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PI 3-kinase activation in BCR/abl-transformed hematopoietic cells does not
require interaction of p85 SH2 domains with p210 BCR/abl
SK Jain, M Susa, ML Keeler, N Carlesso, B Druker and L Varticovski
Department of Biomedical Research, St Elizabeth's Medical Center, Tufts
University School of Medicine, Boston, MA 02135, USA.
BCR/abl is a chimeric oncogene implicated in the pathogenesis of human
chronic myelogenous leukemia. Expression of the BCR/abl gene induces
hematologic malignancies in transgenic mice and transformation of
interleukin-3-dependent hematopoietic cells. The mechanism of BCR/abl-
mediated transformation of hematopoietic cells is poorly understood and
involves activation of at least two signaling pathways, p21ras and PI 3-
kinase. Here we report that PI 3,4-P2 and PI 3,4,5-P3, the enzymatic
products of PI 3-kinase, accumulate in metabolically labeled transformed
hematopoietic cells, in contrast to our previous report on the lack of
accumulation of PI 3-kinase products in nontransformed NIH 3T3 fibroblasts
that express p210 BCR/abl. Transformed cells also have increased PI
3-kinase activity in total cell extracts and membrane fractions. Activation
of PI 3-kinase occurs by occupancy of SH2 domains of PI 3-kinase regulatory
subunit, p85, by phosphorylated YXXM motifs. Therefore, we investigated
whether BCR/abl binds to p85 and whether this binding is mediated by
interaction of p85 SH2 domains with YXXM motif of BCR/abl. Association of
p210 BCR/abl with p85 in immune complexes and with p85 SH2 domains was
evident in hematopoietic cells that express the wt p210 BCR/abl. However,
the binding of BCR/abl to p85 SH2 domains was abolished in cells expressing
mutant, temperature- sensitive (ts) p210 BCR/abl in which the tyrosine in
the YXXM motif of p210 BCR/abl was replaced by histidine. Despite lack of
direct interaction with p85 SH2 domains, expression of ts p210 BCR/abl
resulted in rapid, time-dependent activation of total and membrane-
associated PI 3-kinase and increased PI 3-kinase activity in anti-P-tyr and
anti-abl immunoprecipitates. These data suggest that BCR/abl- induced
activation of PI 3-kinase in hematopoietic cells does not require binding
of p85 SH2 domains to BCR/abl gene product and involves interaction with
other tyrosine phosphorylated intermediate proteins.
Volume 88,
Issue 5,
pp. 1542-1550,
09/01/1996
Copyright © 1996 by The American Society of Hematology
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