Selective interactions of transforming and normal abl proteins with ATP, tyrosine-copolymer substrates, and tyrphostins.
The transforming abl proteins p160gag-abl, p185bcr-abl, and p210bcr-abl and the normal protein p140c-abl have identical catalytic sites, but differ in their N-terminal domains. Previous studies have indicated that the transforming abl proteins possess higher tyrosine kinase activity than the normal abl proto-oncogene product. In the present study, we demonstrate that two transforming abl proteins, p210bcr-abl and p160gag-abl, exhibit a higher affinity toward ATP and synthetic tyrosine containing substrates than p140c-abl. Furthermore, protein tyrosine kinase blockers from the tyrphostin family can discriminate between normal abl and transforming abl proteins of both human and mouse origin. These results suggest that the transforming potency of the abl proteins may result from their higher affinities toward intracellular signal transducers and demonstrate for the first time that oncogene products can differ from their homologous proto-oncogene product in substrate specificity. The ability of tyrphostins to discriminate between normal and transforming abl proteins suggests that it may be possible to design specific abl kinase inhibitors to combat abl-associated human leukemias.
Anafi
M
M
Lautenberg Center for Immunology, Hebrew University Hadassah Medical School, Jerusalem, Israel.
Gazit
A
A
Gilon
C
C
Ben-Neriah
Y
Y
Levitzki
A
A
D000255:Adenosine Triphosphate / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D016374:Oncogene Proteins v-abl / Q000378:metabolism*; D011108:Polymers; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000090063:Proto-Oncogene Mas; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*
C000715470:MAS1 protein, human; D016374:Oncogene Proteins v-abl; D011108:Polymers; D000090063:Proto-Oncogene Mas; D014443:Tyrosine; D000255:Adenosine Triphosphate; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl