WNT1-inducible-signaling pathway protein 1 (WISP-1), also known as CCN4, 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 ''WISP1''

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 ...

Structure

WISP-1 is highly homologous to

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 ...

(CCN2), and 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 (

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 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 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. This family of proteins regulates diverse cellular functions, 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.

Role in bone development

WISP-1 promotes

mesenchymal Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every o ...

cell proliferation and

osteoblastic Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts function ...

differentiation, and represses chondrocytic differentiation. WISP-1 binds BMP2 and enhances BMP2 function in

osteogenesis Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts function ...

. These activities may be modulated by its direct binding to

decorin Decorin is a protein that in humans is encoded by the ''DCN'' gene. Decorin is a proteoglycan that is on average 90 - 140 kilodaltons (kDa) in molecular weight. It belongs to the small leucine-rich proteoglycan (SLRP) family and consists of a p ...

and

biglycan Biglycan is a small leucine-rich repeat proteoglycan (SLRP) which is found in a variety of extracellular matrix tissues, including bone, cartilage and tendon. In humans, biglycan is encoded by the ''BGN'' gene which is located on the X chromosome ...

, two members of a family of small leucine-rich

proteoglycan Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to whic ...

s present in the extracellular matrix of connective tissue.

Clinical significance

WISP-1 attenuates

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

-mediated

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

in response to

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

through activation of the Akt kinase, and inhibits

TNF Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

-induced cell death in cardiomyocytes. Recombinant WISP-1 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 An idiopathic disease is any disease with an unknown cause or mechanism of apparent wikt:spontaneous, spontaneous origin. From Ancient Greek, Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approxi ...

pulmonary fibrosis Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory failu ...

and in a mouse model of bleomycin-induced lung fibrosis. Orotracheal application of WISP-1 neutralizing antibodies to the lung ameliorates

bleomycin -13- (1''H''-imidazol-5-yl)methyl9-hydroxy-5- 1''R'')-1-hydroxyethyl8,10-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazapentadec-1-yl}-2,4'-bi-1,3-thiazol-4-yl)carbonyl]amino}propyl)(dimethyl)sulfonium , chemical_formula = , C=55 , H=84 , N=1 ...

-induced lung fibrosis, raising the possibility that WISP-1 might be a potential target for anti-fibrotic therapy. Expression of WISP-1 promotes tumor growth, and high WISP-1 expression correlates with advanced tumors of the brain, breast, colon, and lung. WISP-1 appears to inhibit

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

although expression of a WISP-1 splicing variant lacking the VWC domain appears to enhance the invasive characteristic of

gastric carcinoma Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...

cells.

References

{{reflist, 33em CCN proteins