NOV (nephroblastoma overexpressed) also known as CCN3 is a

matricellular protein A matricellular protein is a dynamically expressed non-structural protein that is present in the extracellular matrix (ECM). Rather than serving as stable structural elements in the ECM, these proteins are rapidly turned over and have regulatory rol ...

that in humans is encoded by the ''NOV''

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 ba ...

CCN family

NOV is a member of the CCN family of secreted,

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 stru ...

(ECM)-associated signaling proteins (see also

CCN intercellular signaling protein CCN proteins are a family of extracellular matrix (ECM)-associated proteins involved in intercellular signaling. Due to their dynamic role within the ECM they are considered matricellular proteins. Background The acronym CCN is derived from the fi ...

). The CCN acronym is derived from the first three members of the family being identified, namely

CYR61 Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the ''CYR61'' gene. CYR61 is a secreted, extracellular matrix (ECM)-associated signaling protein of the CCN family ...

(cysteine-rich angiogenic inducer 61, or CCN1),

CTGF CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins (see also CCN intercellular signaling protein). CTGF has important roles in many b ...

(connective tissue growth factor, or CCN2), and NOV. These proteins, together with

WISP1 WNT1-inducible-signaling pathway protein 1 (WISP-1), also known as CCN4, is a matricellular protein that in humans is encoded by the ''WISP1'' gene. Structure WISP-1 is highly homologous to CYR61 (CCN1) and CTGF (CCN2), and is a member of the ...

(CCN4),

WISP2 WNT1-inducible-signaling pathway protein 2, or WISP-2 (also named CCN5) is a matricellular protein that in humans is encoded by the ''WISP2'' gene. Function The CCN family of proteins regulates diverse cellular functions, including cell adhesi ...

(CCN5), and

WISP3 WNT1-inducible-signaling pathway protein 3 (WISP3, also named CCN6) is a matricellular protein that in humans is encoded by the ''WISP3'' gene. Structure It is a member of the CCN family (CCN intercellular signaling protein) of secreted, extrac ...

(CCN6) comprise the six-member CCN family in vertebrates and have been renamed CCN1-6 in the order of their discovery by international consensus.

Structure

The human NOV protein contains 357 amino acids with an N-terminal secretory signal peptide followed by four structurally distinct domains with homologies to insulin-like growth factor binding protein (

IGFBP The insulin-like growth factor-binding protein (IGFBP) serves as a transport protein for insulin-like growth factor 1 (IGF-1). Function Approximately 98% of IGF-1 is always bound to one of six binding proteins (IGF-BP). IGFBP-3, the most abund ...

), von Willebrand type C repeats ( vWC), thrombospondin type 1 repeat (TSR), and a

cysteine knot A cystine knot is a protein structural motif containing three disulfide bridges (formed from pairs of cysteine residues). The sections of polypeptide that occur between two of them form a loop through which a third disulfide bond passes, forming ...

motif within the C-terminal (CT) domain.

Function

NOV regulates multiple cellular activities including

cell adhesion Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indir ...

migration Migration, migratory, or migrate may refer to: Human migration * Human migration, physical movement by humans from one region to another ** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...

, proliferation, differentiation, and survival. It functions by direct binding to

integrin receptor 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, as well as other receptors such as

NOTCH1 Neurogenic locus notch homolog protein 1 (Notch 1) is a protein encoded in humans by the ''NOTCH1'' gene. Notch 1 is a single-pass transmembrane receptor. Function This gene encodes a member of the Notch family. Members of this Type 1 transme ...

and fibulin 1c (

FBLN1 FBLN1 is the gene encoding fibulin-1, an extracellular matrix and plasma protein. Function Fibulin-1 is a secreted glycoprotein that is found in association with extracellular matrix structures including fibronectin-containing fibers, elastin-co ...

). NOV is expressed during wound healing and induces

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

in vivo. It is essential for self-renewal of CD34+

hematopoietic stem cell Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...

s from umbilical cord blood. NOV can bind BMP2 and inhibit its functions in promoting

osteogenic Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in the ...

differentiation, and stimulate osteoclastogenesis through a process that may involve

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

flux. Overexpression of Nov in transgenic mice in

osteoblast Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...

s antagonizes both BMP and Wnt-signaling and result in

osteopenia Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop osteop ...

. In February 2017, it was reported that the NOV protein was involved in

regulatory T cell The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosup ...

-mediated

oligodendrocyte Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...

differentiation in the regeneration of

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...

following damage to the myelin sheath. This finding revealed a new function for regulatory T cells that is distinct from their role in

immunomodulation Immunomodulation is modulation (regulatory adjustment) of the immune system. It has natural and human-induced forms, and thus the word can refer to the following: * Homeostasis in the immune system, whereby the system self-regulates to adjust immun ...

. * NOV (CCN3) has recently been implicated in mood disorders, notably in the postpartum period; these effects may be mediated by its effects on myelination

Role in embryo development

In contrast to the lethality of

Cyr61 Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the ''CYR61'' gene. CYR61 is a secreted, extracellular matrix (ECM)-associated signaling protein of the CCN family ...

(CCN1) and

Ctgf CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins (see also CCN intercellular signaling protein). CTGF has important roles in many b ...

(CCN2) genetic knockout in mice, Nov-null mice are viable and largely normal, exhibiting only modest and transient sexually dimorphic skeletal abnormalities. However, Nov-null mice show enhanced blood vessel

neointima Neointima typically refers to scar tissue that forms within tubular anatomical structures such as blood vessels, as the intima is the innermost lining of these structures. Neointima can form as a result of vascular surgery such as angioplasty ...

l thickening when challenged with vascular injury, indicating that NOV inhibits neoinitimal

hyperplasia Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferati ...

Role in cancer

Although NOV inhibits the proliferation of cancer cells, it appears to promote metastasis. Nov overexpression results in reduced tumor size in

glioma 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 ...

cells

xenograft Xenotransplantation (''xenos-'' from the Greek meaning "foreign" or strange), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenograft ...

s, but enhances metastatic potential in xenotransplanted melanoma cells. NOV expression is associated with a higher risk of metastasis and worse prognosis in patients with cancers such as

Ewing's sarcoma Ewing sarcoma is a type of cancer that forms in bone or soft tissue. Symptoms may include swelling and pain at the site of the tumor, fever, and a bone fracture. The most common areas where it begins are the legs, pelvis, and chest wall. In about ...

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

, and

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

. In

chronic myeloid leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulat ...

(CML), NOV is downregulated as a consequence of the

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

activity of BCR- ABL, a

chimeric protein Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this ''fusion gene'' r ...

generated through the chromosomal translocation between chromosome 9 and 22. Forced expression of NOV inhibits proliferation and restores growth control in CML cells, suggesting that NOV may be an alternate target for novel therapeutics against CML.

References

{{reflist , 35em CCN proteins