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Fibronectin

Fibronectin is a high-molecular weight (~440kDa) extracellular matrix glycoprotein that binds to cell membrane|membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans (e.g. syndecans). Fibronectin exists as a 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:
- soluble plasma fibronectin (formerly called "cold-insoluble globulin", or CIg) is a major protein component of blood plasma (300 μg/ml) and is produced in the liver by hepatocytes.
- Insoluble cellular fibronectin is a major component of the extracellular matrix. It is secreted by various cell (biology)|cells, primarily fibroblasts, as a soluble dimer and is then assembled into an insoluble extracellular matrix|matrix in a complex cell-mediated process. Fibronectin plays a major role in cell adhesion, cell growth|growth, cell migration|migration and cellular differentiation|differentiation, and it is important for processes such as wound healing and embryonic development. Altered fibronectin gene expression|expression, protein degradation|degradation, and organization has been associated with a number of pathologies, including cancer and fibrosis.

Structure

Fibronectin exists as a dimer, consisting of two nearly identical polypeptide chains linked by a pair of C-terminal disulfide bonds. Each fibronectin monomer has a molecular weight of 230-250 kDa and contains three types of protein module|modules: type I, II, and III. All three modules are composed of two anti-parallel β-sheets; however, type I and Fibronectin type II domain|type II are stabilized by intra-chain disulfide bonds, while type III modules do not contain any disulfide bridges. The absence of disulfide bonds in type III modules allows them to partially unfold under applied force. Three regions of variable RNA splicing|splicing occur along the length of the fibronectin monomer. One or both of the "extra" type III protein module|modules (EIIIA and EIIIB) may be present in Cell (biology)|cellular fibronectin, but they are never present in Blood plasma|plasma fibronectin. A "variable" V-region exists between III_14-15 (the 14^th and 15^th type III module). The V-region structure is different from the type I, II, and III modules, and it's 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 protein module|modules are arranged into several functional and protein-binding protein domain|domains along the length of a fibronectin monomer. There are four fibronectin-binding domains, allowing fibronectin to associate with other fibronectin macromolecule|molecules. One of these fibronectin-binding domains, I_1-5, is referred to as the "assembly domain", and it is required for the initiation of fibronectin matrix assembly. Modules III_9-10 correspond to the "cell-binding domain" of fibronectin. The RGD sequence (Arg–Gly–Asp) is located in III₁₀ and is the site of cell adhesion|cell attachment via α5β1 and αVβ3 integrins on the cell surface. The "synergy site" is in III₉ and has a role in modulating fibronectin's accociation with α5β1 integrins. Fibronectin also contains domains for fibrin-binding (I_1-5, I_10-12), collagen-binding (I_6-9), heparin-binding and syndecan-binding (III_12-14).

Function

Fibronectin has numerous functions that ensure the normal functioning of vertebrate organisms. It is involved in cell adhesion, cell growth|growth, cell migration|migration and cellular differentiation|differentiation. Cellular fibronectin is assembled into the extracellular matrix, an insoluble network that separates and supports the organs and tissue (biology)|tissues of an organism. Fibronectin plays a crucial role in wound healing. Along with fibrin, blood plasma|plasma fibronectin is deposited at the site of injury, forming a blood clot that stops bleeding and protects the underlying tissue (biology)|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 extracellular matrix|matrix that more resembles the normal, surrounding tissue. Fibroblasts secrete proteases, including matrix metalloproteinases, that digest the plasma fibronectin, and then the fibroblasts secrete cell (biology)|cellular fibronectin and assemble it into an insoluble extracellular matrix|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 α4β1 integrins-expressing cell binding, allowing them to adhere to and forcefully contract the surrounding matrix. Fibronectin is necessary for embryogenesis, and gene knockout|inactivating the gene for fibronectin results in early embryonic lethality. Fibronectin is important for guiding cell adhesion|cell attachment and cell migration|migration during embryonic development. In mammalian development, the absence of fibronectin leads to defects in mesodermal, neural tube, and vascular 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 colonisation (biology)|colonization of the oral cavity and pharynx by potentially pathogenic bacteria.

Matrix Assembly

cell (biology)|Cellular fibronectin is assembled into an insoluble fibrillar extracellular matrix|matrix in a complex cell-mediated process. Fibronectin matrix assembly begins when soluble, compact fibronectin dimers are secreted from cells, often fibroblasts. These soluble dimers bind to α5β1 integrin receptors on the cell surface and aide in clustering the integrins. The local concentration of integrin-bound fibronectin increases, allowing bound fibronectin macromolecule|molecules to more readily interact with one another. Short fibronectin fibrils then begin to form between adjacent cells. As matrix assembly proceeds, the soluble fibrils are converted into larger insoluble fibrils that comprise the extracellular matrix. Fibronectin’s shift from soluble to insoluble fibrils proceeds when cryptic fibronectin-binding sites are exposed along the length of a bound fibronectin macromolecule|molecules. Cells are believed to stretch fibronectin by pulling on their fibronectin-bound integrin receptors. This force partially unfolds the fibronectin ligand (biochemistry)|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 extracellular matrix|matrix.

Role in cancer

Several of the morphology (biology)|morphological changes observed in tumors and tumor-derived cell lines have been attributed to decreased fibronectin gene expression|expression, increased fibronectin protein degradation|degradation, and/or decreased gene expression|expression of fibronectin-binding receptor (biochemistry)|receptors, such as α5β1 integrins. Fibronectin has been implicated in carcinoma development. In lung carcinoma, fibronectin gene expression|expression is increased, especially in non-small cell lung carcinoma. The cell adhesion|adhesion of lung carcinoma cells to fibronectin enhances carcinogen|tumorigenicity and confers drug resistance|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|expression of cyclin D and related genes involved in cell cycle control. These observations suggest that fibronectin may promote lung neoplasm|tumor growth/survival and resistance to therapy, and it could represent a novel biological target|target for the development of new anticancer drugs.

References

External links

- The Fibronectin Protein
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- Fibronectin molecular interactions Category:Glycoproteins

Related Images

- The Modular Structure of Fibronectin with its Binding Domains

Sources: StartLearningNow, Wikipedia | Usage license: GNU FDL

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