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The SH2 domain of P210BCR/ABL is not required for the transformation of
hematopoietic factor-dependent cells
RL Ilaria and RA Van Etten
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Src-homology region 2 (SH2) domains, by binding to tyrosine- phosphorylated
sequences, mediate specific protein-protein interactions important in
diverse signal transduction pathways. Previous studies have shown that
activated forms of the Abl tyrosine kinase, including P210BCR/ABL of human
chronic myelogenous leukemia, require the SH2 domain for the transformation
of fibroblasts. To determine whether SH2 is also required for Bcr/Abl to
transform hematopoietic cells, we have studied two SH2 domain mutations in
P210BCR/ABL: a point mutation in the conserved FLVRES motif (P210/R1033K),
which interferes with phosphotyrosine-binding by SH2, and a complete
deletion of SH2 (P210/delta SH2). Despite a negative effect on intrinsic
Abl kinase activity, both P210 SH2 mutants were still able to transform the
hematopoietic factor-dependent cell lines Ba/F3 and FDC-P1 to growth factor
independence. Unexpectedly, both mutants showed greater transforming
activity than wild-type P210 in a quantitative transformation assay,
probably as a consequence of increased stability of the SH2 mutant proteins
in vivo. Cells transformed by both P210 SH2 mutants were leukemogenic in
synaptic mice and P210/r1053K mice exhibited a distinct disease phenotype,
reminiscent of that induced by v-Abl. These results demonstrate that while
the Abl SH2 domain is essential for BCR/ABL transformation of fibroblasts,
it is dispensable for the transformation of hematopoietic factor-dependent
cell lines.
Volume 86,
Issue 10,
pp. 3897-3904,
11/15/1995
Copyright © 1995 by The American Society of Hematology
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