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J. Biol. Chem., Vol. 280, Issue 46, 38639-38647, November 18, 2005

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Tyrosine Phosphorylation of Sam68 by Breast Tumor Kinase Regulates Intranuclear Localization and Cell Cycle Progression^*

Kiven Erique Lukong1, Daniel Larocque2, Angela L. Tyner3, and Stéphane Richard, Investigator of the Canadian Institutes of Health4

From the Terry Fox Molecular Oncology Group and Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research and Departments of Oncology and Medicine, McGill University, Montreal, Quebec H3T 1E2, Canada and the Departments of Biochemistry and Molecular Genetics and Medicine, University of Illinois, Chicago, Illinois 60607

The breast tumor kinase (BRK) is a growth promoting non-receptor tyrosine kinase overexpressed in the majority of human breast tumors. BRK is known to potentiate the epidermal growth factor (EGF) response in these cells. Although BRK is known to phosphorylate the RNA-binding protein Sam68, the specific tyrosines phosphorylated and the exact role of this phosphorylation remains unknown. Herein, we have generated Sam68 phospho-specific antibodies against C-terminal phosphorylated tyrosine residues within the Sam68 nuclear localization signal. We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal. By indirect immunofluorescence we observed that BRK and EGF treatment not only phosphorylates Sam68 but also induces its relocalization. Tyrosine 440 was identified as a principal modulator of Sam68 localization and this site was phosphorylated in response to EGF treatment in human breast tumor cell lines. Moreover, this phosphorylation event was inhibited by BRK small interfering RNA treatment, consistent with Sam68 being a physiological substrate of BRK downstream of the EGF receptor in breast cancer cells. Finally, we observed that Sam68 suppressed BRK-induced cell proliferation, suggesting that Sam68 does indeed contain anti-proliferative properties that may be neutralized in breast cancer cells by phosphorylation.

Received for publication, May 27, 2005 , and in revised form, August 29, 2005.

^* This work was supported in part by Canadian Institutes of Health Research Grants MT-13377 and the Cancer Research Society Inc. (to S. R.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by a post-doctoral fellowship from the National Cancer Institute of Canada.

² Present address: Cedars-Sinai Medical Center Gene Therapeutics Research Institute, 8700 Beverly Blvd., Los Angeles, CA 90048.

³ Supported by National Institutes of Health Grant DK4452.

⁴ To whom correspondence should be addressed: 3755 Côte Ste.-Catherine Rd., Montréal, Québec H3T 1E2, Canada. Tel.: 514-340-8260; Fax: 514-340-8295; E-mail: stephane.richard{at}mcgill.ca.

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