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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 618-624
Characterization of Grb4, an adapter protein interacting with
Bcr-Abl
Sunita Coutinho,
Thomas Jahn,
Marc Lewitzky,
Stephan Feller,
Peter Hutzler,
Christian Peschel, and
Justus Duyster
From the Department of Internal Medicine III, Technical University
of Munich; Medical Institute for Radiation and Cell Research,
Würzburg; and GSF-Forschungszentrum, Neuherberg, Germany.
We report here the characterization of an adapter protein identified
in a yeast 2-hybrid screen with the use of Bcr-Abl as the bait. Grb4 bound to Bcr-Abl in a variety of systems, both in vitro
and in vivo, and is an excellent substrate of the Bcr-Abl tyrosine
kinase. The association of Grb4 and Bcr-Abl in intact cells was
mediated by an src homology (SH)2-mediated
phosphotyrosine-dependent interaction as well as an SH3-mediated
phosphotyrosine-independent interaction. Grb4 has 68% homology to the
adapter protein Nck and has similar but distinct binding specificities
in K562 lysates. Subcellular localization studies indicate that Grb4
localizes to both the nucleus and the cytoplasm. Coexpression of
kinase-active Bcr-Abl with Grb4 resulted in the translocation of Grb4
from the cytoplasm and the nucleus to the cytoskeleton to colocalize
with Bcr-Abl. In addition, expression of Grb4 with kinase-active
Bcr-Abl resulted in a redistribution of actin-associated Bcr-Abl.
Finally, coexpression of Grb4 and oncogenic v-Abl strongly inhibited
v-Abl-induced AP-1 activation. Together, these data indicate that Grb4
in conjunction with Bcr-Abl may be capable of modulating the
cytoskeletal structure and negatively interfering with the signaling of
oncogenic Abl kinases. Grb4 may therefore play a role in the molecular
pathogenesis of chronic myelogenous leukemia. (Blood.
2000;96:618-624)
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