Protein kinase Cdelta-dependent phosphorylation of syndecan-4 regulates cell migration.
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 PKCdelta activity, measured by in vitro kinase activity assay, and increased PKCdelta phosphorylation. Decreasing PKCdelta activation, using pharmacological inhibitors or antisense oligonucleotides, diminished the antimigratory effect of lysoPC. LysoPC-induced PKCdelta activation was followed by increased phosphorylation of the transmembrane proteoglycan, syndecan-4, and decreased binding of PKCalpha to syndecan-4, with a concomitant decrease in PKCalpha activity. A reciprocal relationship was noted between the interaction of PKCalpha and alpha-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 PKCdelta by lysoPC initiated a cascade of events, including phosphorylation of syndecan-4, displacement and decreased activity of PKCalpha, binding of alpha-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.
Chaudhuri
Pinaki
P
Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Colles
Scott M
SM
Fox
Paul L
PL
Graham
Linda M
LM
D000185:Actinin / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology*; D004789:Enzyme Activation; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D011509:Proteoglycans / Q000378:metabolism*; D053671:Syndecan-4
D008244:Lysophosphatidylcholines; D008562:Membrane Glycoproteins; D016376:Oligonucleotides, Antisense; D011509:Proteoglycans; D053671:Syndecan-4; D000185:Actinin; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta