Versican

Versican is a large extracellular matrix is_associated_with::proteoglycan that is present in a variety of human tissues. It is encoded by the VCAN is_associated_with::gene.

Versican is a large is_associated_with::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 is_associated_with::lectican protein family, with is_associated_with::aggrecan (abundant in is_associated_with::cartilage), is_associated_with::brevican and is_associated_with::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 homologous globular is_associated_with::N-terminal, is_associated_with::C-terminal, and is_associated_with::glycosaminoglycan (GAG) binding regions.

The N-terminal (G1) globular domain consists of Ig-like loop and two link modules, and has is_associated_with::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 is_associated_with::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.

Function
The role of versican in cell adhesion, migration, and proliferation has been extensively studied. Versican is often considered an anti-adhesion molecule. Considering the large size (>1000 kDa) and hydration capability of versican, it is possible that the interaction of is_associated_with::integrins (large family of cell adhesion molecules) with their cell surface receptors is sterically hindered.

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.

N-terminus
The N-terminal of versican has an important role in maintaining the integrity of the ECM 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 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 is_associated_with::syndecan and glypican proteoglycan families. Versican’s C-terminal domain interacts with is_associated_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.

Clinical significance
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 is_associated_with::perineuronal nets, where it may stabilize synaptic connections. Versican can also inhibit nervous system regeneration and axonal growth following an injury to the central nervous system.

Cancer and metastasis
Increased versican expression is often observed in tumor growth in tissues such as breast, brain, ovary, gastrointestinal tract, prostate, and is_associated_with::melanoma, is_associated_with::sarcoma, and is_associated_with::peritoneal mesothelioma. A fifth isoform of versican, V4, that is similar to V1 but with a shortened beta-GAG region, is present and upregulated in human is_associated_with::breast cancer.

Versican is required for is_associated_with::Lewis lung carcinoma in mice to metastasize to lung, liver and adrenal glands, acting via is_associated_with::TLR2 to activate is_associated_with::myeloid cells and produce is_associated_with::TNF-alpha.

Lung disorders
Versican is increased in the changing tissue is_associated_with::extracellular matrix in inflammatory lung disorders such as is_associated_with::chronic obstructive pulmonary disease (COPD), is_associated_with::asthma and bronchiolitis obliterans syndrome (BOS). Cells (is_associated_with::myofibroblasts, is_associated_with::macrophages and other inflammatory cells) can migrate more easily through is_associated_with::extracellular matrix that has a higher versican content.

is_associated_with::Skin disorders
Deposits of versican are not present in normal is_associated_with::skin but are found in the is_associated_with::reticular dermis during is_associated_with::keloid scarring, a condition where is_associated_with::scar formation becomes uncontrolled and overgrowth of is_associated_with::skin tissue occurs at the site of the is_associated_with::wound.

Interactions
Versican has been shown to interact with hyaluronan and a link protein (hyaluronan and proteoglycan link protein 1; is_associated_with::HAPLN1).