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J. Biol. Chem., Vol. 279, Issue 47, 49384-49394, November 19, 2004

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Subcellular Localization of Multiple PREP2 Isoforms Is Regulated by Actin, Tubulin, and Nuclear Export^*

Klaus Haller¶, Isabel Rambaldi, Eugene Daniels||, and Mark Featherstone, A Chercheur-National of the Fonds de la Recherche en Santé du Québec**

From the McGill Cancer Centre and Department of Biochemistry, Departments of ^**Medicine, Oncology, and ^||Anatomy and Cell Biology, McGill University, Montreal, Quebec H3G 1Y6, Canada

The PREP, MEIS, and PBX families are mammalian members of the TALE (three amino acid loop extension) class of homeodomain-containing transcription factors. These factors have been implicated in cooperative DNA binding with the HOX class of homeoproteins, but PREP and MEIS interact with PBX in apparently non-HOX-dependent cooperative DNA binding as well. PREP, MEIS, and PBX have all been reported to reside in the cytoplasm in one or more tissues of the developing vertebrate embryo. In the case of PBX, cytoplasmic localization is due to the modulation of nuclear localization signals, nuclear export sequences, and interaction with a cytoplasmic anchoring factor, non-muscle myosin heavy chain II B. Here we report that murine PREP2 exists in multiple isoforms distinguished by interaction with affinity-purified antibodies raised to N- and C-terminal epitopes and by nuclear versus cytoplasmic localization. Alternative splicing gives rise to some of these PREP2 isoforms, including a 25-kDa variant lacking the C-terminal half of the protein and homeodomain and having the potential to act as dominant-negative. We further show that cytoplasmic localization is due to the concerted action of nuclear export, as evidenced by sensitivity to leptomycin B, and cytoplasmic retention by the actin and microtubule cytoskeletons. Cytoplasmic PREP2 colocalizes with both the actin and microtubule cytoskeletons and coimmunoprecipitates with actin and tubulin. Importantly, disruption of either cytoskeletal system redirects cytoplasmic PREP2 to the nucleus. We suggest that transcriptional regulation by PREP2 is modulated through the subcellular distribution of multiple isoforms and by interaction with two distinct cytoskeletal systems.

Received for publication, June 1, 2004 , and in revised form, August 18, 2004.

^* This work was supported by Operating Grant 36409 from the Canadian Institutes of Health Research (CIHR). 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 a McGill Graduate Studies Fellowship.

To whom correspondence should be addressed: McGill Cancer Center, McGill University, McIntyre Medical Science Bldg., Rm. 714, 3655 Promenade Sir W. Osler, Montreal, Quebec H3G 1Y6, Canada. Tel.: 514-398-8937; Fax: 514-398-6769; E-mail: mark.featherstone{at}mcgill.ca.

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