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Fibronectin is a high-molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to cell membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collagen, fibrin, and heparan sulfate proteoglycans (e.g. syndecans).
Fibronectin exists as a protein dimer, consisting of two nearly identical monomers linked by a pair of disulfide bonds. The fibronectin protein is produced from a single gene, but alternative splicing of its pre-mRNA leads to the creation of several isoforms.
Two types of fibronectin are present in vertebrates:
Fibronectin plays a major role in cell adhesion, cell growth, cell migration, and differentiation, and it is important for processes such as wound healing and embryonic development. Altered fibronectin gene expression, degradation, and organization has been associated with a number of pathologies, including cancer, arthritis, and fibrosis.
Three regions of variable RNA splicing occur along the length of the fibronectin protomer. One or both of the "extra" type III modules (EIIIA and EIIIB) may be present in cellular fibronectin, but they are never present in plasma fibronectin. A "variable" V-region exists between III14–15 (the 14th and 15th type III module). The V-region structure is different from the type I, II, and III modules, and its presence and length may vary. The V-region contains the binding site for α4β1 integrins. It is present in most cellular fibronectin, but only one of the two subunits in a plasma fibronectin dimer contains a V-region sequence.
The modules are arranged into several functional and protein-binding protein domain along the length of a fibronectin monomer. There are four fibronectin-binding domains, allowing fibronectin to associate with other fibronectin molecules. One of these fibronectin-binding domains, I1–5, is referred to as the "assembly domain", and it is required for the initiation of fibronectin matrix assembly. Modules III9–10 correspond to the "cell-binding domain" of fibronectin. The RGD motif (Arg–Gly–Asp) is located in III10 and is the site of cell adhesion via α5β1 and αVβ3 integrins on the cell surface. The "synergy site" is in III9 and has a role in modulating fibronectin's association with α5β1 integrins. Fibronectin also contains domains for fibrin-binding (I1–5, I10–12), collagen-binding (I6–9), fibulin-1-binding (III13–14), heparin-binding and syndecan-binding (III12–14).
Fibronectin plays a crucial role in wound healing. Along with fibrin, blood plasma fibronectin is deposited at the site of injury, forming a blood clot that stops bleeding and protects the underlying tissue. As repair of the injured tissue continues, fibroblasts and macrophages begin to remodel the area, degrading the proteins that form the provisional blood clot matrix and replacing them with a matrix that more resembles the normal, surrounding tissue. Fibroblasts secrete proteases, including matrix metalloproteinases, that digest the plasma fibronectin, and then the fibroblasts secrete cellular fibronectin and assemble it into an insoluble matrix. Fragmentation of fibronectin by proteases has been suggested to promote wound contraction, a critical step in wound healing. Fragmenting fibronectin further exposes its V-region, which contains the site for α4β1 integrin binding. These fragments of fibronectin are believed to enhance the binding of α4β1 integrin-expressing cells, allowing them to adhere to and forcefully contract the surrounding matrix.
Fibronectin is necessary for embryogenesis, and gene knockout the gene for fibronectin results in early embryonic lethality. Fibronectin is important for guiding cell adhesion and cell migration during embryonic development. In mammalian development, the absence of fibronectin leads to defects in mesodermal, neural tube, and Blood vessel development. Similarly, the absence of a normal fibronectin matrix in developing amphibians causes defects in mesodermal patterning and inhibits gastrulation.
Fibronectin is also found in normal human saliva, which helps prevent colonization of the oral cavity and pharynx by pathogenic bacteria.
Fibronectin's shift from soluble to insoluble fibrils proceeds when cryptic fibronectin-binding sites are exposed along the length of a bound fibronectin molecule. Cells are believed to stretch fibronectin by pulling on their fibronectin-bound integrin receptors. This force partially unfolds the fibronectin ligand, unmasking cryptic fibronectin-binding sites and allowing nearby fibronectin molecules to associate. This fibronectin-fibronectin interaction enables the soluble, cell-associated fibrils to branch and stabilize into an insoluble fibronectin matrix.
A transmembrane protein, CD93, has been shown to be essential for fibronectin matrix assembly (fibrillogenesis) in human dermal blood endothelial cells. As a consequence, knockdown of CD93 in these cells resulted in the disruption of the fibronectin fibrillogenesis. Moreover, the CD93 knockout mice retinas displayed disrupted fibronectin matrix at the retinal sprouting front.
Fibronectin has been implicated in carcinoma development. In lung carcinoma, fibronectin gene expression is increased especially in non-small cell lung carcinoma. The cell adhesion of lung carcinoma cells to fibronectin enhances carcinogen and confers drug resistance to apoptosis-inducing chemotherapeutic agents. Fibronectin has been shown to stimulate the gonadal steroids that interact with vertebrate androgen receptors, which are capable of controlling the gene expression of cyclin D and related genes involved in cell cycle control. These observations suggest that fibronectin may promote lung neoplasm/survival and resistance to therapy, and it could represent a novel target for the development of new anticancer drugs.
Fibronectin 1 acts as a potential biomarker for radioresistance and for pan-cancer prognosis.
FN1-FGFR1 fusion is frequent in phosphaturic mesenchymal tumours.
Fibronectin is located in the extracellular matrix of embryonic and adult tissues (not in the basement membranes of the adult tissues), but may be more widely distributed in inflammatory lesions. During blood clotting, the fibronectin remains associated with the clot, covalently cross-linked to fibrin with the help of Factor XIII (fibrin-stabilizing factor). play a major role in wound healing by adhering to fibrin. Fibroblast adhesion to fibrin requires fibronectin, and was strongest when the fibronectin was cross-linked to the fibrin. Patients with Factor XIII deficiencies display impairment in wound healing as fibroblasts don't grow well in fibrin lacking Factor XIII. Fibronectin promotes particle phagocytosis by both and fibroblasts. Collagen deposition at the wound site by fibroblasts takes place with the help of fibronectin. Fibronectin was also observed to be closely associated with the newly deposited collagen fibrils. Based on the size and Histology staining characteristics of the fibrils, it is likely that at least in part they are composed of type III collagen (reticulin). An in vitro study with native collagen demonstrated that fibronectin binds to type III collagen rather than other types.
Fibronectin has been shown to interact with:
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