title: A shared mechanism of adhesion modulation for tenascin-C and fibulin-1.
abstract: Adhesion modulatory proteins are important effectors of cell-matrix interactions during tissue remodeling and regeneration. They comprise a diverse group of matricellular proteins that confer antiadhesive properties to the extracellular matrix (ECM). We compared the inhibitory effects of two adhesion modulatory proteins, fibulin-1 and tenascin-C, both of which bind to the C-terminal heparin-binding (HepII) domain of fibronectin (FN) but are structurally distinct. Here, we report that, like tenascin-C, fibulin-1 inhibits fibroblast spreading and cell-mediated contraction of a fibrin-FN matrix. These proteins act by modulation of focal adhesion kinase and extracellular signal-regulated kinase signaling. The inhibitory effects were bypassed by lysophosphatidic acid, an activator of RhoA GTPase. Fibroblast response to fibulin-1, similar to tenascin-C, was dependent on expression of the heparan sulfate proteoglycan syndecan-4, which also binds to the HepII domain. Therefore, blockade of HepII-mediated signaling by competitive binding of fibulin-1 or tenascin-C represents a shared mechanism of adhesion modulation among disparate modulatory proteins.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Selwyn A
authors.initials: SA
authors.lastname: Williams
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schwarzbauer
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D053671:Syndecan-4 / Q000378:metabolism; D019063:Tenascin / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D005353:Fibronectins; D008246:Lysophospholipids; D053671:Syndecan-4; D019063:Tenascin; C060820:fibulin; D048049:Extracellular Signal-Regulated MAP Kinases; C032881:lysophosphatidic acid