CATALYTIC SPECIFICITY OF PROTEIN-TYROSINE KINASES IS CRITICAL FOR SELECTIVE SIGNALING

How do distinct protein-tyrosine kinases activate specific downstream events? Src-homology-2 (SH2) domains on tyrosine kinases or targets of tyrosine kinases recognize phosphotyrosine in a specific sequence con text and thereby provide some specificity(1-3). The role of the cataly tic site of tyrosine kinases in determining target specificity has not been fully investigated. Here we use a degenerate peptide library to show that each of nine tyrosine kinases investigated has a unique opti mal peptide substrate. We find that the cytosolic tyrosine kinases pre ferentially phosphorylate peptides recognized by their own SH2 domains or closely related SH2 domains (group I; ref. 3), whereas receptor ty rosine kinases preferentially phosphorylate peptides recognized by sub sets of group In SH2 domains(3). The importance of these findings for human disease is underscored by our observation that a point mutation in the RET receptor-type tyrosine kinase, which causes multiple endocr ine neoplasia type 2B, results in a shift in peptide substrate specifi city.