Deletion of an N-terminal regulatory domain of the c-abl tyrosine kinase activates its oncogenic potential.
The requirements for the oncogenic conversion of the c-abl proto-oncogene have been determined by the expression of N-terminal deleted forms and viral gag-fused forms of the c-abl proteins from a selectable retroviral vector. To activate the transforming potential of c-abl, it is necessary that (i) specific N-terminal amino acids are deleted to release the kinase from negative regulation in vivo; (ii) an N-terminal myristylation site is part of the activated kinase; (iii) the fatty-acylated, activated kinase is overproduced. The N-terminal amino acids found to be necessary for the cellular inhibition of c-abl tyrosine phosphorylation are part of a homologous region present in many non-receptor tyrosine kinases, the v-crk oncogene and phospholipase C-II. Overproduction of a deregulated and myristylated c-abl tyrosine kinase induces the transformation of NIH 3T3 cells.
Franz
W M
WM
Department of Biology, UCSD, La Jolla 92093.
Berger
P
P
Wang
J Y
JY
D000011:Abelson murine leukemia virus / Q000235:genetics; D000595:Amino Acid Sequence; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000201:enzymology*; D002872:Chromosome Deletion; D004789:Enzyme Activation; D005347:Fibroblasts; D016044:Fusion Proteins, bcr-abl; D015683:Gene Products, gag; D008979:Moloney murine leukemia virus / Q000235:genetics; D009363:Neoplasm Proteins / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012191:Retroviridae Proteins / Q000235:genetics; D014764:Viral Proteins / Q000502:physiology
D015683:Gene Products, gag; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D012191:Retroviridae Proteins; D014764:Viral Proteins; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl