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J. Biol. Chem., Vol. 281, Issue 41, 30907-30916, October 13, 2006

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Src Family Kinases Phosphorylate the Bcr-Abl SH3-SH2 Region and Modulate Bcr-Abl Transforming Activity^*

Malcolm A. Meyn, III¹, Matthew B. Wilson¹, Fadi A. Abdi, Nathalie Fahey, Anthony P. Schiavone, Jiong Wu^¶, James M. Hochrein^||, John R. Engen^||, and Thomas E. Smithgall²

From the Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, Applied Biosystems, Framingham, Massachusetts 01701, ^¶Cell Signaling Technology, Beverly, Massachusetts 01915, and the ^||Department of Chemistry, University of New Mexico, Albuquerque, New Mexico 87131

Bcr-Abl is the oncogenic protein-tyrosine kinase responsible for chronic myelogenous leukemia. Recently, we observed that inhibition of myeloid Src family kinase activity (e.g. Hck, Lyn, and Fyn) induces growth arrest and apoptosis in Bcr-Abl-transformed cells, suggesting that cell transformation by Bcr-Abl involves Src family kinases (Wilson, M. B., Schreiner, S. J., Choi, H. J., Kamens, J., and Smithgall, T. E. (2002) Oncogene 21, 8075-8088). Here, we report the unexpected observation that Hck, Lyn, and Fyn strongly phosphorylate the SH3-SH2 region of Bcr-Abl. Seven phosphorylation sites were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry: Tyr⁸⁹ and Tyr¹³⁴ in the Abl-derived SH3 domain; Tyr¹⁴⁷ in the SH3-SH2 connector; and Tyr¹⁵⁸, Tyr¹⁹¹, Tyr²⁰⁴, and Tyr²³⁴ in the SH2 domain. SH3 domain Tyr⁸⁹, the most prominent phosphorylation site in vitro, was strongly phosphorylated in chronic myelogenous leukemia cells in a Src family kinase-dependent manner. Substitution of the SH3-SH2 tyrosine phosphorylation sites with phenylalanine substantially reduced Bcr-Abl-mediated transformation of TF-1 myeloid cells to cytokine independence. The positions of these tyrosines in the crystal structure of the c-Abl core and the transformation defect of the corresponding Bcr-Abl mutants together suggest that phosphorylation of the SH3-SH2 region by Src family kinases impacts Bcr-Abl protein conformation and signaling.

Received for publication, June 20, 2006 , and in revised form, August 7, 2006.

^* This work was supported by National Institutes of Health Grant CA101828 (to T. E. S.) and Grants GM70590 and RR016480 (to J. R. E.) and by National Science Foundation Research Experiences for Undergraduates Site Award 0243735 (to N. F.). 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1240 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15261. Tel.: 412-648-9495; Fax: 412-624-1401; E-mail: tsmithga{at}pitt.edu.

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