Fibronectin
Encyclopedia
Fibronectin is a high-molecular weight (~440kDa) glycoprotein
of the extracellular matrix
that binds to 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 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
, growth
, migration
and differentiation
, and it is important for processes such as wound healing
and embryonic development. Altered fibronectin expression
, degradation, and organization has been associated with a number of pathologies, including cancer and fibrosis
.
has a molecular weight of 230–250 kDa
and contains three types of modules: type I, II, and III. All three modules are composed of two anti-parallel β-sheets; however, type I and type II
are stabilized by intra-chain disulfide bonds, while type III modules do not contain any disulfide bonds. The absence of disulfide bonds in type III modules allows them to partially unfold under applied force.
Three regions of variable 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 cellulafibronectin, 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 domains
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 sequence (Arg–Gly–Asp) is located in III10 and is the site of 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 (I1–5, I10–12), collagen
-binding (I6–9), fibulin-1-binding (III13–14), heparin
-binding and syndecan
-binding (III12–14).
organisms. It is involved in cell adhesion
, growth
, migration
and differentiation
. Cellular fibronectin is assembled into 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 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 α4β1 integrins-expressing cell binding, allowing them to adhere to and forcefully contract the surrounding matrix.
Fibronectin is necessary for embryogenesis
, and inactivating
the gene
for fibronectin results in early embryonic lethality. Fibronectin is important for guiding cell attachment
and 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 colonization
of the oral cavity and pharynx
by potentially pathogenic bacteria
.
fibronectin is assembled into an insoluble fibrillar 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 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 molecules
. 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
.
changes observed in tumors and tumor-derived cell lines have been attributed to decreased fibronectin expression
, increased fibronectin degradation, and/or decreased expression
of fibronectin-binding receptors
, such as α5β1 integrins.
Fibronectin has been implicated in carcinoma
development. In lung carcinoma, fibronectin expression
is increased, especially in non-small cell lung carcinoma. The adhesion
of lung carcinoma cells to fibronectin enhances tumorigenicity
and confers 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 expression
of cyclin D
and related genes
involved in cell cycle
control. These observations suggest that fibronectin may promote lung tumor growth/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
.
, including the formation of proper substratum for migration and growth of cells during the development and organization of granulation tissue
as well as remodeling and resynthesis of the connective tissue matrix. The biological significance of fibronectin in invivo was studied during the mechanism of wound healing. Plasma fibronectin levels are decreased in acute inflammation or following surgical trauma and in patients with intravascular disseminated coagulation
.
Fibronectin is located predominantly in the basement membrane
s of the adult tissues, but may be more widely distributed in inflammatory lesions. During clotting of the plasma the fibronectin remains associated with the clot, covalently cross linked to the fibrin
with the help of factor XIII
(fibrin stabilizing factor). Fibroblast
s play a major role in wound healing by adhering to fibrin. The adhesion of fibroblast to the fibrin requires the presence of fibronectin and it was maximum when the fibronectin is crossslinked to the fibrin. Patients with factor XIII deficiencies display impairment in wound healing and also that the fibroblasts don’t grow in the fibrin which is deficient in this factor. Fibronectin promotes phagocytosis of the particles not only by the macrophages but also by the fibroblasts. The deposition of collagen in the wounded site by the 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 histological staining chatracteristics of the fibrils it is likely that atleast in part they are composed of type III collagen (reticulin). The invitro study with the native collagen has demonstrated that the fibronectin binds to type III collagen rather than to any other types.
s, and fibronectin synthesized by cultured
fibroblast
s are similar but not identical; immunological, structural, and functional differences have been reported. It is likely that these differences result from differential processing of a single nascent mRNA. Nevertheless, plasma fibronectin can be insolubilized into the tissue extracellular matrix
in vitro and in vivo. Both plasma and cellular fibronectins in the matrix form high molecular weight, disulfide-bonded
multimers
. The mechanism of formation of these multimers is not known. Plasma fibronectin has been shown to contain two free sulfhydryls
per subunit (X), and cellular fibronectin has been shown to contain at least one. These sulfhydryls probably are buried within the tertiary structure, because sulfhydryls are exposed when the fibronectin is denatured. Such denaturation results in the oxidation of free sulfhydryls and formation of disulfide-bonded fibronectin multimers. This has led to speculation that the free sulfhydryls may be involved in formation of disulfide-bonded fibronectin multimers in the extracellular matrix. Consistent with this, sulfhydryl modification of fibronectin with N-ethylmaleimide
prevents binding to cell layers. Tryptic
cleavage patterns of multimeric fibronectin do not reveal the disulfide-bonded fragments that would be expected if multimerization involved one or both of the free sulfhydryls. The free sulfhydryls of fibronectin are not required for the binding of fibronectin to the cell layer or for its subsequent incorporation into the extracellular matrix. Disulfide-bonded multimerization of fibronectin in the cell layer occurs by disulfide bond exchange in the disulfide-rich amino-terminal one-third of the molecule.
, heparin
, tenascin
, TNF-α, BMP-1, rotavirus NSP-4, and many fibronectin binding proteins from bacteria like FBP-A, FBP-B on the N-terminal domain.
Fibronectin has been shown to interact
with:
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
of the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
that binds to membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
, fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....
and heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...
proteoglycans (e.g. syndecans).
Fibronectin exists as a protein dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
, 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
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA 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 plasmaBlood plasmaBlood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
(300 μg/ml) and is produced in the liverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
by hepatocytes. - insoluble cellular fibronectin is a major component of the extracellular matrix. It is secreted by various cellsCell (biology)The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
, primarily fibroblasts, as a soluble protein dimerProtein dimerIn biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
and is then assembled into an insoluble matrix in a complex cell-mediated process.
Fibronectin plays a major role in cell adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
, growth
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
, migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
and differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
, and it is important for processes such as wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
and embryonic development. Altered fibronectin expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
, degradation, and organization has been associated with a number of pathologies, including cancer and fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
.
Structure
Fibronectin exists as a protein dimer, consisting of two nearly identical polypeptide chains linked by a pair of C-terminal disulfide bonds. Each fibronectin monomerMonomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
has a molecular weight of 230–250 kDa
KDA
KDA may refer to:* Karachi Development Authority* Kongsberg Defence & Aerospace* Kotelawala Defence Academy* Kramer Design Associates* Lithium diisopropylamide, KDA is the potassium analogue of lithium diisopropylamideOr kDa may refer to:...
and contains three types of modules: type I, II, and III. All three modules are composed of two anti-parallel β-sheets; however, type I and type II
Fibronectin type II domain
Fibronectin type II domain is a collagen-binding protein domain.Fibronectin is a multi-domain glycoprotein, found in a soluble form in plasma, and in an insoluble form in loose connective tissue and basement membranes, that binds cell surfaces and various compounds including collagen, fibrin,...
are stabilized by intra-chain disulfide bonds, while type III modules do not contain any disulfide bonds. The absence of disulfide bonds in type III modules allows them to partially unfold under applied force.
Three regions of variable splicing
RNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
occur along the length of the fibronectin protomer
Protomer
In structural biology, a protomer is the structural unit of an oligomeric protein. A protomer can be a protein subunit or several different subunits, that assemble in a defined stoichiometry to form an oligomer. The protomer is the smallest subset of different subunits that form the oligomer. The...
. One or both of the "extra" type III modules (EIIIA and EIIIB) may be present in cellulafibronectin, 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
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
-binding domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
along the length of a fibronectin monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
. 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 sequence (Arg–Gly–Asp) is located in III10 and is the site of cell attachment
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
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
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....
-binding (I1–5, I10–12), collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
-binding (I6–9), fibulin-1-binding (III13–14), heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
-binding and syndecan
Syndecan
Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. These core proteins carry three to five heparan sulfate and chondroitin sulfate chains, which allow for interaction with a large variety of ligands including...
-binding (III12–14).
Function
Fibronectin has numerous functions that ensure the normal functioning of vertebrateVertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
organisms. It is involved in cell adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
, growth
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
, migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
and differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
. Cellular fibronectin is assembled into the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
, an insoluble network that separates and supports the organs and tissues
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
of an organism.
Fibronectin plays a crucial role in wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
. Along with fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....
, plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
fibronectin is deposited at the site of injury, forming a blood clot that stops bleeding and protects the underlying tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
. 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
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
that more resembles the normal, surrounding tissue. Fibroblasts secrete proteases, including matrix metalloproteinases, that digest the plasma fibronectin, and then the fibroblasts secrete cellular
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
fibronectin and assemble it into an insoluble matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
. Fragmentation of fibronectin by proteases has been suggested to promote wound contraction, a critical step in wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
. Fragmenting fibronectin further exposes its V-region, which contains the site for α4β1 integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
-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
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
, and inactivating
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
for fibronectin results in early embryonic lethality. Fibronectin is important for guiding cell attachment
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
and migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
during embryonic development. In mammalian development, the absence of fibronectin leads to defects in mesodermal, neural tube
Neural tube
In the developing vertebrate, the neural tube is the embryo's precursor to the central nervous system, which comprises the brain and spinal cord...
, and vascular
Vascular
Vascular in zoology and medicine means "related to blood vessels", which are part of the circulatory system. An organ or tissue that is vascularized is heavily endowed with blood vessels and thus richly supplied with blood....
development. Similarly, the absence of a normal fibronectin matrix in developing amphibians causes defects in mesodermal patterning and inhibits gastrulation
Gastrulation
Gastrulation is a phase early in the embryonic development of most animals, during which the single-layered blastula is reorganized into a trilaminar structure known as the gastrula. These three germ layers are known as the ectoderm, mesoderm, and endoderm.Gastrulation takes place after cleavage...
.
Fibronectin is also found in normal human saliva, which helps prevent colonization
Colonisation (biology)
Colonisation is the process in biology by which a species spreads into new areas, regions, and continents. It is sometimes also referred to as immigration, but colonisation often refers to successful immigration with integration to a community, having resisted initial local extinction.One classic...
of the oral cavity and pharynx
Pharynx
The human pharynx is the part of the throat situated immediately posterior to the mouth and nasal cavity, and anterior to the esophagus and larynx. The human pharynx is conventionally divided into three sections: the nasopharynx , the oropharynx , and the laryngopharynx...
by potentially pathogenic bacteria
Pathogenic bacteria
Pathogenic bacteria are bacteria that cause bacterial infection. This article deals with human pathogenic bacteria.Although the vast majority of bacteria are harmless or beneficial, quite a few bacteria are pathogenic...
.
Matrix assembly
CellularCell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
fibronectin is assembled into an insoluble fibrillar matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
in a complex cell-mediated process. Fibronectin matrix assembly begins when soluble, compact fibronectin dimers
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
are secreted from cells, often fibroblasts. These soluble dimers bind to α5β1 integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
receptors on the cell surface and aide in clustering the integrins. The local concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
of integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
-bound fibronectin increases, allowing bound fibronectin molecules
Macromolecule
A macromolecule is a very large molecule commonly created by some form of polymerization. In biochemistry, the term is applied to the four conventional biopolymers , as well as non-polymeric molecules with large molecular mass such as macrocycles...
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
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
.
Fibronectin’s shift from soluble to insoluble fibrils proceeds when cryptic fibronectin-binding sites are exposed along the length of a bound fibronectin molecules
Macromolecule
A macromolecule is a very large molecule commonly created by some form of polymerization. In biochemistry, the term is applied to the four conventional biopolymers , as well as non-polymeric molecules with large molecular mass such as macrocycles...
. Cells are believed to stretch fibronectin by pulling on their fibronectin-bound integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
receptors. This force
Force
In physics, a force is any influence that causes an object to undergo a change in speed, a change in direction, or a change in shape. In other words, a force is that which can cause an object with mass to change its velocity , i.e., to accelerate, or which can cause a flexible object to deform...
partially unfolds the fibronectin ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
, 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
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
.
Role in cancer
Several of the morphologicalMorphology (biology)
In biology, morphology is a branch of bioscience dealing with the study of the form and structure of organisms and their specific structural features....
changes observed in tumors and tumor-derived cell lines have been attributed to decreased fibronectin expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
, increased fibronectin degradation, and/or decreased expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of fibronectin-binding receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
, such as α5β1 integrins.
Fibronectin has been implicated in carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
development. In lung carcinoma, fibronectin expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
is increased, especially in non-small cell lung carcinoma. The adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
of lung carcinoma cells to fibronectin enhances tumorigenicity
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
and confers resistance
Drug resistance
Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
to apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
-inducing chemotherapeutic agents. Fibronectin has been shown to stimulate the gonadal steroids that interact with vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
androgen receptors, which are capable of controlling the expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of cyclin D
Cyclin D
Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition...
and related genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
involved in cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
control. These observations suggest that fibronectin may promote lung tumor growth/survival and resistance to therapy, and it could represent a novel target
Biological target
A biological target is a biopolymer such as a protein or nucleic acid whose activity can be modified by an external stimulus. The definition is context-dependent and can refer to the biological target of a pharmacologically active drug compound, or the receptor target of a hormone . The...
for the development of new anticancer drugs.
Fibronectin 1 acts as a potential biomarker for radioresistance
Radioresistance
Radioresistance is the property of organisms that are capable of living in environments with very high levels of ionizing radiation.Radioresistance is surprisingly high in many organisms, in contrast to previously held views...
.
Role in wound healing
Fibronectin has profound effects on wound healingWound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
, including the formation of proper substratum for migration and growth of cells during the development and organization of granulation tissue
Granulation tissue
Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size it heals...
as well as remodeling and resynthesis of the connective tissue matrix. The biological significance of fibronectin in invivo was studied during the mechanism of wound healing. Plasma fibronectin levels are decreased in acute inflammation or following surgical trauma and in patients with intravascular disseminated coagulation
Disseminated intravascular coagulation
Disseminated intravascular coagulation , also known as disseminated intravascular coagulopathy or consumptive coagulopathy, is a pathological activation of coagulation mechanisms that happens in response to a variety of diseases. DIC leads to the formation of small blood clots inside the blood...
.
Fibronectin is located predominantly in the basement membrane
Basement membrane
The basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...
s of the adult tissues, but may be more widely distributed in inflammatory lesions. During clotting of the plasma the fibronectin remains associated with the clot, covalently cross linked to the fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....
with the help of factor XIII
Factor XIII
Factor XIII or fibrin stabilizing factor is an enzyme of the blood coagulation system that crosslinks fibrin.- Function :Factor XIII is a transglutaminase that circulates in the plasma as a heterotetramer of two catalytic A subunits and two carrier B subunits...
(fibrin stabilizing factor). Fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s play a major role in wound healing by adhering to fibrin. The adhesion of fibroblast to the fibrin requires the presence of fibronectin and it was maximum when the fibronectin is crossslinked to the fibrin. Patients with factor XIII deficiencies display impairment in wound healing and also that the fibroblasts don’t grow in the fibrin which is deficient in this factor. Fibronectin promotes phagocytosis of the particles not only by the macrophages but also by the fibroblasts. The deposition of collagen in the wounded site by the fibroblasts takes place with the help of fibronectin. Fibronectin was also observed to be closely associated with the newly deposited collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
fibrils. Based on the size and histological staining chatracteristics of the fibrils it is likely that atleast in part they are composed of type III collagen (reticulin). The invitro study with the native collagen has demonstrated that the fibronectin binds to type III collagen rather than to any other types.
In vivo vs in vitro
Plasma fibronectin, which is synthesized by hepatocyteHepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s, and fibronectin synthesized by cultured
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...
fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s are similar but not identical; immunological, structural, and functional differences have been reported. It is likely that these differences result from differential processing of a single nascent mRNA. Nevertheless, plasma fibronectin can be insolubilized into the tissue extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
in vitro and in vivo. Both plasma and cellular fibronectins in the matrix form high molecular weight, disulfide-bonded
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
multimers
Oligomer
In chemistry, an oligomer is a molecule that consists of a few monomer units , in contrast to a polymer that, at least in principle, consists of an unlimited number of monomers. Dimers, trimers, and tetramers are oligomers. Many oils are oligomeric, such as liquid paraffin...
. The mechanism of formation of these multimers is not known. Plasma fibronectin has been shown to contain two free sulfhydryls
Thiol
In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
per subunit (X), and cellular fibronectin has been shown to contain at least one. These sulfhydryls probably are buried within the tertiary structure, because sulfhydryls are exposed when the fibronectin is denatured. Such denaturation results in the oxidation of free sulfhydryls and formation of disulfide-bonded fibronectin multimers. This has led to speculation that the free sulfhydryls may be involved in formation of disulfide-bonded fibronectin multimers in the extracellular matrix. Consistent with this, sulfhydryl modification of fibronectin with N-ethylmaleimide
N-Ethylmaleimide
N-Ethylmaleimide is an organic compound that is derived from maleic acid. It contains the imide functional group, but more importantly it is an alkene that is reactive toward thiols and is commonly used to modify cysteine residues in proteins and peptides.-Organic chemistry:In the jargon of...
prevents binding to cell layers. Tryptic
Trypsin
Trypsin is a serine protease found in the digestive system of many vertebrates, where it hydrolyses proteins. Trypsin is produced in the pancreas as the inactive proenzyme trypsinogen. Trypsin cleaves peptide chains mainly at the carboxyl side of the amino acids lysine or arginine, except when...
cleavage patterns of multimeric fibronectin do not reveal the disulfide-bonded fragments that would be expected if multimerization involved one or both of the free sulfhydryls. The free sulfhydryls of fibronectin are not required for the binding of fibronectin to the cell layer or for its subsequent incorporation into the extracellular matrix. Disulfide-bonded multimerization of fibronectin in the cell layer occurs by disulfide bond exchange in the disulfide-rich amino-terminal one-third of the molecule.
Interactions
Besides integrin, fibronectin binds to many other host and non-host proteins. For example, it has been shown to interact with fibrinFibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....
, heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
, tenascin
Tenascin
Tenascins are extracellular matrix glycoproteins. They are abundant in the extracellular matrix of developing vertebrate embryos and they reappear around healing wounds and in the stroma of some tumors.-Types:...
, TNF-α, BMP-1, rotavirus NSP-4, and many fibronectin binding proteins from bacteria like FBP-A, FBP-B on the N-terminal domain.
Fibronectin has been shown to interact
Protein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- CD44CD44The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene.- Tissue distribution and isoforms :...
- COL7A1,
- LPALipoprotein(a)Lipoprotein is a lipoprotein subclass. Studies have identified Lp as a putative risk factor for atherosclerotic diseases such as coronary heart disease and stroke....
, - IGFBP3IGFBP3Insulin-like growth factor-binding protein 3, also known as IGFBP3, is a protein that, in humans, is encoded by the IGFBP3 gene.- Function :...
, - TNCTenascin CTenascin is a protein that in humans is encoded by the TNC gene.-Interactions:Tenascin C has been shown to interact with fibronectin.-Further reading:...
, and - TRIB3TRIB3Tribbles homolog 3 is a protein that in humans is encoded by the TRIB3 gene.-Interactions:TRIB3 has been shown to interact with CSNK2B, TIAF1, RELA, MCM3AP, ATF5, Granulin, ATF4, AKT1, Fibronectin and SIAH1.-Further reading:...
.
See also
- Fetal fibronectinFetal fibronectinFetal fibronectin is a fibronectin protein produced by fetal cells. It is found at the interface of the chorion and the decidua ....
- Fibronectin type I domainFibronectin type I domainFibronectin, type I repeats are one of the three repeats found in the fibronectin protein. Fibronectin is a plasma protein that binds cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. Type I domain is approximately 40 residues in length. Four conserved...
- Fibronectin type II domainFibronectin type II domainFibronectin type II domain is a collagen-binding protein domain.Fibronectin is a multi-domain glycoprotein, found in a soluble form in plasma, and in an insoluble form in loose connective tissue and basement membranes, that binds cell surfaces and various compounds including collagen, fibrin,...
- Fibronectin type III domainFibronectin type III domainThe Fibronectin type III domain is an evolutionary conserved protein domain that is widely found in animal proteins. The fibronectin protein in which this domain was first identified contains 16 copies of this domain. The domain is about 100 amino acids long and possesses a beta sandwich...
- MonobodyMonobodyMonobodies, also known as adnectins, are genetically engineered proteins that are able to bind to antigens. Despite their name, they are not structurally related to antibodies, which makes them a type of antibody mimetic. They are being developed by Adnexus, a biotechnology company which has been...
, an engineered antibody mimetic based on the structure of the fibronectin type III domain - Substrate adhesion moleculesSubstrate adhesion moleculesSubstrate adhesion molecules are proteins that attach cells to specific compounds in the extracellular matrix ....