WNT1-inducible-signaling pathway protein 1 (WISP-1),[5] also known as CCN4, is a
matricellular protein that in humans is encoded by the WISP1gene.[6][7]
Structure
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][8][9][10]
Role in bone development
WISP-1 promotes
mesenchymal cell proliferation and
osteoblastic differentiation, and represses
chondrocytic differentiation.[11] WISP-1 binds
BMP2 and enhances BMP2 function in
osteogenesis.[12] These activities may be modulated by its direct binding to
decorin and
biglycan,[13] two members of a family of small leucine-rich
proteoglycans present in the extracellular matrix of connective tissue.
Clinical significance
WISP-1 attenuates
p53-mediated
apoptosis in response to
DNA damage through activation of the
Akt kinase,[14] and inhibits
TNF-induced cell death in cardiomyocytes.[15] 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
idiopathicpulmonary fibrosis and in a mouse model of bleomycin-induced lung fibrosis.[16] Orotracheal application of WISP-1 neutralizing antibodies to the lung ameliorates
bleomycin-induced lung fibrosis,[16] raising the possibility that WISP-1 might be a potential target for anti-fibrotic therapy.[5]
Expression of WISP-1 promotes tumor growth,[17] and high WISP-1 expression correlates with advanced tumors of the brain, breast, colon, and lung.[18][19][20][21] WISP-1 appears to inhibit
metastasis[22][23] although expression of a WISP-1 splicing variant lacking the VWC domain appears to enhance the invasive characteristic of
gastric carcinoma cells.[24]
^Leask A, Abraham DJ (Dec 2006). "All in the CCN family: essential matricellular signaling modulators emerge from the bunker". Journal of Cell Science. 119 (Pt 23): 4803–10.
doi:
10.1242/jcs.03270.
PMID17130294.
S2CID334940.
^Xie D, Nakachi K, Wang H, Elashoff R, Koeffler HP (Dec 2001). "Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features". Cancer Research. 61 (24): 8917–23.
PMID11751417.
^Tanaka S, Sugimachi K, Saeki H, Kinoshita J, Ohga T, Shimada M, Maehara Y, Sugimachi K (Sep 2001). "A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in scirrhous gastric carcinoma". Oncogene. 20 (39): 5525–32.
doi:
10.1038/sj.onc.1204723.
PMID11571650.
S2CID19149969.