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A more recent version of this article appeared on November 1, 2003
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Submitted on March 31, 2003
Revised on June 25, 2003
Accepted on July 21, 2003
Localization in Skeletal Muscle is Regulated by Phosphorylation and Interaction with Syntrophins
1 Department of Cellular and Molecular Medicine, Center
for Neuromuscular Disease, University of Ottawa, 451 Smyth Rd, Ottawa,
ON K1H 8M5, Canada
2 Huntsman Cancer Institute and
Department of Internal Medicine, University of Utah, Salt Lake City, UT
84112 USA
* Corresponding author. E-mail address: stevegee{at}uottawa.ca.
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 (DAG) to yield phosphatidic acid (PA).
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 (PKC)-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 (ERK)-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.
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