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(Circulation Research. 2005;97:674.)
© 2005 American Heart Association, Inc.

Cellular Biology

Protein Kinase C–Dependent Phosphorylation of Syndecan-4 Regulates Cell Migration

Pinaki Chaudhuri, Scott M. Colles, Paul L. Fox, Linda M. Graham

From the Departments of Biomedical Engineering (P.C., S.M.C., L.M.G.), Cell Biology (P.L.F.), and Vascular Surgery (L.M.G.), Cleveland Clinic Foundation, Cleveland, Ohio.

Correspondence to Linda M. Graham, MD, Department of Biomedical Engineering/ND-20, Cleveland Clinic Foundation, Cleveland, OH 44195. E-mail grahamL{at}ccf.org

Endothelial cell (EC) migration is a complex process requiring exquisitely coordinated focal adhesion assembly and disassembly. Protein kinase C (PKC) is known to regulate focal adhesion formation. Because lysophosphatidylcholine (lysoPC), a major lipid constituent of oxidized low-density lipoprotein, can activate PKC and inhibit EC migration, we explored the signaling cascade responsible for this inhibition. LysoPC increased PKC activity, measured by in vitro kinase activity assay, and increased PKC phosphorylation. Decreasing PKC activation, using pharmacological inhibitors or antisense oligonucleotides, diminished the antimigratory effect of lysoPC. LysoPC-induced PKC activation was followed by increased phosphorylation of the transmembrane proteoglycan, syndecan-4, and decreased binding of PKC to syndecan-4, with a concomitant decrease in PKC activity. A reciprocal relationship was noted between the interaction of PKC and -actinin with syndecan-4. These changes were temporally related to the observed changes in cell morphology and the inhibition of migration of ECs incubated with lysoPC. The data suggested that generalized activation of PKC by lysoPC initiated a cascade of events, including phosphorylation of syndecan-4, displacement and decreased activity of PKC, binding of -actinin to syndecan-4, and disruption of the time- and site-specific regulation of focal adhesion complex assembly and disassembly required for normal cell migration.

Key Words: endothelial cell • migration • lysophosphatidylcholine • protein kinase C • syndecan-4 • -actinin

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