic chondrocytes and the interactions between collagen X and other cartilage matrix components have not been studied to any significant extent. It has been proposed that the interaction of collagen X with other matrix components is important for regional extracellular matrix organisation permissive for mineralisation and vascularisation prior to new bone formation (Luckman et al., 2003). The present study further corroborates an earlier study that the collagen X network does support cell adhesion and also supports the notion that collagen X has regulatory roles besides its structural function in the matrix, possibly via activation of receptor tyrosine kinases. Since DDR2 is a signalling receptor with important functions in bone growth (Labrador et al., 2001), our present study provides the basis for future studies into the role of DDR2 signalling in bone formation.
    Experimental procedures
    Acknowledgments
    Introduction Interactions between tissue L-690,330 what and extracellular matrix (EM) play a central role in normal physiological processes. Changes in EM interactions contribute to tissue fibrosis and malignant transformation. Integrins and syndecans represent well known families of receptors that mediate cell–matrix interactions in synergistic manner. The extracellular domains of these receptors bind to protein molecules of the EM such as collagens, fibronectin and laminin and to intracellular elements conforming the cell cytoskeleton elements as well as to other cytoplasmic signaling molecules. The interplay between EM with cell membrane adhesion molecules results in the physical and mechanical integration of cells into tissues in addition to a coupled with functional of the cell processes such as regulation of gene expression, cell proliferation, and cell motile activity [1], [2], [3]. DDR1 and DDR2 are transmembrane adhesion molecules that bind native collagens and can function as direct signaling molecules [4], [5] through an intracellular tyrosine kinase domain that is activated by collagen binding. DDR activation depends on the triple helical binding domain present in individual collagen molecules and does not require supramolecular collagen organization [6]. DDR receptor effector mechanisms are not well understood. Most descriptions of DDR function have focused on downstream signaling pathways activated by collagen that regulate cell proliferation and transcriptional activation [7]. Natural occurring or induced DDR2−/− genotypes in mice induce dwarfism, reduce fibroblasts have proliferation [8], [9], delayed cutaneous wound repair, as well as decreased expression of syndecan 1 and the collagen crosslinking enzymes lysyl oxidase and lysyl hydroxylase [10]. Conversely, functional mutations in DDR2 contribute to development of squamous cell lung cancer [11]. However, DDR functions involving collagen interactions, e.g., DDR1−/− smooth muscle cell adhesion to collagen [12] and DDR control of collagen are independent of tyrosine kinase activation [13], [14]. In addition, DDR1 is required for cell chemotaxis towards soluble collagen [15], [16], [17]: yet not all aspects of DDR-dependent cell motile activity depend on DDR-collagen interactions. DDR1 is required for collective cancer cell migration in organotypic collagen culture models. Fibroblast migration through matrigel, which is inhibited in DDR2−/− cells, occurs with serum rather than collagen as the chemotactic stimulus [18].