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Beschreibung

Epithelial discoidin domain-containing receptor 1 (EC 2.7.10.1, UniProt Q08345, also known as CD167 antigen-like family member A, CD167a, Cell adhesion kinase, Discoidin receptor tyrosine kinase, Epithelial discoidin domain receptor 1, HGK2, Mammary carcinoma kinase 10, MCK-10, Protein-tyrosine kinase 3A, Protein-tyrosine kinase RTK-6, TRK E, Tyrosine kinase DDR, Tyrosine-protein kinase CAK) is encoded by the DDR1 (also known as CAK, EDDR1, MCK10, NEP, NTRK4, PTK3A, RTK6, TRKE) gene (Gene ID 780) in human. Discoidin domain-containing receptors (DDRs) belong to the superfamily of transmembrane receptor tyrosine kinases (RTKs). DDRs are distinguished from other RTKs by their extracellular discoidin motif and their utilization of collagens as internal ligands. While DDR1 binds essentially all types of collagens, DDR2 shows a preference for type I, II and III fibrillar collagens, and nonfibrillar type X collagen. DDR1 is widely expressed in epithelial cells in lung, kidney, colon, and brain, whereas DDR2 is primarily expressed in mesenchymal cells including fibroblasts, myofibroblasts, smooth muscle cells, and chondrocytes in kidney, skin, lung, heart, and connective tissues. DDRs are important mediators of fundamental cellular processes, such as proliferation, survival, differentiation, adhesion and matrix remodeling, their dysregulations are reported to cause a number of human diseases, including fibrotic disorders, atherosclerosis and cancer. DDR1 is initially produced with a signal peptide sequence (a.a. 1-20), the removal of which yields the mature protein with an extracellular region (a.a. 21-417) that contains the Discoidin domain (F5/8 type C domain or C2-like domain) at the N-terminal half (a.a. 31-185) and a collagen-binding site within the membrane-distal DS domain (a.a. 192-367), followed by a transmembrane segment (a.a. 418-438) and a cytoplasmic region (a.a. 439-913) that harbors a WW domain-interacting PPxY motif (a.a. 481-484) and the kinase domain (a.a. 610-905). Alternative splicings produce five isoforms, isoforms 2 (CAK II, DDR1a, Short) and 5 are expressed with a truncated cytoplasmic domain, while isoform 3 (DDR1d) is expressed in a 243-a.a. soluble form and isoform 4 is expressed with a 6-a.a. insertion (SFSLFS) between Ala665 and Arg666 of the canonical isoform 1 (CAK I, DDR1b) sequence.