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Global effects of BCR/ABL and TEL/PDGFRbeta expression on the proteome and phosphoproteome: Identification of the Rho pathway as a target of BCR/ABL.
Unwin RD, Sternberg DW, Lu Y, Pierce A, Gilliland DG, Whetton A
J Biol Chem. 2005;280(8):6316-6326.
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Abstract
Many leukaemic oncogenes form as a consequence of gene fusions or mutation that result in the activation or overexpression of a tyrosine kinase. To identify commonalities and differences in the action of two such kinases, BCR/ABL and TEL/PDGFRbeta, 2-dimensional gel electrophoresis was employed to characterise their effects on the proteome. Whilst both oncogenes affected expression of specific proteins, few common effects were observed. A number of proteins whose expression is altered by BCR/ABL, including gelsolin and stathmin, are related to cytoskeletal function whereas no such changes were seen in TEL/PDGFRbeta-transfected cells. Treatment of cells with the kinase inhibitor STI571 for 4hours reversed changes in expression of some of these cytoskeletal proteins. Correspondingly, BCR/ABL-transfected cells were less responsive to chemotactic and chemokinetic stimuli than non-transfected cells and TEL/PDGFRbeta-transfected Ba/F3 cells. Decreased motile response was reversed by 16hr treatment with STI571. A phosphoprotein-specific gel stain was used to identify TEL/PDGFRbeta and BCR/ABL-mediated changes in the phosphoproteome. These included changes on Crkl, Ras-GAP binding protein 1 and for BCR/ABL, cytoskeletal proteins such as tubulin and Nedd5. Decreased phosphorylation of Rho-GTPase dissociation inhibitor (Rho GDI) was also observed in BCR/ABL-transfected cells. This results in the activation of the Rho pathway and treatment of cells with Y27632, an inhibitor of Rho kinase, inhibited DNA synthesis in BCR/ABL-transfected Ba/F3 cells but not Tel/PDGFRbeta-expressing cells. Expression of a dominant negative RhoA inhibited both DNA synthesis and transwell migration, demonstrating the significance of this pathway in BCR/ABL mediated transformation.