It is a multifunctional molecule found in the extracellular matrix and plasma.
Although it primarily plays a role in cell adhesion, it is involved in many parts of the inflammatory reaction.
It is a kind of glycoproteins of high molecular weight, including adhesion, cytoskeleton organization, oncogenic transformation, cell migration, phagocytosis, hemostasis and embryonic differentiation.
It binds to a variety of structures, including some bacteria and immune complexes.
Cellular fibronectin represents only 5% of circulating fibronectins and is synthesized by a wide variety of cells, including endothelial cells, fibroblasts, and macrophages. It is released from endothelial cells and the extracellular matrix after endothelial injury.
In 1984, Stubbs et al. reported that plasma fibronectin concentrations were elevated in women with pre-eclampsia, and subsequently several investigators evaluated the role of fibronectin as an early predictor of pre-eclampsia.
In 2007, Leeflang et al. published a systematic review on the precision of fibronectin for predicting pre-eclampsia that included 12 studies, of which only five (n = 573) reported sufficient data to allow calculation of estimates of predictive precision.
Total plasma fibronectin was measured in three studies, cellular fibronectin in one and both in another. Sensitivities vary widely, depending on the cut chosen. Requiring a sensitivity of at least 50%, the specificity achieved with total fibronectin ranged between 43 and 94%.
For cellular fibronectin, the specificities ranged from 72 to 96%. Positive odds ratios ranged from 1.2 to 11.0 for total fibronectin and from 1.6 to 11.5 for cellular fibronectin.
Negative likelihood ratios ranged from 0.4 to 0.7 for total fibronectin and from 0.0 to 0.6 for cellular fibronectin. Such results suggest that plasma fibronectin concentrations are not clinically useful for the prediction of preeclampsia.
Two types of fibronectin are present in vertebrates:
Soluble plasma fibronectin (previously referred to as “cold insoluble globulin” or ICg), is a major protein component of blood plasma (300 μg / ml) and is produced in the liver by hepatocytes.
Insoluble cellular fibronectin is a main component of the extracellular matrix. It is secreted by various cells, primarily fibroblasts, as a soluble protein dimer and then assembled into an insoluble matrix in a complex cell-mediated process.
Fibronectin plays an important role in cell adhesion, growth, migration, and differentiation, and is important for processes such as wound healing and embryonic development.
Altered fibronectin expression, degradation, and organization have been associated with a number of pathologies, including cancer and fibrosis.
Fibronectin occurs as a protein dimer, consisting of two nearly equal polypeptide chains linked by a pair of C-terminal disulfide bonds. Each fibronectin subunit has a molecular weight of 230-250 kDa and contains three types of modules: type I, II and III.
The three modules are composed of two antiparallel β sheets that result in a Beta sandwich; however, types I and II are stabilized by intrachain disulfide bonds, while type III modules do not contain disulfide bonds.
The absence of disulfide bonds in type III modules makes possible their partial unfolding under the applied force.
Three variable splice regions occur along the fibronectin protomer. One or both of the “extra” type III modules (IBD and IBD) may be present in cellular fibronectin, but are never present in plasma fibronectin.
A “variable” V region exists between III14-15 (the module type III 14th and 15th). The structure of the V region is different from type I, II, and III modules, and its presence and length may vary.
Region V contains the binding site for the α4β1 integrins. It is present in most cellular fibronectins, but only one of the two subunits in a plasma fibronectin dimer contains a V region sequence.
The modules are organized into various functional and protein-binding domains through a fibronectin monomer. There are four binding domains of fibronectin, which allow fibronectin to associate with other fibronectin molecules.
One of these fibronectin-binding domains, I1-5, is called the “assembly domain” and is required for the initiation of fibronectin matrix assembly. Modules III9-10 correspond to the “cell binding domain” of fibronectin.
The RGD sequence (Arg-Gly-Asp) is located in III10 and is the site of attachment of cells through the integrins α5β1 and αVβ3 on the cell surface. The “synergy site” is at III9 and has a role in modulating the association of fibronectin 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 has numerous functions that ensure the normal functioning of vertebrate organisms. It is involved in cell adhesion, growth, migration, and differentiation.
Cellular fibronectin assembles itself in the extracellular matrix, an insoluble network that separates and supports the organs and tissues of an organism.
Fibronectin plays a crucial role in wound healing. Along with fibrin, plasma fibronectin is deposited at the injury site, forming a blood clot that stops bleeding and protects the underlying tissue.
As repair of the injured tissue continues, fibroblasts and macrophages begin to reshape the area, breaking down the proteins that make up the provisional matrix of the blood clot and replacing them with a matrix that more closely resembles the surrounding normal tissue.
Fibroblasts secrete proteases, including matrix metalloproteinases, which digest plasma fibronectin, and fibroblasts then secrete cellular fibronectin and bundle it into an insoluble matrix.
Fibronectin fragmentation by proteases has been reported to promote lesion contraction, which is a critical factor in lesion healing. The cleavage fibronectin further exposes its V region, which contains the site for the α4β1 integrin binding.
These pieces of fibronectin are considered to enhance the attachment of cells by expressing the ββ integrin, which allows them to strongly adhere and contract the surrounding matrix.
Fibronectin is required for embryogenesis, and inactivation of the gene for fibronectin results in early embryonic lethality. Fibronectin is important to guide cell attachment and migration during embryonic development.
In mammalian evolution, the lack of fibronectin leads to abnormalities in mesodermal, neural, and vascular development. Similarly, the absence of a normal fibronectin matrix in amphibian development causes defects in mesodermal modeling and inhibits gastrulation.
Fibronectin is also found in normal human saliva, which helps prevent colonization of the oral cavity and pharynx by potentially pathogenic bacteria.
Cellular fibronectin assembles into an insoluble fibrillar matrix in a complex cell-mediated process. The assembly of the fibronectin matrix begins when soluble and compact fibronectin dimers are secreted from cells, often fibroblasts.
Soluble dimers adhere to αβ integrin receptors on the cell surface and help to group the integrins together. The local concentration of fibronectin bound to the integrin increases, allowing the bound fibronectin molecules to interact more frequently with each other.
Short fibronectin fibrils begin to form between adjacent cells. As matrix assembly proceeds, soluble fibrils develop into larger insoluble fibrils that comprise the extracellular matrix.
The change of fibronectin from soluble to insoluble fibrils occurs when cryptic fibronectin-binding sites are exposed along a bound fibronectin molecule. Cells are understood to extend fibronectin by pulling its built-in integrin emitters to fibronectin.
This force partially unfolds the fibronectin ligand, unmasking cryptic fibronectin binding sites and allowing the association of nearby fibronectin molecules.
This type of fibronectin-fibronectin interaction allows soluble, cell-associated fibrils to bifurcate and consolidate into an insoluble fibronectin matrix.
Role in cancer
Some of the morphological changes observed in tumors and cell lines derived from tumors have been attributed to a reduction in the manifestation of fibronectin, an increase in the breakdown of fibronectin and / or a decrease in the manifestation of fibronectin. fibronectin-binding receptors, such as αβ integrins.
Fibronectin has been implicated in the development of carcinoma. In lung carcinoma, fibronectin expression is increased, especially in non-small cell lung carcinoma.
The adhesion of lung carcinoma cells to fibronectin increases tumorigenicity and confers resistance to apoptosis-inducing chemotherapeutic agents.
Fibronectin has been shown to stimulate gonadal steroids that interact with vertebrate androgen receptors, which are capable of controlling the expression of cyclin D and related genes that are involved in cell cycle control.
These observations suggest that fibronectin may promote lung tumor growth / survival and resistance to therapy, and could represent a new target for the development of new anticancer drugs.
Fibronectin 1 acts as a potential biomarker for radioresistance.
FN1-FGFR1 fusion is common in phosphaturic mesenchymal tumors.
Role in wound healing
Fibronectin is found in the extracellular matrix of embryonic and adult tissues (not in the basement membranes of adult tissues), but may be more widely distributed in inflammatory lesions.
Directed cell migration is an important step in effective wound healing and requires dynamic control of the formation of extracellular cell-matrix interactions.
Plasma fibronectin is an extracellular matrix glycoprotein present in blood plasma that plays a crucial role in modulating cell adhesion and migration and thereby helps mediate all steps of wound healing.
Wound healing is a dynamic process consisting of hemostasis, inflammation, proliferation, and remodeling.
Fibronectin, an extracellular matrix glycoprotein (ECM), plays an important role in the different stages of wound healing, with its main function being cell adhesion and mediating cell migration.
Fibronectin interacts with and activates cell surface integrin receptors which in turn recruit a series of cellular proteins involved in connection with the actin cytoskeleton within the cell; This initiates the formation of specialized integrin-based adhesive organelles called focal adhesions (FA).
Coupling of the actin cytoskeleton and fibronectin to the extracellular matrix through focal adhesions dynamically drives targeted cell migration during wound healing.
Initially, cellular protrusions that are characterized by actin polymerization should form a dense actin network; these extend in the direction of migration, which is followed by binding of the protrusions to fibronectin in the extracellular matrix.
This in turn forms nascent adhesions (newborn focal adhesions). These nascent adhesions subsequently mature and grow in size through myosin II-mediated contractile forces that are transduced along the actin filament bundles.
Mature focal adhesions transfer contractile forces from the actin cytoskeleton to fibronectin in the extracellular matrix, thus pulling the cell body forward.
Finally, disassembly of focal adhesion is accompanied by myosin II-driven contractile forces that retract the posterior border of the fibronectin cell from the extracellular matrix.
Fibronectin from the extracellular matrix outside the cell that is bound to the actin cytoskeleton within the cell through focal adhesions is closely associated during the wound healing process with the dynamic control of cell adhesion and thus , directed cell migration.
There are two forms of fibronectin, plasma fibronectin and cellular fibronectin. Plasma fibronectin is synthesized by hepatocytes and then released into blood plasma, while cellular fibronectin is produced by many cell types, including fibroblasts, endothelial cells, myocytes, and chondrocytes.
During wound healing, plasma fibronectin has been reported to accumulate to a remarkable extent in the wound in vivo after wounding.
This accumulation is crucial for the various functions of platelets, fibroblasts, and endothelial cells, and these include adhesion, migration, and aggregation.
This indicates that plasma fibronectin is likely to serve as a suitable substrate to accelerate wound repair in vivo.
In vivo vs in vitro
Plasma fibronectin, which is synthesized by hepatocytes, and fibronectin synthesized by fermented fibroblasts are similar but not the same; immunological, structural, and functional discrepancies have been reported.
These differences are likely to be the result of differential processing of a single nascent messenger RNA (mRNA).
However, plasma fibronectin can be insolubilized in the extracellular tissue matrix in vitro and in vivo. Both plasma and cellular fibronectins in the matrix form multimeters connected to each other by high molecular weight disulfide bridges.
The mechanism of formation of these multimers is not known at present. Plasma fibronectin has been shown to contain two free sulfhydryls per subunit (X) and cellular fibronectin has been shown to contain at least one.
Sulfhydryls are likely to be buried within the tertiary structure, because sulfhydryls are exposed by denaturing fibronectin. Such denaturation results in the oxidation of free sulfhydryls and the creation of disulfide-related fibronectin multimers.
This has led to the conjecture that free sulfhydrates could be involved in the conformation of disulfide-linked fibronectin multimers in the extracellular matrix. Therefore, sulfhydryl alteration of fibronectin with N-ethylmaleimide prevents adhesion to cell layers.
The multimeric tryptic cleavage patterns of multimeric fibronectin do not reveal the disulfide-linked fragments that would be expected if the multimerization involved one or both of the free sulfhydrates.
Free fibronectin sulfhydrates are unnecessary for the adhesion of fibronectin to the cell membrane or for its subsequent integration into the extracellular matrix.
Multimerization of disulfide-linked fibronectin in the cell layer occurs by exchange of disulfide bonds in the disulfide-rich amino terminal third of the molecule.
In addition to integrin, fibronectin binds to many other host and non-receptor molecules. For example, interaction with proteins such as fibrin, tenascin, tumor necrosis factor α (TNF-α), BMP-1, rotavirus NSP-4, and numerous fibronectin-bound proteins from bacteria (such as FBP-A; FBP-B in the N-terminal area), like glycosaminoglycan, heparan sulfate.
Fibronectin has been shown to interact with:
The CD44 antigen : is a glycoprotein that is found on the cell surface and influences the relationships between cells, cell adhesion and mobility. In humans, the CD44 antigen is encoded by the CD44 gene on chromosome 11.
CD44 is called HCAM (localizing cell adhesion molecule), Pgp-1 (phagocytic glycoprotein-1), Hermes antigen, localizing lymphocyte receptor, ECM-III, and HUTCH-1.
COL7A1, the collagen alpha-1 (VII) chain : is a protein that in humans is encoded by the COL7A1 gene.
Lipoprotein (a) (also called Lp (a) or LPA) : is a subclass of lipoprotein. In genetic studies and in many epidemiological cases, Lp (a) has been recognized as the danger factor for atherosclerotic conditions, such as coronary heart disease and stroke.
Insulin-like growth factor binding protein 3 : Also known as IGFBP-3, is a protein that in humans is encoded by the IGFBP3 gene.
Insulin-like growth factor-binding protein 3 is one of six insulin-like growth factor-binding proteins (IGFBP-1 to IGFBP-6) that have highly conserved structures and bind to similar growth factors. to insulin IGF-1 and IGF-2 high affinity.
IGFBP-7, sometimes inappropriately included in this family, shares neither the conserved structural features nor the high affinity of insulin-like growth factor.
Tenascin C (TN-C) : is a glycoprotein that in humans is encoded by the TNC gene. It is expressed in the extracellular matrix of various tissues during development, disease, or injury, and in restricted neurogenic areas of the central nervous system.
Tenascin-C is the founding member of the tenascin family of proteins. In the embryo it is made up of migratory cells such as the neural crest; it is also abundant in developing tendons, bones, and cartilage.
Tribbles homolog 3 : is a protein that in humans is encoded by the TRIB3 gene.