Recently cross talk between DDR and the
Recently, cross-talk between DDR2 and the insulin receptor and between Notch1 and DDR1 was proposed. Stimulation of cells with collagen I and insulin promotes Tyr740 as well as total tyrosine phosphorylation of DDR2 receptor to a greater extent than the phosphorylation stimulated by collagen I alone (Iwai et al., 2013a). Finally, it has been proposed that collagen-stimulated DDR1 promotes survival of cancer cells by binding to and activating Notch1 thus promoting the activation of the two transcription factors Hes1 and Hey2 (Kim et al., 2011).
In conclusion, cross-talk of DDRs with various receptors is critical for the regulation of cell survival, migration, and differentiation in development as well as in pathological conditions (Fig. 1).
DDR function in development The generation of global DDR1- and DDR2-null mice has contributed significantly to the understanding of the role of these two receptors in development. Global deletion of DDR1 or DDR2 does not impair embryonic development, although DDR1-null and DDR2-null mice present with a wide range of defects. DDR1 ablation in mice results in reduced calcification of the fibula bone, defects in mammary gland morphogenesis which result in a lactation impairment, and reproduction defects due to the inability of blastocysts to implant properly in the uterine wall (Vogel et al., 2001). DDR-2 deletion in mice results in reduced bone growth due to reduced chondrocyte proliferation as well as impaired dermal wound healing due to reduced fibroblast proliferation (Olaso et al., 2002). Interestingly, Smallie, a spontaneous mutation that causes dwarfism in mice was shown to be the result of DDR2 deletion (Kano et al., 2008) and mutations of DDR2 have been found in patients with spondylo-meta-epiphyseal dysplasia, a rare human genetic disorder characterized by disproportionate short stature and bone abnormalities (Ali et al., 2010). All together, these findings indicate that DDR signaling is required for normal skeletal development, mammary gland branching morphogenesis, and pyruvate dehydrogenase kinase implantation (Fig. 2).
DDRs in disease Despite some of the developmental defects found in DDR-null mice, these mice have been valuable in understating the role of these receptors in various diseases, including cancer, atherosclerosis, lung and liver fibrosis, renal injury, and osteoarthritis (Fig. 2).
Inhibiting DDR: what we know and what we should know The contribution of DDRs to fibrotic diseases and cancer progression indicates that blocking these receptors might represent a promising therapeutic strategy. A plausible approach is to prevent DDR expression (Fig. 3), as DDR levels increase significantly in disease. In this regard, in glomerulonephritis, DDR1 expression increases up to 17 fold and reducing by 50% DDR1 expression using antisense oligonucleotides, results in improved renal function similar to that seen in DDR1-null mice (Kerroch et al., 2012). Furthermore, reduction of DDR2 expression in DDR2-haploinsufficient (Ddr2+/−) mice reduces the severity of osteoarthritis both in genetic models of osteoarthritis and in surgical destabilization of the medial meniscus (Xu et al., 2010). Other strategies to prevent DDR-mediated function could be aimed to block the interaction of DDRs with collagen or to sterically block the conformational change required for receptor activation (Fig. 3). For instance, Actinomycin D inhibits collagen I-mediated activation of DDR2 in cell cultures without affecting the activation of other receptor tyrosine kinases (Siddiqui et al., 2009) and monoclonal antibodies to the extracellular domain of DDR1, specifically to the DS-like domain, inhibit collagen-induced DDR1 activation without affecting collagen binding (Carafoli et al., 2012). Another appealing alternative is to target the DDR tyrosine kinase activity in order to block DDR-mediated downstream signaling (Fig. 3). Protein tyrosine kinases (PTKs) catalyze the transfer of the γ-phosphate of ATP to the hydroxyl group of tyrosine residues on various protein substrates. Tyrosine phosphorylation induces conformational changes which result in increased catalytic activity and/or generation of docking sites for other proteins to bind, thus amplifying signaling pathways (Lemmon and Schlessinger, 2010, Taylor and Kornev, 2011). Because uncontrolled activation of PTKs has been associated with cancer, inflammatory and fibrotic diseases, the identification of small molecule compounds that inhibit their activity has been pursued intensely in the last decade [reviewed in (Smyth and Collins, 2009, Zhang et al., 2009, Dar and Shokat, 2011, Endicott et al., 2012, Liu et al., 2013)]. Most of the kinase inhibitors to date are ATP competitive and can be classified as type I (if the inhibitor targets the catalytically competent conformation of the kinase with the activation loop in the DFG-IN conformation) or as type II (if the inhibitor targets the inactive conformation of the kinase with activation loop in the DFG-OUT conformation). Type II inhibitors tend to be more selective because the inactive DFG-OUT kinase conformation allows additional interactions between the inhibitor and specific, not-well-conserved exposed hydrophobic sites within the kinase domain. On the other hand, type I inhibitors tend to be promiscuous, because they tend to target well-conserved active kinase binding sites. However type I inhibitors have the advantage of inhibiting kinases that have acquired mutations resistant to type II inhibitors (Tokarski et al., 2006). Another class of inhibitors, type III inhibitors, does not target the ATP binding site, but rather allosteric sites that regulate kinase activation (Taylor and Kornev, 2011).