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Vol. 14, Issue 11, 4499-4511, November 2003

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Diacylglycerol Kinase- Localization in Skeletal Muscle Is Regulated by Phosphorylation and Interaction with Syntrophins

Hanan Abramovici ^* , Angela B. Hogan ^* , Christopher Obagi ^*, Matthew K. Topham , and Stephen H. Gee ^* 

^* Department of Cellular and Molecular Medicine, Center for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Huntsman Cancer Institute and Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84112

Submitted March 31, 2003; Revised June 25, 2003; Accepted July 21, 2003
Monitoring Editor: Mary Beckerle

Syntrophins are scaffolding proteins that link signaling molecules to dystrophin and the cytoskeleton. We previously reported that syntrophins interact with diacylglycerol kinase- (DGK-), which phosphorylates diacylglycerol to yield phosphatidic acid. Here, we show syntrophins and DGK- form a complex in skeletal muscle whose translocation from the cytosol to the plasma membrane is regulated by protein kinase C-dependent phosphorylation of the DGK- MARCKS domain. DGK- mutants that do not bind syntrophins were mislocalized, and an activated mutant of this sort induced atypical changes in the actin cytoskeleton, indicating syntrophins are important for localizing DGK- and regulating its activity. Consistent with a role in actin organization, DGK- and syntrophins were colocalized with filamentous (F)-actin and Rac in lamellipodia and ruffles. Moreover, extracellular signal-related kinase-dependent phosphorylation of DGK- regulated its association with the cytoskeleton. In adult muscle, DGK- was colocalized with syntrophins on the sarcolemma and was concentrated at neuromuscular junctions (NMJs), whereas in type IIB fibers it was found exclusively at NMJs. DGK- was reduced at the sarcolemma of dystrophin-deficient mdx mouse myofibers but was specifically retained at NMJs, indicating that dystrophin is important for the sarcolemmal but not synaptic localization of DGK-. Together, our findings suggest syntrophins localize DGK- signaling complexes at specialized domains of muscle cells, which may be critical for the proper control of lipid-signaling pathways regulating actin organization. In dystrophic muscle, mislocalized DGK- may cause abnormal cytoskeletal changes that contribute to disease pathogenesis.

These authors contributed equally to this study.

Corresponding author. E-mail address: stevegee{at}uottawa.ca.

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