BCR-ABL is the oncogenic
fusion product of tyrosine kinase ABL1
and a highly frequent driver of acute lymphocytic leukemia (ALL) and
chronic myeloid leukemia (CML). The kinase activity of BCR-ABL is
strongly elevated; however, changes of substrate specificity in comparison
to wild-type ABL1 kinase are less well characterized. Here, we heterologously
expressed full-length BCR-ABL kinases in yeast. We exploited the proteome
of living yeast as anin vivophospho-tyrosine substrate
for assaying human kinase specificity. Phospho-proteomic analysis
of ABL1 and BCR-ABL isoforms p190 and p210 yielded a high-confidence
data set of 1127 phospho-tyrosine sites on 821 yeast proteins. We
used this data set to generate linear phosphorylation site motifs
for ABL1 and the oncogenic ABL1 fusion proteins. The oncogenic kinases
yielded a substantially different linear motif when compared to ABL1.
Kinase set enrichment analysis with human pY-sites that have high
linear motif scores well-recalled BCR-ABL driven cancer cell lines
from human phospho-proteome data sets.