ACTIVATION OF DISTINCT ALPHA(5)BETA(1)-MEDIATED SIGNALING PATHWAYS BYFIBRONECTINS CELL-ADHESION AND MATRIX ASSEMBLY DOMAINS

The interaction of cells with fibronectin generates a series of comple x signaling events that serve to regulate several aspects of cell beha vior, including growth, differentiation, adhesion, and motility. The f ormation of a fibronectin matrix is a dynamic, cell-mediated process t hat involves both ligation of the alpha(5) beta(1) integrin with the A rg-Gly-Asp (RGD) sequence in fibronectin and binding of the amino term inus of fibronectin to cell surface receptors, termed ''matrix assembl y sites,'' which mediate the assembly of soluble fibronectin into inso luble fibrils. Our data demonstrate that the amino-terminal type I rep eats of fibronectin bind to the alpha(5) beta(1) integrin and support cell adhesion. Furthermore, the amino terminus of fibronectin modulate s actin assembly, focal contact formation, tyrosine kinase activity, a nd cell migration. Amino-terminal fibronectin fragments and RGD peptid es were able to cross-compete for binding to the alpha(5) beta(1) inte grin, suggesting that these two domains of fibronectin cannot bind to the alpha(5) beta(1) integrin simultaneously. Cell adhesion to the ami no-terminal domain of fibronectin was enhanced by cytochalasin D, sugg esting that the ligand specificity of the alpha(5) beta(1) integrin is regulated by the cytoskeleton. These data suggest a new paradigm for integrin-mediated signaling, where distinct regions within one ligand can modulate outside-in signaling through the same integrin.