NOV (nephroblastoma overexpressed) also known as CCN3 is a matricellular protein that in humans is encoded by the NOV gene. [5] [6]
NOV (nephroblastoma overexpressed) also known as CCN3 is a matricellular protein that in humans is encoded by the NOV gene. [5] [6]
NOV is a member of the CCN family of secreted, extracellular matrix (ECM)-associated signaling proteins (see also CCN intercellular signaling protein). [7] [8] The CCN acronym is derived from the first three members of the family being identified, namely CYR61 (cysteine-rich angiogenic inducer 61, or CCN1), CTGF (connective tissue growth factor, or CCN2), and NOV. These proteins, together with WISP1 (CCN4), WISP2 (CCN5), and 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. [9]
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 cysteine knot motif within the C-terminal (CT) domain. [10] [11]
NOV regulates multiple cellular activities including cell adhesion, migration, proliferation, differentiation, and survival. It functions by direct binding to integrin receptors, [12] [13] [14] as well as other receptors such as NOTCH1 [15] and fibulin 1c (FBLN1). [16] NOV is expressed during wound healing and induces angiogenesis in vivo. [12] [14] It is essential for self-renewal of CD34+ hematopoietic stem cells from umbilical cord blood. [17] Nov is regulated by the hematopoietic transcription factor MZF-1. [18]
NOV can bind BMP2 and inhibit its functions in promoting osteogenic differentiation, [19] and stimulate osteoclastogenesis through a process that may involve calcium flux. [20] Overexpression of Nov in transgenic mice in osteoblasts antagonizes both BMP and Wnt-signaling and result in osteopenia. [21]
In February 2017, it was reported that the NOV protein was involved in regulatory T cell-mediated oligodendrocyte differentiation in the regeneration of myelin following damage to the myelin sheath. This finding revealed a new function for regulatory T cells that is distinct from their role in immunomodulation. [22] NOV (CCN3) has recently been implicated in mood disorders, notably in the postpartum period; these effects may be mediated by its effects on myelination [23]
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. [24] However, Nov-null mice show enhanced blood vessel neointimal thickening when challenged with vascular injury, indicating that NOV inhibits neoinitimal hyperplasia. [25]
Although NOV inhibits the proliferation of cancer cells, [26] it appears to promote metastasis. [27] [28] Nov overexpression results in reduced tumor size in glioma cells xenografts, [29] but enhances metastatic potential in xenotransplanted melanoma cells. [30] NOV expression is associated with a higher risk of metastasis and worse prognosis in patients with cancers such as Ewing's sarcoma, melanoma, and breast cancer. [31] In chronic myeloid leukemia (CML), NOV is downregulated as a consequence of the kinase activity of BCR-ABL, a chimeric protein generated through the chromosomal translocation between chromosome 9 and 22. [32] 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. [7] [33]
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