WNT1-inducible-signaling pathway protein 1 (WISP-1), [5] is a member of the CCN protein family and should correctly be referred to as CCN4 as suggested by the International CCN Society. [6] It is a matricellular protein that in humans is encoded by the WISP1 gene. [7] [8]
CCN4/WISP-1 is highly homologous to CYR61 (CCN1) and CTGF (CCN2), and is a member of the CCN family of secreted, extracellular matrix (ECM)-associated signaling proteins (CCN intercellular signaling protein). The CCN family of proteins shares a common molecular protein structure, characterized by an N-terminal secretory signal peptide followed by four 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. This family of proteins regulates diverse cellular functions, including cell adhesion, migration, proliferation, differentiation, and survival. [5] [9] [10] [11]
CCN4/WISP-1 promotes mesenchymal cell proliferation and osteoblastic differentiation, and represses chondrocytic differentiation. [12] WISP-1 binds BMP2 and enhances BMP2 function in osteogenesis. [13] These activities may be modulated by its direct binding to decorin and biglycan, [14] two members of a family of small leucine-rich proteoglycans present in the extracellular matrix of connective tissue.
In cells CCN4 has a range of actions including stimulating cell migration [15] [16] and cell proliferation [17] and is a pro-survival factor. [18] These effects appear to be conserved across a range of cell types including vascular smooth muscle cells, [15] [16] [18] monocytes, [19] fibroblasts [20] and cancer cell lines. [21] The effects are also preserved across species from mouse [16] [18] and rat [15] to human [19] cells studied in vitro.
Expression of CCN4 promotes tumor growth, [22] and high CCN4 expression correlates with advanced tumors of the brain, breast, colon, and lung. [23] [24] [25] [26] CCN4 appears to inhibit metastasis [27] [28] although expression of a CCN4 splicing variant lacking the VWC domain appears to enhance the invasive characteristic of gastric carcinoma cells. [29]
Recombinant CCN4 enhances ECM deposition in human fibroblasts, suggesting that it might play a role in matrix remodeling in vivo. WISP-1 is upregulated in human patients with idiopathic pulmonary fibrosis and in a mouse model of bleomycin-induced lung fibrosis. [30]
Orotracheal application of CCN4 neutralizing antibodies to the lung ameliorates bleomycin-induced lung fibrosis, [30] raising the possibility that CCN4 might be a potential target for anti-fibrotic therapy. [5]
CCN4 activates human cardiac fibroblasts via integrin β1-Akt signaling pathway to induce collagen deposition and promote fibrosis. In a mouse model of cardiac fibrosis deletion of the CCN4 gene reduced the severity of fibrosis. [20]
CCN4 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase, [31] and inhibits TNF-induced cell death in cardiomyocytes. [32]
In a mouse carotid artery ligation model of intimal thickening, deletion of the CCN4 gene reduced intimal thickening, while elevation of CCN4 using an adenovirus increased intimal thickening. Knocking out the CCN4 gene reduced the number of proliferating cells. Mouse aortic vascular smooth muscle cells in tissue culture addition of CCN4 increased cell migration and this effect was integrin dependent. [16]
In samples from atherosclerotic human coronary arteries unstable plaques had lower CCN4 compared to stable plaques. [18] Loss of CCN4 resulted in more apoptosis, leading to loss of the plaque fibrous cap, increased lipid core size and more unstable plaque phenotype. Rupture of these unstable plaques can lead to plaque growth via incorporation of thrombus into a new layer of plaque. [33] Using the high fat fed ApoE mouse model of atherosclerosis (created by Jan Breslow), elevation of CCN4 using helper dependent adenovirus reduced apoptosis, number of macrophages and lipid core size and reduced atherosclerosis. Knocking out the CCN4 gene increased apoptosis and the severity of atherosclerosis. [34]
In a mouse model of aortic aneurysm CCN4 increased the severity of aneurysms and increased cell proliferation in the wall of the aorta. Human blood monocytes in vitro migrated more following the addition of CCN4; and adhesion of the monocytes to a layer of human umbilical vein endothelial cells was also increased. [19]
In molecular genetics, the Krüppel-like family of transcription factors (KLFs) are a set of eukaryotic C2H2 zinc finger DNA-binding proteins that regulate gene expression. This family has been expanded to also include the Sp transcription factor and related proteins, forming the Sp/KLF family.
Bone morphogenetic protein 6 is a protein that in humans is encoded by the BMP6 gene.
The activin A receptor also known as ACVR1C or ALK-7 is a protein that in humans is encoded by the ACVR1C gene. ACVR1C is a type I receptor for the TGFB family of signaling molecules.
Interleukin 20 (IL20) is a protein that is in humans encoded by the IL20 gene which is located in close proximity to the IL-10 gene on the 1q32 chromosome. IL-20 is a part of an IL-20 subfamily which is a part of a larger IL-10 family.
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. CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.
Sphingosine-1-phosphate (S1P) is a signaling sphingolipid, also known as lysosphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.
Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP-11), is a protein that in humans is encoded by the growth differentiation factor 11 gene. GDF11 is a member of the Transforming growth factor beta family.
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.
Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene. LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.
P2Y purinoceptor 2 is a protein that in humans is encoded by the P2RY2 gene.
Angiotensin II receptor type 2, also known as the AT2 receptor is a protein that in humans is encoded by the AGTR2 gene.
CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.
NOV also known as CCN3 is a matricellular protein that in humans is encoded by the NOV gene.
Allograft inflammatory factor 1 (AIF-1) also known as ionized calcium-binding adapter molecule 1 (IBA1) is a protein that in humans is encoded by the AIF1 gene.
Tumor necrosis factor receptor superfamily member 12A also known as the TWEAK receptor (TWEAKR) is a protein that in humans is encoded by the TNFRSF12A gene.
Fibroblast growth factor 18 (FGF-18) is a protein that is encoded by the FGF18 gene in humans. The protein was first discovered in 1998, when two newly-identified murine genes Fgf17 and Fgf18 were described and confirmed as being closely related by sequence homology to Fgf8. The three proteins were eventually grouped into the FGF8 subfamily, which contains several of the endocrine FGF superfamily members FGF8, FGF17, and FGF18. Subsequent studies identified FGF18's role in promoting chondrogenesis, and an apparent specific activity for the generation of the hyaline cartilage in articular joints.
WNT1-inducible-signaling pathway protein 3 is a matricellular protein that in humans is encoded by the WISP3 gene.
WNT1-inducible-signaling pathway protein 2, or WISP-2 is a matricellular protein that in humans is encoded by the WISP2 gene.
Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.
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.
