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Molecular and Cellular Biology, August 2003, p. 5489-5501, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5489-5501.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Alternative Splicing Controls Myotonic Dystrophy Protein Kinase Structure, Enzymatic Activity, and Subcellular Localization

Derick G. Wansink,^1* René E. M. A. van Herpen,¹ Marga M. Coerwinkel-Driessen,¹ Patricia J. T. A. Groenen,^1, Brian A. Hemmings,² and Bé Wieringa¹

Department of Cell Biology, Nijmegen Center for Molecular Life Sciences, University Medical Center, 6500 HB Nijmegen, The Netherlands,¹ Friedrich Miescher Institute, CH-4058 Basel, Switzerland²

Received 7 February 2003/ Returned for modification 19 March 2003/ Accepted 20 May 2003

Transcripts of the myotonic dystrophy protein kinase (DMPK) gene, a member of the Rho kinase family, are subject to cell-type specific alternative splicing. An imbalance in the splice isoform profile of DMPK may play a role in the pathogenesis of DM1, a severe multisystemic disorder. Here, we report how structural subdomains determine biochemical properties and subcellular distribution of DMPK isoforms. A newly developed kinase assay revealed that DMPK is a Lys/Arg-directed kinase. Individual DMPK isoforms displayed comparable transphosphorylation activity and sequence preference for peptide substrates. However, DMPK autophosphorylation and phosphorylation of MYPT1 (as putative in vivo target of DMPK), were dependent on presence of an alternatively spliced VSGGG motif and the nature of the C terminus. In-gel effects of the VSGGG motif on the migration behavior of full-length kinase provide evidence for a model in which this motif mediates 3-D-conformational changes in DMPK isoforms. Finally, different C termini endow DMPK with the ability to bind to either endoplasmic reticulum or mitochondria or to adopt a cytosolic location. Our results suggest that DMPK isoforms have cell-type and location dependent substrate specificities with a role in organellar and cytoarchitectural dynamics.

Present address: Department of Pathology, University Medical Center, 6500 HB Nijmegen, The Netherlands.

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