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.