The binding and activation of the discoidin domain receptor 1 by collagen has led to the conclusion that proteins from the extracellular matrix can directly induce receptor tyrosine kinase-mediated signaling cascades. A region in the extracellular domain of DDR1 homologous to the Dictyostelium discoideum protein discoidin-I is also present in the secreted human protein RS1. Mutations in RS1 cause retinoschisis, a genetic disorder characterized by ablation of the retina. By introducing point mutations into the discoidin domain of DDR1 at positions homologous to the retinoschisis mutations, ligand binding epitopes in the discoidin domain of DDR1 were mapped. Surprisingly, some residues only affected receptor phosphorylation, whereas others influenced both collagen-binding and receptor activation. Furthermore, two truncated DDR1 variants, lacking either the discoidin domain or the stalk region between the discoidin and transmembrane domain, were generated. We showed that (i) the discoidin domain was necessary and sufficient for collagen binding, (ii) only the region between discoidin and transmembrane domain was glycosylated, and (iii) the entire extracellular domain was essential for transmembrane signaling. Using these results, we were able to predict key sites in the collagen-binding epitope of DDR1 and to suggest a potential mechanism of signaling.Discoidin domain receptors 1 and 2 (DDR1 and DDR2) 1 have been recognized as a distinct tyrosine kinase receptor subfamily because of structural and functional homologies. In their extracellular region, both receptors show a domain homologous to the Dictyostelium discoideum protein discoidin I. DDR1 and DDR2 are also functionally related by the observation that collagen acts as cognate ligand for both receptors. Whereas DDR1 activation is achieved by all collagens so far tested (types I-VI and VIII), DDR2 is only activated by fibrillar collagens, in particular by collagen type I and type III. In contrast to most other tyrosine kinase receptors, activation of DDRs can take several hours (1, 2).The cDNA coding for human DDR1 has been cloned from several tissues or carcinoma cells (3-7). Gene orthologs to human DDR1 have been identified in mice, rats, and Caenorhabditis elegans (8 -10). Expression of human DDR1 is predominantly seen in epithelial cells, particularly from kidney, lung, gastrointestinal tract, and brain, but also in corneal and dermal fibroblasts (7, 9, 11-13). DDR1 seems to be also involved in the differentiation of cerebellar granular neurons (14). Upregulated DDR1 expression has been reported from breast, ovarian, esophagus and brain tumors (5,(15)(16)(17)(18)(19). Human DDR1 is located on chromosome 6p21.3 in close proximity to HLA genes, which belong to the telomeric region (class I) of the major histocompatibility complex (20). The juxtamembrane regions in DDR1 and DDR2 are much longer than in other receptor tyrosine kinases (176 and 147 amino acids, respectively). Furthermore, the extracellular domain of DDR1 is shed by an unidentified protease, res...

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