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J. Biol. Chem., Vol. 279, Issue 53, 56014-56023, December 31, 2004

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Multiple Promoters Direct Expression of Three AKAP12 Isoforms with Distinct Subcellular and Tissue Distribution Profiles^*

Jeffrey W. Streb, Chad M. Kitchen, Irwin H. Gelman¶, and Joseph M. Miano||

From the Center for Cardiovascular Research in the Aab Institute of Biomedical Sciences, University of Rochester, Rochester, New York 14642, and the ^¶Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263

A Kinase Anchoring Protein 12 (AKAP12; also known as src-suppressed C kinase substrate (SSeCKS) and Gravin) is a multivalent anchoring protein with tumor suppressor activity. Although expression of AKAP12 has been examined in a number of contexts, its expression control remains to be elucidated. Herein, we characterize the genomic organization of the AKAP12 locus, its regulatory regions, and the spatial distribution of the proteins encoded by the AKAP12 gene. Using comparative genomics and various wet-lab assays, we show that the AKAP12 locus is organized as three separate transcription units that are governed by non-redundant promoters coordinating distinct tissue expression profiles. The proteins encoded by the three AKAP12 isoforms (designated , , and ) share >95% amino acid sequence identity but differ at their N termini. Analysis of the targeting of each isoform reveals distinct spatial distribution profiles. An N-terminal myristoylation motif present in AKAP12 is shown to be necessary and sufficient for targeted expression of this AKAP12 isoform to the endoplasmic reticulum, a novel subcellular compartment for AKAP12. Our results demonstrate heretofore unrecognized complexity within the AKAP12 locus and suggest a mechanism for genetic control of signaling specificity through distinct regulation of alternately targeted anchoring protein isoforms.

Received for publication, August 3, 2004 , and in revised form, September 30, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY695056, AY695057, AY695058, AY695059, AY695060, and AY695061.

^* This work was supported by National Institutes of Health Grants R01-HL70077 (to J. M. M.) and R01-CA94108 (to I. H. G.). 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 National Institutes of Health institutional training grant T32-HL07949.

^|| To whom correspondence should be addressed: University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 585-273-1664; Fax: 585-273-1497; E-mail: j.m.miano{at}rochester.edu.

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