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J. Biol. Chem., Vol. 278, Issue 30, 27413-27420, July 25, 2003

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Characterization of a Myeloid Tyrosine Phosphatase, Lyp, and Its Role in the Bcr-Abl Signal Transduction Pathway^*

Wenwen Chien , Nicola Tidow , Elizabeth A. Williamson, Lee-Yung Shih ¶, Utz Krug, Arminja Kettenbach, Anthony C. Fermin, Chaim M. Roifman || ** and H. Phillip Koeffler 

From the Department of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048, ^¶Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taipei 105, Taiwan, and the ^||Division of Immunology and Allergy, Department of Pediatrics, University of Toronto and The Hospital for Sick Children, Toronto M5G 1X8, Canada

The Bcr-Abl protein-tyrosine kinase is implicated in the development of chronic myeloid leukemia. The potential role of protein-tyrosine phosphatase in the regulation of Bcr-Abl signaling was explored. First, expression patterns of tyrosine phosphatases in leukemic cell lines were investigated using degenerate primers for reverse transcription-PCR followed by cloning and sequencing of the cDNA. Distinct patterns of distribution of phosphatase were found in erythroid and myeloid leukemic cell lines. Whereas some phosphatases were ubiquitously expressed, others were limited to specific cell types. Surprisingly, a previously cloned "lymphocyte-specific" phosphatase, Lyp, was frequently detected in a number of myeloid cell lines as well as normal granulocytes and monocytes. Lyp was localized to the cytosol, and overexpression of Lyp caused reduction in the phosphorylation levels of multiple proteins in KCL22 chronic myeloid leukemia blast cells including Cbl, Bcr-Abl, Erk1/2, and CrkL. Co-expression of Lyp and Bcr-Abl in Cos-7 cells resulted in decreased levels of Bcr-Abl, Grb2, and Myc. Overexpression of Lyp markedly suppressed anchorage-independent clonal growth of KCL22 cells. Taken together, the data suggest that Lyp may play an antagonistic role in signaling by the Bcr-Abl fusion protein.

Received for publication, May 1, 2003

^* This work was supported in part by grants from the National Cancer Institute of Canada and the NCI, National Institutes of Health, as well as the C. and H. Koeffler Fund and the Parker Hughes Fund. 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.

A recipient of a fellowship of the Deutsche Forschungsgemein-schaft.

^** Holds the Donald and Audrey Campbell Chair of Immunology in the Hospital for Sick Children in Toronto, Canada.

Holds the Mark Goodson Chair in Oncology Research and is a member of the Molecular Biology Institute and the Jonsson Cancer Center of UCLA.

To whom correspondence should be addressed: Dept. of Hematology/Oncology, Cedars-Sinai Medical Center, 110 George Burns Rd., D5065, Los Angeles, CA 90048. Tel.: 310-423-7759; Fax: 310-423-0225; E-mail: chienw{at}cshs.org.

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