Protein NOV homolog, also known as Nephroblastoma-overexpressed gene protein homolog, NOV, and CCN3, is a putative ligand for integrin receptors, is tightly associated with the extracellular matrix, and mediates diverse cellular functions, including cell adhesion and proliferation. CCN3 has been shown to negatively regulate growth althoμgh it promotes migration in a cell type-specific manner. This secreted protein belongs to the CCN family, and its expression was observed in a broad variety of tissues from the early stage of development, and altered expression of CCN3 has been observed in a variety of tumors, including hepatocellular carcinomas, Wilm's tumors, Ewing's sarcomas, gliomas, rhabdomyosarcomas, and adrenocortical carcinomas. Mature CCN3 protein has five distinct modules and truncated protein variants with altered function are found in many cancers. CCN3 acts throμgh the core stem cell signaling pathways including Notch and Bone Morphogenic Protein, connecting CCN3 with the modulation of self-renewal and maturation of some cell lineages including hematopoietic, osteogenic, and chondrogenic. CCN3 may affect the extracellular environment of the niche for hematopoietic stem cells. CCN3 has emerged as a key player in stem cell regulation, hematopoiesis, and a crucial component within the bone marrow microenvironment.
NOV, also called CCN3, is a secreted protein of CCN family members. CCN family members are highly conserved cysteine rich proteins sharing a common modular structure having 4 conserved domains, insulin-like growth factor-binding protein (IGFBP) domain, von Willebrand type C (VWC) domain, thrombospondin-1 (TSP-1) domain, and C-terminal (CT) domain (absent in CCN5). By specific interactions with these domains, CCN proteins modulate multiple signalling pathways including BMPs, Wnt, TGFs, Notch and integrins to regulate cell proliferation, differentiation, adhesion, migration, angiogenesis, and survival. CCN3 is firstly characterized as a promoter of progenitor activity of human hematopoietic stem cells, as knockdown of CCN3 can abrogate the function of primitive progenitors. Recent studies showed that CCN3 is also actively involved in the process of wound healing. CCN3 is highly expressed in granulation tissues of cutaneous wounds and capable of inducing synthetic responses of fibroblasts.
Neuregulin 1 or NRG1 is one of four proteins in the neuregulin family that act on the EGFR family of receptors. This growth factor was originally identified as a 44-kD glycoprotein that interacts with the NEU / ERBB2 receptor tyrosine kinase to increase its phosphorylation on tyrosine residues. NRG1 is a trophic factor that has been implicated in neural development, neurotransmission, and synaptic plasticity. NRG1 has multiple isoforms that are generated by the usage of different promoters and alternative splicing of a single gene. Neuregulin 1 (NRG1) is essential for the development and function of multiple organ systems, and its dysregulation has been linked to diseases such as cancer and schizophrenia. NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. Schizophrenia is a complex disorder, with etiology likely due to epistasis.
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