Abstract
The p210bcr-abl and p190bcr-abl fusion proteins, respectively responsible for chronic myelogenous leukemia and acute lymphoblastic leukemia, present deregulated tyrosine kinase activity and abnormal localization. The Dbl homology domain of Bcr, activating Rho GTPases, is present in p210bcr-abl, but absent in p190bcr-abl. We investigated the interaction of Bcr-Abl chimeras and Rho proteins by coimmunoprecipitation, pull-down experiments and GEF activity measurement. RhoA, Rac1 and Cdc42 interact in vivo with p210bcr-abl only. Moreover, the three types of GTPases are activated in vitro and in vivo by p210bcr-abl. Nevertheless, Rac1 and Cdc42, but not RhoA, are activated by p190bcr-abl in vitro and in vivo. Part of this GEF activity of p190bcr-abl is probably attributable to p95vav, which is complexed with both p190bcr-abl and p210bcr-abl in an activated form. p160bcr, also in complex with Bcr-Abl, presents no GEF activity in p190bcr-abl-expressing cells. These results suggest that differential activation of Rho proteins should play a major role in Bcr-Abl-induced leukemogenesis.
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Acknowledgements
We thank George Daley and Rick Van Etten for providing us material and encouragement for this work. We also thank Bernard Payrastre and Alan Hall for GST-fused GTPases, and J Collard for sending us GST-PAK-CRIB and GST-RTK with the complete protocol. We also thank Rick Van Etten and Jean de Gunsburg for interesting helpful discussions, and Valérie Tourenne for helpful technical assistance. This work was in part supported by grants provided by the ‘Ligue Nationale centre le Cancer, Charente-maritime and Vienne’.
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Harnois, T., Constantin, B., Rioux, A. et al. Differential interaction and activation of Rho family GTPases by p210bcr-abl and p190bcr-abl. Oncogene 22, 6445–6454 (2003). https://doi.org/10.1038/sj.onc.1206626
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DOI: https://doi.org/10.1038/sj.onc.1206626
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