Fibronectin is a high-
molecular weight (~500-~600
kDa)
glycoprotein 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 s ...
that binds to
membrane-spanning
receptor proteins called
integrins.
Fibronectin also binds to other extracellular matrix proteins such as
collagen,
fibrin, and
heparan sulfate proteoglycans (e.g.
syndecans).
Fibronectin exists as a
protein dimer, consisting of two nearly identical
monomers linked by a pair of
disulfide bonds.
The fibronectin protein is produced from a single gene, but
alternative splicing of its
pre-mRNA leads to the creation of several
isoforms.
Two types of fibronectin are present in
vertebrates:
* 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 int ...
(300 μg/ml) and is produced in the
liver by
hepatocytes.
* insoluble cellular fibronectin is a major component of the extracellular matrix. It is secreted by various
cells
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
, primarily
fibroblasts, as a soluble
protein dimer and is then assembled into an insoluble matrix in a complex cell-mediated process.
Fibronectin plays a major role in
cell adhesion,
growth
Growth may refer to:
Biology
* Auxology, the study of all aspects of human physical growth
* Bacterial growth
* Cell growth
* Growth hormone, a peptide hormone that stimulates growth
* Human development (biology)
* Plant growth
* Secondary grow ...
,
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
Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...
, 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 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, ...
has a molecular weight of ~230–~275 kDa and contains three types of
modules
Broadly speaking, modularity is the degree to which a system's components may be separated and recombined, often with the benefit of flexibility and variety in use. The concept of modularity is used primarily to reduce complexity by breaking a s ...
: type I, II, and III. All three modules are composed of two anti-parallel
β-sheets
The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...
resulting in a
Beta-sandwich
Beta-sandwich, β-sandwich domains consisting of 80 to 350 amino acids occur commonly in proteins. They are characterized by two opposing antiparallel beta sheets (β-sheets). The number of strands found in such domains may differ from one protein ...
; 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 cellular fibronectin, but they are never present in plasma fibronectin. A "variable" V-region exists between III
14–15 (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
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, res ...
-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, I
1–5, is referred to as the "assembly domain", and it is required for the initiation of fibronectin matrix assembly. Modules III
9–10 correspond to the "cell-binding domain" of fibronectin. The
RGD sequence (Arg–Gly–Asp) is located in III
10 and is the site of
cell attachment via
α5β1 and
αVβ3 integrins on the cell surface. The "synergy site" is in III
9 and has a role in modulating fibronectin's association with
α5β1 integrins.
Fibronectin also contains domains for
fibrin-binding (I
1–5, I
10–12),
collagen-binding (I
6–9),
fibulin-1-binding (III
13–14),
heparin-binding and
syndecan-binding (III
12–14).
Function
Fibronectin has numerous functions that ensure the normal functioning of
vertebrate organisms.
It is involved in
cell adhesion,
growth
Growth may refer to:
Biology
* Auxology, the study of all aspects of human physical growth
* Bacterial growth
* Cell growth
* Growth hormone, a peptide hormone that stimulates growth
* Human development (biology)
* Plant growth
* Secondary grow ...
,
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 s ...
, 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
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...
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
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...
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, 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. Fragmenting fibronectin further exposes its V-region, which contains the site for
α4β1 integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle ...
binding. These fragments of fibronectin are believed to enhance the binding of α4β1 integrin-expressing cells, allowing them to adhere to and forcefully contract the surrounding matrix.
Fibronectin is necessary for
embryogenesis, and
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. 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), fu ...
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
pathogenic bacteria.
Matrix assembly
Cellular fibronectin is assembled into an
insoluble
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 solubi ...
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 integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle ...
receptors on the cell surface and aid 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
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 s ...
.
Fibronectin's shift from
soluble to insoluble fibrils proceeds when cryptic fibronectin-binding sites are exposed along the length of a bound fibronectin molecule. Cells are believed to stretch fibronectin by pulling on their fibronectin-bound integrin receptors. This
force partially unfolds the fibronectin
ligand, unmasking cryptic fibronectin-binding sites and allowing nearby fibronectin molecules to associate. This fibronectin-fibronectin interaction enables the soluble, cell-associated fibrils to branch and stabilize into an insoluble fibronectin
matrix
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 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 ...
of lung carcinoma cells to fibronectin enhances
tumorigenicity and confers
resistance 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. Chemothera ...
. Fibronectin has been shown to stimulate the
gonadal steroids
Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects are ...
that interact with
vertebrate 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 control. These observations suggest that fibronectin may promote lung
tumor growth/survival and resistance to therapy, and it could represent a novel
target
Target may refer to:
Physical items
* Shooting target, used in marksmanship training and various shooting sports
** Bullseye (target), the goal one for which one aims in many of these sports
** Aiming point, in field artillery, fi ...
for the development of new
anticancer drugs.
Fibronectin 1 acts as a potential
biomarker for
radioresistance and for pan-cancer prognosis.
FN1-FGFR1 fusion is frequent in phosphaturic mesenchymal tumours.
Role in wound healing
Fibronectin has profound effects on
wound healing, including the formation of proper substratum for migration and growth of cells during the development and organization of
granulation tissue
Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any siz ...
, 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 membranes of the adult tissues), but may be more widely distributed in inflammatory lesions. During blood clotting, the fibronectin remains associated with the clot, covalently cross-linked to
fibrin with the help of
Factor XIII (fibrin-stabilizing factor).
Fibroblasts play a major role in wound healing by adhering to fibrin. Fibroblast adhesion to fibrin requires fibronectin, and was strongest when the fibronectin was cross-linked to the fibrin. Patients with Factor XIII deficiencies display impairment in wound healing as fibroblasts don't grow well in fibrin lacking Factor XIII. Fibronectin promotes particle
phagocytosis by both
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 fibroblasts 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 s ...
''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 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, 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
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
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
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
There are four members of the tenasc ...
, 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
Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...
with:
*
CD44
*
COL7A1,
*
LPA,
*
IGFBP3,
*
TNC,
and
*
TRIB3
Tribbles homolog 3 is a protein that in humans is encoded by the ''TRIB3'' gene.
Function
The protein encoded by this gene is a putative protein kinase that is induced by the transcription factor NF-kappaB. It is a pseudoenzyme that is tho ...
.
See also
*
Fetal fibronectin
*
Fibronectin type I domain
*
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 surfa ...
*
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 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 matrix, while other ...
References
Further reading
*
*
*
*
*
*
*
*
External links
Fibronectin, an Extracellular Adhesion MoleculeThe Fibronectin Protein*
Fibronectin molecular interactions*
*
{{Globulins
Glycoproteins
Diagnostic obstetrics and gynaecology
Extracellular matrix proteins