Oncogenic activation of c-ABL by mutation within its last exon.
The c-ABL proto-oncogene is a predominantly nuclear localized tyrosine kinase. A random mutagenesis scheme was used to isolate c-ABL mutants whose expression produced a transformed phenotype in rodent fibroblast cells. An in-frame deletion within the central region of the last exon was identified in one ABL mutant. The mechanism of c-ABL oncogenic activation by mutation within the last exon differs both functionally and structurally from those of v-ABL and BCR/ABL. This class of ABL mutants shows increased tyrosine phosphorylation of cellular proteins in vivo but low levels of autophosphorylation. Last-exon ABL mutants are distinguished from v-ABL or BCR/ABL by their inability to transform primary bone marrow cells or support the growth of transformed pre-B cells. These findings define a new mechanism of oncogenic activation for the ABL kinase through mutations in the last exon which do not require amino-terminal deletions or mutations within the src homology regions.
Goga
A
A
Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90024.
McLaughlin
J
J
Pendergast
A M
AM
Parmar
K
K
Muller
A
A
Rosenberg
N
N
Witte
O N
ON
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002451:Cell Compartmentation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003593:Cytoplasm / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005091:Exons; D016313:Genes, abl; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009841:Oligonucleotides / Q000737:chemistry; D011494:Protein Kinases / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics*; D011994:Recombinant Proteins; D017384:Sequence Deletion; D013329:Structure-Activity Relationship
D004268:DNA-Binding Proteins; D009841:Oligonucleotides; D011994:Recombinant Proteins; D011494:Protein Kinases; D016315:Proto-Oncogene Proteins c-abl