Fibronectin
   HOME

TheInfoList



OR:

Fibronectin is a high-
molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
(~500-~600 kDa)
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as g ...
of the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struc ...
that binds to
membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. ...
-spanning
receptor proteins In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a recepto ...
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 In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' h ...
, 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 Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the ...
(300 μg/ml) and is produced in the
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
by hepatocytes. * insoluble cellular fibronectin is a major component of the extracellular matrix. It is secreted by various cells, primarily fibroblasts, as a soluble
protein dimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' h ...
and is then assembled into an insoluble matrix in a complex cell-mediated process. Fibronectin plays a major role in cell adhesion, growth, migration, and differentiation, and it is important for processes such as
wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier aga ...
and
embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
. Altered fibronectin expression, degradation, and organization has been associated with a number of pathologies, including cancer, arthritis, and fibrosis.


Structure

Fibronectin exists as a protein dimer, consisting of two nearly identical polypeptide chains linked by a pair of
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
disulfide bonds. Each fibronectin
subunit Subunit may refer to: *Subunit HIV vaccine, a class of HIV vaccine *Protein subunit, a protein molecule that assembles with other protein molecules *Monomer, a molecule that may bind chemically to other molecules to form a polymer *Sub-subunit, a ...
has a molecular weight of ~230–~275 kDa and contains three types of modules: type I, II, and III. All three modules are composed of two anti-parallel β-sheets resulting in a Beta-sandwich; however,
type I Type 1 or Type I or ''variant'', may refer to: Health *Diabetes mellitus type 1 (also known as "Type 1 Diabetes"), insulin-dependent diabetes * Type I female genital mutilation * Type 1 personality *Type I hypersensitivity (or immediate hypersensit ...
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 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 Integrin α4β1 (very late antigen-4) is an integrin dimer. It is composed of CD49d (alpha 4) and CD29 (beta 1). The alpha 4 subunit is 155 kDa, and the beta 1 subunit is 150 kDa. Function The integrin VLA-4 is expressed on the cell surfaces ...
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 Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
-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 α5β1, also known as the fibronectin receptor, is an integrin that binds to matrix macromolecules and proteinases and thereby stimulates angiogenesis. It is composed of α5 ( ITGA5/CD49e) and β1 ( ITGB1/CD29) subunits. It is the primary recepto ...
and αVβ3 integrins on the cell surface. The "synergy site" is in III9 and has a role in modulating fibronectin's association with
α5β1 α5β1, also known as the fibronectin receptor, is an integrin that binds to matrix macromolecules and proteinases and thereby stimulates angiogenesis. It is composed of α5 ( ITGA5/CD49e) and β1 ( ITGB1/CD29) subunits. It is the primary recepto ...
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).


Function

Fibronectin has numerous functions that ensure the normal functioning of
vertebrate Vertebrates () comprise all animal taxon, taxa within the subphylum Vertebrata () (chordates with vertebral column, backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the ...
organisms. It is involved in cell adhesion, growth, migration, and differentiation. Cellular fibronectin is assembled into the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struc ...
, an insoluble network that separates and supports the organs and tissues of an organism. Fibronectin plays a crucial role in
wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier aga ...
. 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 Matrix most commonly refers to: * ''The Matrix'' (franchise), an American media franchise ** '' The Matrix'', a 1999 science-fiction action film ** "The Matrix", a fictional setting, a virtual reality environment, within ''The Matrix'' (franchi ...
that more resembles the normal, surrounding tissue. Fibroblasts secrete
proteases A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
, including matrix metalloproteinases, that digest the plasma fibronectin, and then the fibroblasts secrete cellular fibronectin and assemble it into an insoluble
matrix Matrix most commonly refers to: * ''The Matrix'' (franchise), an American media franchise ** '' The Matrix'', a 1999 science-fiction action film ** "The Matrix", a fictional setting, a virtual reality environment, within ''The Matrix'' (franchi ...
. Fragmentation of fibronectin by proteases has been suggested to promote wound contraction, a critical step in
wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier aga ...
. Fragmenting fibronectin further exposes its V-region, which contains the site for
α4β1 Integrin α4β1 (very late antigen-4) is an integrin dimer. It is composed of CD49d (alpha 4) and CD29 (beta 1). The alpha 4 subunit is 155 kDa, and the beta 1 subunit is 150 kDa. Function The integrin VLA-4 is expressed on the cell surfaces ...
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 An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
, and inactivating the
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
for fibronectin results in early embryonic lethality. Fibronectin is important for guiding cell attachment and migration during
embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
. In
mammalian Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
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 The pharynx (plural: pharynges) is the part of the throat behind the mouth and nasal cavity, and above the oesophagus and trachea (the tubes going down to the stomach and the lungs). It is found in vertebrates and invertebrates, though its ...
by pathogenic bacteria.


Matrix assembly

Cellular fibronectin is assembled into an insoluble fibrillar
matrix Matrix most commonly refers to: * ''The Matrix'' (franchise), an American media franchise ** '' The Matrix'', a 1999 science-fiction action film ** "The Matrix", a fictional setting, a virtual reality environment, within ''The Matrix'' (franchi ...
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 α5β1, also known as the fibronectin receptor, is an integrin that binds to matrix macromolecules and proteinases and thereby stimulates angiogenesis. It is composed of α5 ( ITGA5/CD49e) and β1 ( ITGB1/CD29) subunits. It is the primary recepto ...
integrin receptors on the cell surface and aid in clustering the integrins. The local
concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', '' number concentration'' ...
of integrin-bound fibronectin increases, allowing bound fibronectin
molecules A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioc ...
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 In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struc ...
. Fibronectin's shift from
soluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solub ...
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 In physics, a force is an influence that can change the motion of an object. A force can cause an object with mass to change its velocity (e.g. moving from a state of rest), i.e., to accelerate. Force can also be described intuitively as a ...
partially unfolds the fibronectin
ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
, 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 Matrix most commonly refers to: * ''The Matrix'' (franchise), an American media franchise ** '' The Matrix'', a 1999 science-fiction action film ** "The Matrix", a fictional setting, a virtual reality environment, within ''The Matrix'' (franchi ...
. 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.


Role in cancer

Several morphological changes has been observed in tumors and tumor-derived cell lines that have been attributed to decreased fibronectin expression, increased fibronectin degradation, and/or decreased expression of fibronectin-binding receptors, such as
α5β1 α5β1, also known as the fibronectin receptor, is an integrin that binds to matrix macromolecules and proteinases and thereby stimulates angiogenesis. It is composed of α5 ( ITGA5/CD49e) and β1 ( ITGB1/CD29) subunits. It is the primary recepto ...
integrins. Fibronectin has been implicated in carcinoma development. In lung carcinoma, fibronectin expression is increased especially in non-small cell lung carcinoma. The
adhesion Adhesion is the tendency of dissimilar particles or surfaces to cling to one another ( cohesion refers to the tendency of similar or identical particles/surfaces to cling to one another). The forces that cause adhesion and cohesion can b ...
of lung carcinoma cells to fibronectin enhances tumorigenicity and confers
resistance Resistance may refer to: Arts, entertainment, and media Comics * Either of two similarly named but otherwise unrelated comic book series, both published by Wildstorm: ** ''Resistance'' (comics), based on the video game of the same title ** ''T ...
to apoptosis-inducing
chemotherapeutic agents Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemoth ...
. Fibronectin has been shown to stimulate the gonadal steroids that interact with
vertebrate Vertebrates () comprise all animal taxon, taxa within the subphylum Vertebrata () (chordates with vertebral column, backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the ...
androgen receptors, which are capable of controlling the expression of
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. Cyclin D protein is anywhere from 155 (in zebra mus ...
and related genes involved in
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA ( DNA replication) and some of its organelles, and sub ...
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 In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
for radioresistance and for pan-cancer prognosis. FN1-FGFR1 fusion is frequent in phosphaturic mesenchymal tumours.


Role in wound healing

Fibronectin has profound effects on
wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier aga ...
, 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 vivo'' was studied during the mechanism of wound healing. Plasma fibronectin levels are decreased in acute inflammation or following surgical trauma and in patients with disseminated intravascular coagulation. Fibronectin is located in the extracellular matrix of embryonic and adult tissues (not in the
basement membrane The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tissues including mesothelium and ...
s 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).
Fibroblast A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of ...
s 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 Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis i ...
by both macrophages 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 histological 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.


''In vivo'' vs ''in vitro''

Plasma fibronectin, which is synthesized by hepatocytes, and fibronectin synthesized by
cultured Culture () is an umbrella term which encompasses the social behavior, institutions, and norms found in human societies, as well as the knowledge, beliefs, arts, laws, customs, capabilities, and habits of the individuals in these groups.Tylor ...
fibroblast A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of ...
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 biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struc ...
''in vitro'' and ''in vivo''. Both plasma and cellular fibronectins in the matrix form high molecular weight, disulfide-bonded
multimers Protein quaternary structure is the fourth (and highest) classification level of protein structure. Protein quaternary structure refers to the structure of proteins which are themselves composed of two or more smaller protein chains (also refe ...
. The mechanism of formation of these multimers is not presently 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 Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may int ...
, 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.


Interactions

Besides integrin, fibronectin binds to many other host and non-host molecules. For example, it has been shown to interact with proteins such fibrin, 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), as well as the glycosaminoglycan, heparan sulfate. Fibronectin has been shown to interact with: * CD44 * COL7A1, * LPA, *
IGFBP3 Insulin-like growth factor-binding protein 3, also known as IGFBP-3, is a protein that in humans is encoded by the ''IGFBP3'' gene. IGFBP-3 is one of six insulin-like growth factor-binding protein, IGF binding proteins (IGFBP1, IGFBP-1 to IGFBP6, I ...
, * TNC, and * TRIB3.


See also

* Fetal fibronectin *
Fibronectin type I domain Fibronectin, 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 (FN1) is a ...
*
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 surfac ...
* Fibronectin type III domain * Monobody, an engineered antibody mimetic based on the structure of the fibronectin type III domain *
Substrate adhesion molecules Substrate adhesion molecules (SAMs) are proteins that attach cell (biology), cells to specific compounds in the extracellular matrix (a process known as cell adhesion). Some of the amino acids in the SAM bind to components of the extracellular mat ...


References


Further reading

* * * * * * * *


External links


Fibronectin, an Extracellular Adhesion Molecule

The Fibronectin Protein
*
Fibronectin molecular interactions
* * {{Globulins Glycoproteins Diagnostic obstetrics and gynaecology Extracellular matrix proteins