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J. Biol. Chem., Vol. 279, Issue 52, 54398-54404, December 24, 2004

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The Nuclear Tyrosine Kinase BRK/Sik Phosphorylates and Inhibits the RNA-binding Activities of the Sam68-like Mammalian Proteins SLM-1 and SLM-2^*

Andrea Haegebarth, Darien Heap¶||, Wenjun Bie, Jason J. Derry, Stéphane Richard**, and Angela L. Tyner¶

From the Departments of Biochemistry and Molecular Genetics and ^¶Medicine, University of Illinois, Chicago, Illinois 60607 and ^**Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Departments of Oncology and Medicine, McGill University, Montreal, Quebec H3T 1E2, Canada

Expression of the intracellular tyrosine kinase BRK/Sik is epithelial-specific and regulated during differentiation. Only a few substrates have been identified for BRK/Sik, including the KH domain containing RNA-binding protein Sam68 and the novel adaptor protein BKS. Although the physiological role of Sam68 is unknown, it has been shown to regulate mRNA transport, pre-mRNA splicing, and polyadenylation. Here we demonstrate that the Sam68-like mammalian proteins SLM-1 and SLM-2 but not the related KH domain containing heterogeneous nuclear ribonucleoprotein K are novel substrates of BRK/Sik. The expression of active BRK/Sik results in increased SLM-1 and SLM-2 phosphorylation and increased retention of BRK/Sik within the nucleus. The phosphorylation of SLM-1 and SLM-2 has functional relevance and leads to inhibition of their RNA-binding abilities. We show that SLM-1, SLM-2, and BRK/Sik have restricted patterns of expression unlike the ubiquitously expressed Sam68. Moreover, BRK/Sik, SLM-1, and Sam68 transcripts were coexpressed in the mouse gastrointestinal tract and skin, suggesting that SLM-1 and Sam68 could be physiologically relevant BRK/Sik targets in vivo. The ability of BRK/Sik to negatively regulate the RNA-binding activities of the KH domain RNA binding proteins SLM-1 and Sam68 may have an impact on the posttranscriptional regulation of epithelial cell gene expression.

Received for publication, August 20, 2004 , and in revised form, September 29, 2004.

^* This work was supported in part by National Institutes of Health Grant DK44525 and Department of Defense Army Grant DAMD17-01-1-0273 (to A. L. T.). 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.

Supported by the German Academic Exchange Service (DAAD) and the Schering Foundation.

^|| Supported by National Institutes of Health Training Grant DK07788.

Supported by Grant MT-13377 from the Canadian Institutes of Health Research and a grant from the Cancer Research Society, Inc.

To whom correspondence should be addressed: University of Illinois College of Medicine, Department of Biochemistry and Molecular Genetics, M/C 669, 900 S. Ashland Ave., Chicago, IL 60607. Tel.: 312-996-7964; Fax: 312-413-0353; E-mail: atyner{at}uic.edu.

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