While these previous correlative studies have measured
While these previous correlative studies have measured tDDR1 protein by IHC, these studies have not considered that pDDR1 could also be an important marker of cancer prognosis. A phosphoproteomic survey of lung cancer tissues did identify pDDR1 as one of the most commonly phosphorylated receptor kinases invasive lung cancer, but outcome data were not available for cases in this study. Not surprisingly, we found that all cases of ESCC with high levels of pDDR1 also showed high total MMP-2 Inhibitor I of the protein, but even greater predictive value for poor outcome was seen in those cases with high pDDR1 as well as high tDDR1.
Over the past decade, activation of specific protein kinases has been found to be effective targets cancer therapy, and a wide variety of inhibitors of protein kinases have been developed. DDR1 is one such kinase activated by collagen through phosphorylation, and several multikinase inhibitors, including imatinib, nilotinib, and dasatinib, inhibit DDR1 with similar potency.30, 31 Unfortunately, however, a number of clinical trials with these kinase inhibitors in the treatment of cancers that have activated DDR1 have been disappointing, possibly because the activity of this kinase is regulated not only by kinases, but rather by an intimate balance between kinases and antagonist phosphatases. Future strategies to target kinase activation might include kinase inhibitors in combination with agents that activate tumor suppressor phosphatase.
Acknowledgment This study was funded by Juntendo University Shizuoka Medical Research Center for Disaster and the Commonwealth Fund of Johns Hopkins.
Introduction DDR1 and DDR2 are RTKs comprising an extracellular Discoidin (DS) homology domain that encompasses the collagen-binding site, a DS-like domain that contributes to collagen-induced receptor activation, an extracellular juxtamembrane region that contains N- and O-glycosylation sites and matrix metalloproteinase cleavage sites . In addition, DDRs have a single transmembrane helix, an intracellular juxtamembrane regulatory region upstream of a cytoplasmic tyrosine kinase domain . The DDR family comprises two distinct members, DDR1 and DDR2. DDR1 has five isoforms, whereas DDR2 has a single one . Upon activation by binding of fibrillar collagens I–III, V, or network-forming collagen IV, DDR1 undergoes phosphorylation and initiates various downstream signaling pathways. Multiple tyrosine residues within the intracellular juxtamembrane region and tyrosine kinase domain of DDR1 can be phosphorylated and recruit proteins, such as ShcA, SHP-2, and the p85 subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) 3, 4, 5, 6. DDR1 stimulates several signaling pathways in a context- and cell type-dependent manner. For example, DDR1 activates extracellular signal-regulated kinases (ERK) signaling in vascular smooth muscle cells , but inhibits ERK in mesangial cells , and has no effect on ERK activation in T47D breast cancer cells . In addition, DDR1 modulates signaling pathways initiated by other matrix receptors (e.g., integrins) , cytokines [e.g., transforming growth factor (TGF)-β] , and transmembrane receptors (e.g., Notch1) . Interaction of DDR1 with various receptors is important for the regulation of cell survival, migration, and differentiation in development and pathological conditions 5, 9, 12, 13. Our understanding of the role of DDR1 in development, tissue homeostasis, and disease has been significantly enhanced by availability of DDR1-deficient mice. These mice have defects in mammary gland morphogenesis and inability of blastocysts to implant properly in the uterine wall . In contrast to these findings, DDR1 ablation has been shown to have a beneficial role in various mouse models of fibrotic diseases, including atherosclerosis , pulmonary fibrosis , and renal fibrosis . Thus, inhibiting DDR1 might be a promising therapeutic strategy for fibrotic diseases.