Fibronectin

Fibronectin is a fibrillar extracellular matrix (ECM) glycoprotein that binds to cells and other matrix molecules, thereby contributing to the organization of the matrix and providing important adhesive sites for cells. Fibronectin is found throughout the vertebrate body, including the brain, which lacks a recognizable ECM but expresses ECM molecules like fibronectin transiently in early development. Fibronectin is a dimer of 240-kDa monomers linked at the C-terminus by a pair of disulfide bonds. The protein is made of similar but nonidentical repeating domains (types I, II, III), most of which are derived from a single exon. The type III repeat, about 90 amino acid residues in length, occurs 15 times in each monomer and is a structural element found in other proteins as well. While the protein is encoded by a single gene, multiple splicing variants give rise to diverse isoforms that differ in their cell binding sites and functions. One isoform is found as an abundant protein in blood and is thought to participate in wound healing, phagocytosis by white blood cells, and blood clotting. Other forms are incorporated into fibrils in the ECM. The regions of the protein that bind to matrix molecules and cells have been uncovered by using mild proteinase digestion and column chromatography to isolate and characterize the fragments. The fibronectin monomer has two binding sites each for heparin and fibrin, and a single binding site for collagen. Further analysis of small synthetic peptides has led to the identification of the sequence -Arg-Gly-Asp- (RGD), which is bound by many cells via integrin receptors alpha-5/beta-1, alpha-3/beta-b1, alpha-v/beta-1, and alpha-v/beta-3. The RGD site occurs in a type III repeat on a loop extended above the surface of the domain, which is thought to provide easy access to cells. The RGD sequence is also found in other matrix proteins recognized by integrins, such as vitronectin. An alternatively spliced region (type III connecting segment or V) contains a second binding motif -Leu-Asp-Val- (LDV), which is the main part of the binding site for another integrin (alpha-4/beta-1).

Fibronectin is one of the best-characterized ECM glycoproteins. In vitro, it supports adhesion of many cell types, and it can also stimulate cell proliferation, differentiation, and migration. Cells in culture often flatten and develop prominent actin arrays in response to fibronectin. The response depends on the particular cell type and its array of fibronectin receptors. The importance of fibronectin in migration of cells has been demonstrated for neural crest cells in birds and gastrulating embryonic cells of frogs, where injected antibodies and RGD-containing peptides will block cell migration. In genetically engineered mice lacking fibronectin, death occurs early in embryogenesis in part because of a failure of mesodermal cells to develop, resulting in defects in the development of the notochord, somites, blood vessels, and heart.

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