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J. Biol. Chem., Vol. 282, Issue 50, 36265-36274, December 14, 2007

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Heterogeneous Ribonucleoprotein M Is a Splicing Regulatory Protein That Can Enhance or Silence Splicing of Alternatively Spliced Exons^*

Ruben H. Hovhannisyan and Russ P. Carstens¹

From the Renal-Electrolyte and Hypertension Division, Department of Medicine and Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Splicing of fibroblast growth factor receptor 2 (FGFR2) alternative exons IIIb and IIIc is regulated by the auxiliary RNA cis-element ISE/ISS-3 that promotes splicing of exon IIIb and silencing of exon IIIc. Using RNA affinity chromatography, we have identified heterogeneous nuclear ribonucleoprotein M (hnRNP M) as a splicing regulatory factor that binds to ISE/ISS-3 in a sequence-specific manner. Overexpression of hnRNP M promoted exon IIIc skipping in a cell line that normally includes it, and association of hnRNP M with ISE/ISS-3 was shown to contribute to this splicing regulatory function. Thus hnRNP M, along with other members of the hnRNP family of RNA-binding proteins, plays a combinatorial role in regulation of FGFR2 alternative splicing. We also determined that hnRNP M can affect the splicing of several other alternatively spliced exons. This activity of hnRNP M included the ability not only to induce exon skipping but also to promote exon inclusion. This is the first report demonstrating a role for this abundant hnRNP family member in alternative splicing in mammals and suggests that this protein may broadly contribute to the fidelity of splice site recognition and alternative splicing regulation.

Received for publication, May 21, 2007 , and in revised form, October 23, 2007.

^* This work was supported by National Institutes of Health Grant CA093769. 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 To whom correspondence should be addressed: Dept. of Medicine, University of Pennsylvania School of Medicine, 480 Hill Pavilion, 380 S. University Ave., Philadelphia, PA 19104-4539. Tel.: 215-573-1838; Fax: 215-898-0189; E-mail: russcars{at}mail.med.upenn.edu.

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