Syndecan-4 proteoglycan regulates the distribution and activity of protein kinase C.
During cell-matrix adhesion, both tyrosine and serine/threonine kinases are activated. Integrin ligation correlates with tyrosine phosphorylation, whereas the later stages of spreading and focal adhesion and stress fiber formation in primary fibroblasts requires interactions of cell surface proteoglycan with heparin-binding moieties. This correlates with protein kinase C (PKC) activation, and PKCalpha can become localized to focal adhesions in normal, but not transformed, cells. PKC activation has been thought to be downstream of initial receptor-ligand interactions. We now show, however, that syndecan-4 transmembrane heparan sulfate proteoglycan and PKC co-immunoprecipitate and co-patch in vivo. The core protein of syndecan-4 can directly bind the catalytic domain of PKCalpha and potentiate its activation by phospholipid mediators. It can also directly activate PKCalpha in the absence of other mediators. This activity resides in the sequence LGKKPIYKK in the center of the short cytoplasmic domain, and other syndecans lack this sequence and PKC regulatory properties. Syndecan-4 is a focal adhesion component, and this interaction may both localize PKC and amplify its activity at sites of forming adhesions. This represents the first report of direct transmembrane signaling through cell surface proteoglycans.
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Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Woods
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Couchman
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D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion; D004789:Enzyme Activation; D007527:Isoenzymes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D053671:Syndecan-4
D007527:Isoenzymes; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D011994:Recombinant Proteins; C508307:Sdc4 protein, rat; D053671:Syndecan-4; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha