DISEASE SPECIFICITY OF KINASE DOMAINS - THE SRC-ENCODED CATALYTIC DOMAIN CONVERTS ERBB INTO A SARCOMA ONCOGENE

src and erbB are two tyrosine kinase-encoding oncogenes carried by ret roviruses, which have distinct disease specificities, The former induc es predominantly sarcomas, and the latter, leukemias. Src and ErbB hav e similar catalytic domains but have very different regulatory domains , A wealth of information exists concerning how different regulatory d omains [Src homology 2 (SH2) and SH3 domains and autophosphorylation s ites] control substrate and disease specificities. Whether the catalyt ic domain helps determine these specificities remains to be explored, Here we show that the Src catalytic domain is enzymatically active whe n substituted into the ErbB backbone and interacts with the ErbB regul atory domain. This ErbB/Src chimera displays autophosphorylation and s ubstrate phosphorylation patterns different from those off both Src an d ErbB. Neither SH2 and SH3 nor autophosphorylation sites are required for the Src catalytic domain to exert its fibroblast transforming abi lity. Most significantly, the catalytic domain can convert erbB from a leukemogenic oncogene into a sarcomagenic oncogene, suggesting that t he leukemogenic determinants in part reside within the ErbB catalytic domain.