NOV (gene)

NOV (nephroblastoma overexpressed) also known as CCN3 is a is_associated_with::matricellular protein that in humans is encoded by the NOV is_associated_with::gene.

CCN family
NOV is a member of the CCN family of secreted, is_associated_with::extracellular matrix (ECM)-associated signaling proteins (see also is_associated_with::CCN intercellular signaling protein). The CCN acronym is derived from the first three members of the family being identified, namely is_associated_with::CYR61 (cysteine-rich angiogenic inducer 61, or CCN1), is_associated_with::CTGF (connective tissue growth factor, or CCN2), and NOV. These proteins, together with is_associated_with::WISP1 (CCN4), is_associated_with::WISP2 (CCN5), and is_associated_with::WISP3 (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), von Willebrand type C repeats (vWC), thrombospondin type 1 repeat (TSR), and a is_associated_with::cysteine knot motif within the C-terminal (CT) domain.

Function
NOV regulates multiple cellular activities including is_associated_with::cell adhesion, migration, proliferation, differentiation, and survival. It functions by direct binding to is_associated_with::integrin receptors,  as well as other receptors such as is_associated_with::NOTCH1 and fibulin 1c (is_associated_with::FBLN1). NOV is expressed during wound healing and induces is_associated_with::angiogenesis in vivo. It is essential for self-renewal of CD34+ is_associated_with::hematopoietic stem cells from umbilical cord blood.

NOV can bind BMP2 and inhibit its functions in promoting is_associated_with::osteogenic differentiation, and stimulate osteoclastogenesis through a process that may involve calcium flux. Overexpression of Nov in transgenic mice in is_associated_with::osteoblasts antagonizes both BMP and Wnt-signaling and result in is_associated_with::osteopenia.

Role in embryo development
In contrast to the lethality of Cyr61 (CCN1) and Ctgf (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 is_associated_with::neointimal thickening when challenged with vascular injury, indicating that NOV inhibits neoinitimal is_associated_with::hyperplasia.

Role in cancer
Although NOV inhibits the proliferation of cancer cells, it appears to promote metastasis. Nov overexpression results in reduced tumor size in is_associated_with::glioma cells is_associated_with::xenografts, 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 is_associated_with::Ewing’s sarcoma, is_associated_with::melanoma, and is_associated_with::breast cancer. In is_associated_with::chronic myeloid leukemia (CML), NOV is downregulated as a consequence of the is_associated_with::kinase activity of BCR-ABL, a is_associated_with::chimeric protein 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.