Versican
Encyclopedia
Versican, also known as VCAN, is a large extracellular matrix proteoglycan
that is present in a variety of human tissues. It is encoded by the VCAN gene
.
Versican is a large chondroitin sulfate proteoglycan
with an apparent molecular mass of more than 1000kDa. In 1989, Zimmermann and Ruoslahti cloned and sequenced the core protein of fibroblast chondroitin sulfate proteoglycan. They designated it versican in recognition of its versatile modular structure. Versican belongs to the lectican protein family, with aggrecan
(abundant in cartilage
), brevican and neurocan (nervous system proteoglycans) as other members. Versican is also known as chondroitin sulfate proteoglycan core protein 2 or chondroitin sulfate proteoglycan 2 (CSPG2), and PG-M.
globular N-terminal, C-terminal, and glycosaminoglycan
(GAG) binding regions.
The N-terminal (G1) globular domain consists of Ig
-like loop and two link modules, and has Hyaluronan
(HA) binding properties.
Versican occurs in 4 isoforms : V0, V1, V2, V3.
The central domain of versican V0 contains both the GAG-α and GAG-β domains. V1 isoforms has the GAG-β domain, V2 has the GAG-α domain, and V3 is void of any GAG attachment domains. The GAGs, being composed of repeating disaccharide units, contribute to the negative charge and many other properties of proteoglycans.
The C-terminal (G3) globular domain consists of one or two Epidermal growth factor
(EGF) repeats, a C-type lectin domain and complement regulatory protein (CRP)-like domain. The C-terminal domain binds a variety of ligands in ECM which contribute significantly to the functions of lecticans.
is extensively studied. Versican is often considered an anti-adhesive molecule. Considering the large size (>1000 kDa) and hydration capability of versican, it is possible that the interaction of integrins (large family of cell adhesion molecules) with their cell surface receptors is sterically hindered.
by interacting with hyaluronan. Its interactions with link protein has also been studied.
Because of their negatively charged sulfates or carboxyl groups, chondroitin sulfate chains are attracted to various positively charged molecules such as certain growth factors, cytokines, and chemokines. This interaction in the extracellular matrix or on the cell surface is important in the formation of immobilized gradients of these factors, their protection from proteolytic cleavage, and their presentation to specific cell-surface receptors. The binding of versican with leukocyte adhesion molecules L-selectin, P-selectin, and CD44 is also mediated by the interaction of CS chains of versican with the carbohydrate-binding domain
of these molecules. Both CD44 and L-selectin have been implicated in leukocyte trafficking. The ability of versican to bind a large panel of chemokines and the biological consequences of such binding has also been examined. Versican can bind specific chemokines through its CS chains and this interaction down-regulates the chemokines function. Recently, in light of results that V1 and V2 isoforms of versican have opposite effects on cell proliferation, glycosaminoglycan domain GAG-β has been implicated in versican-enhanced cell proliferation and versican-induced reduction of cell apoptosis.
and glypican proteoglycan families. Versican’s C-terminal domain interacts with Fibulin-2, a protein whose expression is associated with that of versican in the developing heart. The EGF domain of the C-terminal of versican also binds the EGF-receptor molecule, in vivo.
Versican is a key factor in inflammation through interactions with adhesion molecules on the surfaces of inflammatory leukocytes and interactions with chemokines that are involved in recruiting inflammatory cells.
In the adult central nervous system, versican is found in perineuronal net
s, where it may stabilize synaptic connections. Versican can also inhibit nervous system regeneration and axonal growth following an injury to the central nervous system.
, Sarcoma
, and peritoneal mesothelioma
.
Versican is required for Lewis lung carcinoma
in mice to metastasize to lung, liver and adrenal glands, acting via TLR2 to activate myeloid cells and produce TNF-alpha.
with HAPLN1
and Aggrecan
.
Proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
that is present in a variety of human tissues. It is encoded by the VCAN 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...
.
Versican is a large chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans are proteoglycans consisting of a core protein and chondroitin sulfate. They are structural components of a variety of human tissues, for example of cartilage.The following CSPGs have been identified:...
with an apparent molecular mass of more than 1000kDa. In 1989, Zimmermann and Ruoslahti cloned and sequenced the core protein of fibroblast chondroitin sulfate proteoglycan. They designated it versican in recognition of its versatile modular structure. Versican belongs to the lectican protein family, with aggrecan
Aggrecan
Aggrecan also known as cartilage-specific proteoglycan core protein or chondroitin sulfate proteoglycan 1 is a protein that in humans is encoded by the ACAN gene. This gene is a member of the aggrecan/versican proteoglycan family...
(abundant in cartilage
Cartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
), brevican and neurocan (nervous system proteoglycans) as other members. Versican is also known as chondroitin sulfate proteoglycan core protein 2 or chondroitin sulfate proteoglycan 2 (CSPG2), and PG-M.
Structure
These proteoglycans share a homologousHomology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
globular N-terminal, C-terminal, and glycosaminoglycan
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...
(GAG) binding regions.
The N-terminal (G1) globular domain consists of Ig
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
-like loop and two link modules, and has Hyaluronan
Hyaluronan
Hyaluronan is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues...
(HA) binding properties.
Versican occurs in 4 isoforms : V0, V1, V2, V3.
The central domain of versican V0 contains both the GAG-α and GAG-β domains. V1 isoforms has the GAG-β domain, V2 has the GAG-α domain, and V3 is void of any GAG attachment domains. The GAGs, being composed of repeating disaccharide units, contribute to the negative charge and many other properties of proteoglycans.
The C-terminal (G3) globular domain consists of one or two Epidermal growth factor
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
(EGF) repeats, a C-type lectin domain and complement regulatory protein (CRP)-like domain. The C-terminal domain binds a variety of ligands in ECM which contribute significantly to the functions of lecticans.
Function
The role of versican in cell adhesion, migration, and proliferationCell 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"...
is extensively studied. Versican is often considered an anti-adhesive molecule. Considering the large size (>1000 kDa) and hydration capability of versican, it is possible that the interaction of integrins (large family of cell adhesion molecules) with their cell surface receptors is sterically hindered.
N-terminus
The N-terminal of Versican has an important role in maintaining the integrity of the ECMExtracellular 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...
by interacting with hyaluronan. Its interactions with link protein has also been studied.
Glycosaminoglycan binding region
The central domain of Versican is decorated with glycosaminoglycans. The structural and functional diversity of Versican is increased by variations in GAG sulfation patterns and the type of GAG chains bound to the core protein. There is a single versican gene, however alternative splicing of its mRNA produces 4 distinct versican isoforms that differ in their potential number of GAG chains. All isoforms have homologous N-terminal (HA binding) and C-terminal (lectin-like) domains. The central domain of versican V0 contains both the GAG-α and GAG-β domains. V1 isoforms has the GAG-β domain, V2 has the GAG-α domain, and V3 is void of any GAG attachment domains, and only consists of the N-terminal and C-terminal globular domains. It is known that the isoforms are differentially expressed in different tissue types. The biological significance of alternative splicing is yet to be determined.Because of their negatively charged sulfates or carboxyl groups, chondroitin sulfate chains are attracted to various positively charged molecules such as certain growth factors, cytokines, and chemokines. This interaction in the extracellular matrix or on the cell surface is important in the formation of immobilized gradients of these factors, their protection from proteolytic cleavage, and their presentation to specific cell-surface receptors. The binding of versican with leukocyte adhesion molecules L-selectin, P-selectin, and CD44 is also mediated by the interaction of CS chains of versican with the carbohydrate-binding domain
Carbohydrate-binding module
In molecular biology, a carbohydrate-binding module is a protein domain found in carbohydrate-active enzymes . The majority of these domains have carbohydrate-binding activity. Some of these domains are found on cellulosomal scaffoldin proteins. CBMs were previously known as cellulose-binding...
of these molecules. Both CD44 and L-selectin have been implicated in leukocyte trafficking. The ability of versican to bind a large panel of chemokines and the biological consequences of such binding has also been examined. Versican can bind specific chemokines through its CS chains and this interaction down-regulates the chemokines function. Recently, in light of results that V1 and V2 isoforms of versican have opposite effects on cell proliferation, glycosaminoglycan domain GAG-β has been implicated in versican-enhanced cell proliferation and versican-induced reduction of cell apoptosis.
C-terminus
The C-terminal of Versican interacts with a variety of molecules in the matrix. One important family of ligands is the tenascin family. For example, The C-lectin domain of versican interacts with Tenascin R through its fibronectin type III (FnIII) repeat 3-5 domain in a calcium dependent manner, in vivo. Different tenascin domains interact with a wide range of cellular receptors, including integrins, cell adhesion molecules and members of the syndecanSyndecan
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...
and glypican proteoglycan families. Versican’s C-terminal domain interacts with Fibulin-2, a protein whose expression is associated with that of versican in the developing heart. The EGF domain of the C-terminal of versican also binds the EGF-receptor molecule, in vivo.
Tissue expression
Expression of versican is observed in various adult tissues such as blood vessels, skin, and developing heart. Smooth muscle cells of blood vessels, epithelial cells of skin, and the cells of central and peripheral nervous system are a few examples of cell types that express versican physiologically. Versican is involved in development, guiding embryonic cell migration important in the formation of the heart and outlining the path for neural crest cell migration.Versican is a key factor in inflammation through interactions with adhesion molecules on the surfaces of inflammatory leukocytes and interactions with chemokines that are involved in recruiting inflammatory cells.
In the adult central nervous system, versican is found in perineuronal net
Perineuronal net
Perineuronal nets are specialized extracellular matrix structures responsible for synaptic stabilization in the adult brain. These PNNs are found around certain neuron cell bodies and proximal neurites in the central nervous system...
s, where it may stabilize synaptic connections. Versican can also inhibit nervous system regeneration and axonal growth following an injury to the central nervous system.
Role in cancer and metastasis
Increased versican expression is often observed in tumor growth in tissues such as breast, brain, ovary, gastrointestinal tract, prostate, and melanomaMelanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
, Sarcoma
Sarcoma
A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
, and peritoneal mesothelioma
Peritoneal mesothelioma
Peritoneal mesothelioma is the name given to the cancer that attacks the lining of the abdomen. This type of cancer affects the lining that protects the contents of the abdomen and which also provides a lubricating fluid to enable the organs to move and work properly.The peritoneum is made of two...
.
Versican is required for Lewis lung carcinoma
Lewis lung carcinoma
In 1975, Munson discovered that cannabinoids suppress Lewis lung carcinoma cell growth. The mechanism of this action was shown to be inhibition of DNA synthesisCannabinoids increase the life span of mice carrying Lewis lung tumors and decrease primary tumor size. There are multiple modes of...
in mice to metastasize to lung, liver and adrenal glands, acting via TLR2 to activate myeloid cells and produce TNF-alpha.
Interactions
Versican has been shown to interactProtein-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 HAPLN1
HAPLN1
Hyaluronan and proteoglycan link protein 1 is a protein that in humans is encoded by the HAPLN1 gene.-Interactions:HAPLN1 has been shown to interact with Versican.-Further reading:...
and Aggrecan
Aggrecan
Aggrecan also known as cartilage-specific proteoglycan core protein or chondroitin sulfate proteoglycan 1 is a protein that in humans is encoded by the ACAN gene. This gene is a member of the aggrecan/versican proteoglycan family...
.