Alternative titles; symbols
HGNC Approved Gene Symbol: DDR1
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38) : 6:30,880,970-30,900,156 (from NCBI)
By screening a placenta cDNA library with a sequence common to several receptor tyrosine kinases, Johnson et al. (1993) cloned human DDR1, which they called DDR. The predicted protein contains 913 amino acids and has a calculated molecular mass of 105 kD. It has an N-terminal signal sequence, followed by extracellular, transmembrane, and cytoplasmic regions. The extracellular region contains a discoidin I-like domain, a pro/gly-rich region, 4 putative N-glycosylation sites, and 7 cysteines. The cytoplasmic domain contains a pro/gly-rich region and a C-terminal tyrosine kinase domain. Northern blot analysis detected a 4.0-kb transcript in multiple human cell lines, with highest expression in breast carcinoma cell lines and an epidermoid carcinoma cell line. Expression was also detected in several mouse tissues, with highest levels in kidney, spleen, and placenta. Immunoblot analysis revealed a 120-kD DDR protein in transfected COS-7 cells. The DDR protein was detected in human breast carcinoma cell lines, but not in a variety of other human cell lines.
Using PCR to identify protein tyrosine kinases in HeLa cells, Perez et al. (1994) obtained a cDNA encoding DDR1, which they they called CAK. The deduced 913-amino acid protein has a calculated molecular mass of 101 kD. It has an N-terminal signal sequence, followed by an extracellular domain, a transmembrane region, and a cytoplasmic receptor tyrosine kinase domain. The N-terminal extracellular domain shares similarity with phospholipid-binding sequences found in cell adhesion molecules, such as neuronal A5 antigen and factors V (F5; 612309) and VIII (F8; 300841), and it has 7 cysteines, 4 potential N-glycosylation sites, and a furin (FUR; 136950) cleavage site (RxRR). The C-terminal kinase domain contains motifs characteristic of a receptor tyrosine kinase, including a canonical GxGxxG sequence of the ATP-binding loop and 4 tyrosine phosphorylation sites, 3 of which may be autophosphorylated. Northern blot analysis detected a 5-kb transcript in all tissues examined, with highest expression in brain and lung. CAK expression was also detected in mouse brain and in several human cell lines.
By screening a keratinocyte cDNA library with the catalytic domain of TRKA (NTRK1; 191315), followed by screening fetal brain and keratinocyte cDNA libraries, Di Marco et al. (1993) cloned a splice variant of DDR1 that they designated TRKE. The deduced 876-amino acid protein has an N-terminal signal sequence, followed by an extracellular domain with 5 consensus N-glycosylation sites and 7 cysteines, a transmembrane domain, and a cytoplasmic domain with a kinase catalytic domain that includes an ATP-binding site and a putative autophosphorylation site. Northern blot analysis detected a 3.9-kb TRKE transcript in human keratinocytes and in all adult and fetal human tissues examined except liver.
Using PCR, Laval et al. (1994) cloned a splice variant of DDR1 that they called RTK6 from a human epithelial ovarian cancer cell line. The deduced 876-amino acid protein, which is identical to TRKE (Di Marco et al., 1993), has a calculated molecular mass of 97 kD. Compared with the DDR protein (Johnson et al., 1993), RTK6 lacks 37 amino acids between the transmembrane region and the catalytic domain. Northern blot analysis detected high expression of a 4.5-kb RTK6 transcript in brain, with lower expression in heart, placenta, lung, liver, muscle, kidney, and pancreas. RT-PCR detected expression of both DDR and RTK6 in placenta and in all ovarian cell lines tested. In situ hybridization detected RTK6 in epithelial cells of human ovary, small intestine, thymus, fetal lung, fetal kidney, and gray matter of fetal brain. RTK6 was expressed at high levels in moderately and poorly differentiated malignant ovarian tumors and at lower levels in normal, benign, and borderline tumors. Western blot analysis detected RTK6 at an apparent molecular mass of 140 kD, suggesting that the fully processed, mature protein is glycosylated.
Playford et al. (1996) identified 2 splice variants of DDR1, which they called EDDR1 and EDDR2. EDDR1 lacks exon 11 and corresponds to TRKE/RTK6 (Di Marco et al., 1993; Laval et al., 1994). EDDR2 uses a cryptic splice site in the 5-prime region of exon 14, resulting in an in-frame addition of 6 amino acids in the catalytic domain compared with DDR.
Edelhoff et al. (1995) noted that DDR1 shares 93% amino acid identity with its putative mouse homolog, Nep, also called Ptk3. Nep is widely expressed in fetal and adult mouse tissues. During mouse development, Nep is an early and persistent marker of proliferating neuroepithelial cells in the ependymal zones surrounding the central canal of the spinal cord and brain ventricles, as detected by in situ hybridization. It is also expressed in craniofacial structures.
Sakuma et al. (1996) showed that DDR expression was upregulated by p53 protein (191170) in human osteosarcoma cells.
Shrivastava et al. (1997) found that fibrillar collagens, including types I (see COL1A1; 120150), II (see COL2A1; 120140), III (see COL3A1; 120180), and V (see COL5A1; 120215), bound to the ectodomains of human DDR1 and DDR2 (191311). The fibrillar collagens and immobilized collagen activated DDR1 receptor phosphorylation after prolonged treatment.
Bhatt et al. (2000) showed that Ddr1 was highly expressed in the cerebellum of developing and adult mouse brain, and that both Ddr1 and collagen IV (see COL4A1; 120130) were highly expressed in the pial layer of the cerebellar cortex. Cocultures of collagen I- and IV-expressing mouse pial cells with Ddr1-expressing granule cells resulted in granule cell neurite extension. Inhibition of collagen-Ddr1 signaling reduced granule cell neurite elongation.
Sakuma et al. (1996) cloned genomic DNA of the DDR1 gene. The gene contains 15 exons spanning approximately 9 kb. The promoter region of the gene contains a consensus binding site for p53.
Playford et al. (1996) determined that the DDR1 gene contains 17 exons and spans about 12 kb. They identified an inverted repeat of 20 bp at the 3-prime exon-intron junction of exon 11, which results in a lariat loop-like secondary structure. A polymorphic (GT)17 repeat was present in intron 5 and had a heterozygosity of 0.71 in 18 unrelated individuals.
Laval et al. (1994) determined that the 5-prime UTR of the DDR1 gene is CG-rich.
Using FISH, Perez et al. (1994) mapped the DDR1 gene to chromosome 6p21.3. They mapped the mouse Ddr1 gene to the proximal region of chromosome 17. Analyzing somatic cell hybrids by PCR amplification using oligonucleotide primers specific for EDDR1, Shelling et al. (1995) assigned the DDR1 gene to chromosome 6. By fluorescence in situ hybridization, they regionalized the DDR1 gene to chromosome 6q16. Using fluorescence in situ hybridization with a mouse Nep cDNA probe, Edelhoff et al. (1995) mapped the human NEP gene to chromosome 6p21.3 and the mouse Nep gene to 17C. Valent et al. (1996) prepared a human NTRK4 cDNA probe by PCR amplification and assigned the gene to chromosome 6p21 by Southern blotting and fluorescence in situ hybridization. Sakuma et al. (1996) used radiation hybrid mapping to refine the mapping of the DDR1 gene to chromosome 6p21.3, near the marker D6S478.
Associations Pending Confirmation
For discussion of a possible association between variation near the DDR1 gene and age-related macular degeneration, see ARMD1 (603075).
Hou et al. (2001) found that expression of Ddr1 mRNA and protein increased after balloon catheter injury of the rat carotid artery. They developed Ddr1-null mice and found that the cross-sectional area of the neointima and the amount of collagen deposited were significantly lower in Ddr1-null mice than in wildtype mice following mechanical injury to the carotid arteries. Ddr1-null aortic smooth muscle cells showed reduced attachment, chemotaxis, and proliferation on collagen in culture, as well as reduced induction of matrix metalloprotease (see MMP9; 120361) activity.
Vogel et al. (2001) obtained Ddr1 -/- mice at a mendelian ratio. Ddr1 -/- mice appeared normal, but they were proportionally smaller than wildtype mice at all developmental stages. The majority of Ddr1 -/- females were unable to bear offspring due to a lack of blastocyst implantation into the uterine wall. When implantation occurred, mutant females had normal-sized litters, but unless the pups were moved to foster mothers, they died shortly after birth due to a lactation deficiency in Ddr1 -/- females. Histologic analysis showed that the alveolar epithelium of Ddr1 -/- females failed to secrete milk proteins into the lumen of mammary glands. The lactation defect appeared to be caused by hyperproliferation and abnormal branching of mammary ducts, suggesting that Ddr1 is a mediator of stromal-epithelial interaction during ductal morphogenesis in the mammary gland. In addition, a high percentage of Ddr1 -/- mice were unable to control their ear movements, and their ears were curled back, suggesting that Ddr1 is also necessary for proper formation of the mouse ear.
Bhatt, R. S., Tomoda, T., Fang, Y., Hatten, M. E. Discoidin domain receptor 1 functions in axon extension of cerebellar granule neurons. Genes Dev. 14: 2216-2228, 2000. [PubMed: 10970885] [Full Text: https://doi.org/10.1101/gad.821600]
Di Marco, E., Cutuli, N., Guerra, L., Cancedda, R., De Luca, M. Molecular cloning of trkE, a novel trk-related putative tyrosine kinase receptor isolated from normal human keratinocytes and widely expressed by normal human tissues. J. Biol. Chem. 268: 24290-24295, 1993. [PubMed: 8226977]
Edelhoff, S., Sweetser, D. A., Disteche, C. M. Mapping of the NEP receptor tyrosine kinase gene to human chromosome 6p21.3 and mouse chromosome 17C. Genomics 25: 309-311, 1995. [PubMed: 7774938] [Full Text: https://doi.org/10.1016/0888-7543(95)80144-b]
Hou, G., Vogel, W., Bendeck, M. P. The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair. J. Clin. Invest. 107: 727-735, 2001. [PubMed: 11254672] [Full Text: https://doi.org/10.1172/JCI10720]
Johnson, J. D., Edman, J. C., Rutter, W. J. A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain. Proc. Nat. Acad. Sci. 90: 5677-5681, 1993. Note: Erratum: Proc. Nat. Acad. Sci. 90: 10891 only, 1993. [PubMed: 8390675] [Full Text: https://doi.org/10.1073/pnas.90.12.5677]
Laval, S., Butler, R., Shelling, A. N., Hanby, A. M., Poulsom, R., Ganesan, T. S. Isolation and characterization of an epithelial-specific receptor tyrosine kinase from an ovarian cancer cell line. Cell Growth Diff. 5: 1173-1183, 1994. [PubMed: 7848919]
Perez, J. L., Shen, X., Finkernagel, S., Sciorra, L., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Wong, T. W. Identification and chromosomal mapping of a receptor tyrosine kinase with a putative phospholipid binding sequence in its ectodomain. Oncogene 9: 211-219, 1994. [PubMed: 8302582]
Playford, M. P., Butler, R. J., Wang, X. C., Katso, R. M., Cooke, I. E., Ganesan, T. S. The genomic structure of discoidin receptor tyrosine kinase. Genome Res. 6: 620-627, 1996. [PubMed: 8796349] [Full Text: https://doi.org/10.1101/gr.6.7.620]
Sakuma, S., Saya, H., Tada, M., Nakao, M., Fujiwara, T., Roth, J. A., Sawamura, Y., Shinohe, Y., Abe, H. Receptor protein tyrosine kinase DDR is up-regulated by p53 protein. FEBS Lett. 398: 165-169, 1996. [PubMed: 8977099] [Full Text: https://doi.org/10.1016/s0014-5793(96)01234-3]
Shelling, A. N., Butler, R., Jones, T., Laval, S., Boyle, J. M., Ganesan, T. S. Localization of an epithelial-specific receptor kinase (EDDR1) to chromosome 6q16. Genomics 25: 584-587, 1995. [PubMed: 7789998] [Full Text: https://doi.org/10.1016/0888-7543(95)80065-t]
Shrivastava, A., Radziejewski, C., Campbell, E., Kovac, L., McGlynn, M., Ryan, T. E., Davis, S., Goldfarb, M. P., Glass, D. J., Lemke, G., Yancopoulos, G. D. An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Molec. Cell 1: 25-34, 1997. [PubMed: 9659900] [Full Text: https://doi.org/10.1016/s1097-2765(00)80004-0]
Valent, A., Meddeb, M., Danglot, G., Duverger, A., Nguyen, V. C., Bernheim, A. Assignment of the NTRK4 (trkE) gene to chromosome 6p21. Hum. Genet. 98: 12-15, 1996. [PubMed: 8682498] [Full Text: https://doi.org/10.1007/s004390050152]
Vogel, W. F., Aszodi, A., Alves, F., Pawson, T. Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development. Molec. Cell. Biol. 21: 2906-2917, 2001. [PubMed: 11283268] [Full Text: https://doi.org/10.1128/MCB.21.8.2906-2917.2001]