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J. Biol. Chem., Vol. 280, Issue 8, 6316-6326, February 25, 2005

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Global Effects of BCR/ABL and TEL/PDGFR Expression on the Proteome and Phosphoproteome

IDENTIFICATION OF THE RHO PATHWAY AS A TARGET OF BCR/ABL^*

Richard D. Unwin, David W. Sternberg¶||, Yuning Lu, Andrew Pierce, D. Gary Gilliland¶**, and Anthony D. Whetton

From the Faculty of Medical and Human Sciences, University of Manchester and the Mass Spectrometry Laboratory, Paterson Institute for Cancer Research, Christie Hospital, Withington, Manchester M20 9BX, United Kingdom, the ^¶Hematology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, the ^||Mount Sinai Medical School, New York, New York 10029, and the ^**Howard Hughes Medical Institute, Chevy Chase, Maryland 20815

Many leukemic 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, breakpoint cluster region (BCR)/ABL and TEL/PDGFR, two-dimensional gel electrophoresis was employed to characterize their effects on the proteome. While 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/PDGFR-transfected cells. Treatment of cells with the kinase inhibitor STI571 for 4-h 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/PDGFR-transfected Ba/F3 cells. Decreased motile response was reversed by a 16-h treatment with STI571. A phosphoprotein-specific gel stain was used to identify TEL/PDGFR 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/PDGFR-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.

Received for publication, September 15, 2004 , and in revised form, November 2, 2004.

^* This work was supported by the Leukemia Research Fund, United Kingdom. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Faculty of Medical and Human Sciences, University of Manchester, Christie Hospital, Withington, Manchester M20 9BX, United Kingdom. Tel.: 44-0-161-446-3155; Fax: 44-0-161-446-3109; E-mail: awhetton{at}picr.man.ac.uk.

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