Tenascin C (TN-C) is a
glycoprotein that in humans is encoded by the ''TNC''
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 ...
.
It is expressed in 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 ...
of various tissues during development, disease or injury, and in restricted
neurogenic
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...
areas of the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
.
Tenascin-C is the founding member of the
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 tenas ...
protein family. In the embryo it is made by migrating cells like the
neural crest
Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, per ...
; it is also abundant in developing tendons, bone and cartilage.
Gene and expression
The human tenascin C gene, ''TN-C'', is located on
chromosome 9
Chromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 138 million base pairs of nucleic acids (the building blocks of D ...
with location of the cytogenic band at the 9q33. The entire Tenascin family coding region spans approximately 80
kilobase
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DN ...
s translating into 2203
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
s.
Expression of TN-C changes from development to adulthood. TN-C is highly expressed during
embryogenesis and is briefly expressed during organogenesis, while in developed organs, expression is absent or in trace amounts.
TN-C has been shown to be
upregulated
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pro ...
under pathological conditions caused by
inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
, infection, tumorigenesis, and at sites that are subject to unique
biomechanics
Biomechanics is the study of the structure, function and motion of the mechanical aspects of biological systems, at any level from whole organisms to organs, cells and cell organelles, using the methods of mechanics. Biomechanics is a branch of ...
forces.
The regulation of TN-C is induced or repressed by a number of different factors that are expressed during embryonic tissue, as well as developed tissues during remodeling, injured, or neoplastic.
TGF-β1,
tumor necrosis factor-α,
interleukin-1
The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Discovery
Discovery of these cytokines began with studies on t ...
,
nerve growth factor, and
keratinocyte growth factor are factors that have been shown to regulate TN-C.
Other extracellular matrix components such as matrix
metalloprotein
Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-binding protein domains al ...
s and
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 ...
s are also frequently co-expressed with TN-C.
In the developing central nervous system, TN-C is involved in regulating the proliferation of both
oligodendrocyte precursor cells and
astrocytes
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...
. Expression of TN-C by radial
glia
Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...
precedes the onset of
gliogenesis, during which time it is thought to drive the
differentiation of astrocytes.
In the adult brain, TN-C expression is downregulated except for the areas that maintain neurogenesis into adulthood and the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
.
TN-C is also present in central nervous system injuries and
gliomas
A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours.
Signs and symptoms
...
.
Structure
Tenascin C is an
oligomeric glycoprotein composed of individual poly
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
s with
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 ...
s ranging from 180 to ~300kDa. The Tenascin family of proteins shares a similar structural pattern. These similar modules include
heptad repeat
The heptad repeat is an example of a structural motif that consists of a repeating pattern of seven amino acids:
''a b c d e f g''
H P P H C P C
where H represents hydrophobic residues, C represents, typically, charged residues, and P repre ...
s,
EGF-like repeats,
fibronectin type III domain
The Fibronectin type III domain is an evolutionarily 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 am ...
s, and a
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 ...
globular domain shared with
fibrinogen
Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood cl ...
s. These protein modules are lined up like beads on a string and give rise to long and extended molecules.
At the
N-terminus each Tenascin has an oligomerization domain which in the case of TN-C leads to the formation of
hexamer
In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relative ...
s.
TN-C and -R are known to be subject to
alternative splicing. In human TN-C there exists, in addition to the eight constant repeats, nine extra repeats subject to alternative splicing. This results in a multitude of TN-C subunits differing in the number and identity of fibronectin type III domain repeats.
Interactions
Tenascin-C has been shown to
interact
Advocates for Informed Choice, 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 traits. The organizati ...
with
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
.
This interaction is shown to have the potential to modify cell adhesion.
A solid-state interaction between fibronectin and TN-C results in cellular upregulation of
matrix metalloproteinase
Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs be ...
expression.
TN-C also interacts with one or more TN-C receptors on cells which activate and repress the same
signal transduction pathway. An example of this interaction is the adhesion of SW80
carcinoma cells to the third FN-III repeat of TN-C via the
αvβ3 integrin receptor leads to cell spreading,
phosphorylation of
focal adhesion kinase
PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the ''PTK2'' gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to ...
, paxillin and ERK2 MAPK, and proliferation.
In contrast, when these same cells use either α
9β
1 or α
vβ
6 integrins to adhere to the same third FN type III repeat, cell spreading is attenuated and activation of these signaling mediators and cell growth is suppressed or fails to occur.
Function
Tenascin C is a very diverse protein that can produce different functions within the same cell type. These myriad functions are accomplished through alternative splicing of mRNA as well as the temporal activation of signal transduction pathways and/or target genes at different stages of growth or differentiation.
TN-C is classified as an adhesion-modulating protein, because it has been found to inhibit cellular adhesion to fibronectin.
Much of the functional studies are inferred from various TN-C knockout mice models. TN-C clearly plays a role in cell signaling as evidenced by its ability to be induced during events such as trauma, inflammation, or cancer development. Also, TN-C is important in regulating cell proliferation and migration, especially during developmental differentiation and wound healing.
Clinical significance
Tenascin C continues to be researched 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 a number of diseases such as
myocarditis and different forms of cancer. The numerous involvements with cellular functioning and signaling make TN-C a popular protein to study in developing new therapies and detection methods.
Recent work has shown that TN-C inhibits HIV infection in immune cells by binding to a
chemokine
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...
coreceptor
A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.
Properties
The t ...
site on the HIV-1 envelope protein, blocking the virus' entry into the host cells.
Role in cancer
Tenascin C is implicated in a number of different cancers such as
osteosarcomas,
chondrosarcoma
Chondrosarcoma is a bone sarcoma, a primary cancer composed of cells derived from transformed cells that produce cartilage. A chondrosarcoma is a member of a category of tumors of bone and soft tissue known as sarcomas. About 30% of bone sarcomas ...
s,
bladder cancer,
and
glioblastomas
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality cha ...
.
In glioblastoma cells, Tenascin-C expression provides much clinical and functional significance in terms of cancer prognosis and tumor progression. The endogenous pool of tenascin-C isoforms in gliomas supports both tumor cell proliferation and migration.
Because tenascin-C is essential to the survival of these various forms of cancers, tenascin-c expression could be 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 cancer detection. Also, tenascin-C antibodies have been used to diagnose and create therapies for many different types of cancers.
See also
*
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 tenas ...
References
Further reading
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{{Use dmy dates, date=April 2017
Tenascins