Motifs of cadherin- and fibronectin type III-related sequences and evolution of the receptor-type-protein tyrosine kinases: sequence similarity between proto-oncogene ret and cadherin family.

Immunoglobulin (Ig)-, fibronectin type III (FN-III)-, and cadherin-related sequences are often found in multiple repeats in the extracellular regions of various cell adhesion molecules. The amino acid sequences of 82 different cadherin-like repeats from 13 known members of the cadherin superfamily were compared for six highly conserved regions, and a frequency matrix represented as amino acids versus position matrix was calculated based on the alignment. With the frequency matrix, further members of the cadherin superfamily were searched for in the protein data base. It was found that the ret protein, a receptor-type-protein tyrosine kinase, contains cadherin-like repeats in the extracellular region. A similar analysis was also carried out for the FN-III superfamily. Nine receptor-type-protein tyrosine kinases were shown to exhibit significant similarities, in terms of sequence, with known FN-III-like repeats. Several receptor-type-protein tyrosine kinases have already been reported to have Ig-like repeats in their extracellular regions. Thus these receptor-type-protein tyrosine kinases--together with the remaining receptors, whose structures are not yet characterized--may be classified into at least four distinct groups based on the structural differences in the extracellular domains. A molecular phylogenetic tree inferred from the shared kinase domains of these receptor-type-protein tyrosine kinases revealed a close relationship between the branching patterns and the grouping based on the structural differences of the extracellular region.