WNT1-inducible-signaling pathway protein 1

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.{{cite journal | vauthors = Chen CC, Lau LF | title = Functions and mechanisms of action of CCN matricellular proteins | journal = The International Journal of Biochemistry & Cell Biology | volume = 41 | issue = 4 | pages = 771–783 | date = April 2009 | pmid = 18775791 | pmc = 2668982 | doi = 10.1016/j.biocel.2008.07.025 }}{{cite journal | vauthors = Holbourn KP, Acharya KR, Perbal B | title = The CCN family of proteins: structure-function relationships | journal = Trends in Biochemical Sciences | volume = 33 | issue = 10 | pages = 461–473 | date = October 2008 | pmid = 18789696 | pmc = 2683937 | doi = 10.1016/j.tibs.2008.07.006 }}{{cite journal | vauthors = Leask A, Abraham DJ | title = All in the CCN family: essential matricellular signaling modulators emerge from the bunker | journal = Journal of Cell Science | volume = 119 | issue = Pt 23 | pages = 4803–4810 | date = December 2006 | pmid = 17130294 | doi = 10.1242/jcs.03270 | s2cid = 334940 | doi-access = }}

CCN4/WISP-1 promotes mesenchymal cell proliferation and osteoblastic differentiation, and represses chondrocytic differentiation.{{cite journal | vauthors = French DM, Kaul RJ, D'Souza AL, Crowley CW, Bao M, Frantz GD, Filvaroff EH, Desnoyers L | title = WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair | journal = The American Journal of Pathology | volume = 165 | issue = 3 | pages = 855–867 | date = September 2004 | pmid = 15331410 | pmc = 1618601 | doi = 10.1016/S0002-9440(10)63348-2 }} WISP-1 binds BMP2 and enhances BMP2 function in osteogenesis.{{cite journal | vauthors = Ono M, Inkson CA, Kilts TM, Young MF | title = WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity | journal = Journal of Bone and Mineral Research | volume = 26 | issue = 1 | pages = 193–208 | date = January 2011 | pmid = 20684029 | pmc = 3179320 | doi = 10.1002/jbmr.205 }} These activities may be modulated by its direct binding to decorin and biglycan,{{cite journal | vauthors = Desnoyers L, Arnott D, Pennica D | title = WISP-1 binds to decorin and biglycan | journal = The Journal of Biological Chemistry | volume = 276 | issue = 50 | pages = 47599–47607 | date = December 2001 | pmid = 11598131 | doi = 10.1074/jbc.M108339200 | doi-access = free }} 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{{cite journal | vauthors = Liu H, Dong W, Lin Z, Lu J, Wan H, Zhou Z, Liu Z | title = CCN4 regulates vascular smooth muscle cell migration and proliferation | journal = Molecules and Cells | volume = 36 | issue = 2 | pages = 112–118 | date = August 2013 | pmid = 23807044 | pmc = 3887954 | doi = 10.1007/s10059-013-0012-2 }}{{cite journal | vauthors = Williams H, Mill CA, Monk BA, Hulin-Curtis S, Johnson JL, George SJ | title = Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 36 | issue = 7 | pages = 1417–1424 | date = July 2016 | pmid = 27199447 | doi = 10.1161/ATVBAHA.116.307626 }} and cell proliferation{{cite journal | vauthors = Liu H, Dong W, Lin Z, Lu J, Wan H, Zhou Z, Liu Z | title = CCN4 regulates vascular smooth muscle cell migration and proliferation | journal = Molecules and Cells | volume = 36 | issue = 2 | pages = 112–118 | date = August 2013 | pmid = 23807044 | pmc = 3887954 | doi = 10.1007/s10059-013-0012-2 }} and is a pro-survival factor.{{cite journal | vauthors = Mill C, Monk BA, Williams H, Simmonds SJ, Jeremy JY, Johnson JL, George SJ | title = Wnt5a-induced Wnt1-inducible secreted protein-1 suppresses vascular smooth muscle cell apoptosis induced by oxidative stress | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 34 | issue = 11 | pages = 2449–2456 | date = November 2014 | pmid = 25212236 | doi = 10.1161/ATVBAHA.114.303922 }} These effects appear to be conserved across a range of cell types including vascular smooth muscle cells, monocytes,{{cite journal |vauthors=Williams H, Wadey KS, Frankow A, Blythe HC, Forbes T, Johnson JL, George SJ |date=September 2021 |title=Aneurysm severity is suppressed by deletion of CCN4 |journal=Journal of Cell Communication and Signaling |volume=15 |issue=3 |pages=421–432 |doi=10.1007/s12079-021-00623-5 |pmc=8222476 |pmid=34080128}} fibroblasts{{cite journal | vauthors = Li Z, Williams H, Jackson ML, Johnson JL, George SJ | title = WISP-1 Regulates Cardiac Fibrosis by Promoting Cardiac Fibroblasts' Activation and Collagen Processing | journal = Cells | volume = 13 | issue = 11 | pages = 989 | date = June 2024 | pmid = 38891121 | pmc = 11172092 | doi = 10.3390/cells13110989 | doi-access = free }} and cancer cell lines.{{cite journal | vauthors = Chiang KC, Yeh CN, Chung LC, Feng TH, Sun CC, Chen MF, Jan YY, Yeh TS, Chen SC, Juang HH | title = WNT-1 inducible signaling pathway protein-1 enhances growth and tumorigenesis in human breast cancer | journal = Scientific Reports | volume = 5 | issue = 1 | pages = 8686 | date = March 2015 | pmid = 25732125 | pmc = 4346832 | doi = 10.1038/srep08686 | bibcode = 2015NatSR...5E8686C }} The effects are also preserved across species from mouse and rat to human cells studied in vitro.

Expression of CCN4 promotes tumor growth,{{cite journal | vauthors = Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ | title = WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene | journal = Genes & Development | volume = 14 | issue = 5 | pages = 585–595 | date = March 2000 | pmid = 10716946 | pmc = 316421 | doi = 10.1101/gad.14.5.585 }} and high CCN4 expression correlates with advanced tumors of the brain, breast, colon, and lung.{{cite journal | vauthors = Kim Y, Kim KH, Lee J, Lee YA, Kim M, Lee SJ, Park K, Yang H, Jin J, Joo KM, Lee J, Nam DH | title = Wnt activation is implicated in glioblastoma radioresistance | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 92 | issue = 3 | pages = 466–473 | date = March 2012 | pmid = 22083670 | doi = 10.1038/labinvest.2011.161 | doi-access = free }}{{cite journal | vauthors = Xie D, Nakachi K, Wang H, Elashoff R, Koeffler HP | title = Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features | journal = Cancer Research | volume = 61 | issue = 24 | pages = 8917–8923 | date = December 2001 | pmid = 11751417 }}{{cite journal | vauthors = Tian C, Zhou ZG, Meng WJ, Sun XF, Yu YY, Li L, Luo HZ, Yang L, Zhou B, Gu J | title = Overexpression of connective tissue growth factor WISP-1 in Chinese primary rectal cancer patients | journal = World Journal of Gastroenterology | volume = 13 | issue = 28 | pages = 3878–3882 | date = July 2007 | pmid = 17657846 | pmc = 4611224 | doi = 10.3748/wjg.v13.i28.3878 | doi-access = free }}{{cite journal | vauthors = Chen PP, Li WJ, Wang Y, Zhao S, Li DY, Feng LY, Shi XL, Koeffler HP, Tong XJ, Xie D | title = Expression of Cyr61, CTGF, and WISP-1 correlates with clinical features of lung cancer | journal = PLOS ONE | volume = 2 | issue = 6 | pages = e534 | date = June 2007 | pmid = 17579708 | pmc = 1888724 | doi = 10.1371/journal.pone.0000534 | bibcode = 2007PLoSO...2..534C | doi-access = free }} {{open access}} CCN4 appears to inhibit metastasis{{cite journal | vauthors = Hashimoto Y, Shindo-Okada N, Tani M, Nagamachi Y, Takeuchi K, Shiroishi T, Toma H, Yokota J | title = Expression of the Elm1 gene, a novel gene of the CCN (connective tissue growth factor, Cyr61/Cef10, and neuroblastoma overexpressed gene) family, suppresses In vivo tumor growth and metastasis of K-1735 murine melanoma cells | journal = The Journal of Experimental Medicine | volume = 187 | issue = 3 | pages = 289–296 | date = February 1998 | pmid = 9449709 | pmc = 2212122 | doi = 10.1084/jem.187.3.289 }}{{cite journal | vauthors = Soon LL, Yie TA, Shvarts A, Levine AJ, Su F, Tchou-Wong KM | title = Overexpression of WISP-1 down-regulated motility and invasion of lung cancer cells through inhibition of Rac activation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 13 | pages = 11465–11470 | date = March 2003 | pmid = 12529380 | doi = 10.1074/jbc.M210945200 | doi-access = free }} although expression of a CCN4 splicing variant lacking the VWC domain appears to enhance the invasive characteristic of gastric carcinoma cells.{{cite journal | vauthors = Tanaka S, Sugimachi K, Saeki H, Kinoshita J, Ohga T, Shimada M, Maehara Y, Sugimachi K | title = A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in scirrhous gastric carcinoma | journal = Oncogene | volume = 20 | issue = 39 | pages = 5525–5532 | date = September 2001 | pmid = 11571650 | doi = 10.1038/sj.onc.1204723 | s2cid = 19149969 | doi-access = }}

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.{{cite journal | vauthors = Königshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, Rose F, Fink L, Seeger W, Schaefer L, Günther A, Eickelberg O | title = WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis | journal = The Journal of Clinical Investigation | volume = 119 | issue = 4 | pages = 772–787 | date = April 2009 | pmid = 19287097 | pmc = 2662540 | doi = 10.1172/JCI33950 }}

Orotracheal application of CCN4 neutralizing antibodies to the lung ameliorates bleomycin-induced lung fibrosis, raising the possibility that CCN4 might be a potential target for anti-fibrotic therapy.

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.

CCN4 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase,{{cite journal | vauthors = Su F, Overholtzer M, Besser D, Levine AJ | title = WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase | journal = Genes & Development | volume = 16 | issue = 1 | pages = 46–57 | date = January 2002 | pmid = 11782444 | pmc = 155313 | doi = 10.1101/gad.942902 }} and inhibits TNF-induced cell death in cardiomyocytes.{{cite journal | vauthors = Venkatachalam K, Venkatesan B, Valente AJ, Melby PC, Nandish S, Reusch JE, Clark RA, Chandrasekar B | title = WISP1, a pro-mitogenic, pro-survival factor, mediates tumor necrosis factor-alpha (TNF-alpha)-stimulated cardiac fibroblast proliferation but inhibits TNF-alpha-induced cardiomyocyte death | journal = The Journal of Biological Chemistry | volume = 284 | issue = 21 | pages = 14414–14427 | date = May 2009 | pmid = 19339243 | pmc = 2682890 | doi = 10.1074/jbc.M809757200 | doi-access = free }}

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.

In samples from atherosclerotic human coronary arteries unstable plaques had lower CCN4 compared to stable plaques. 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.{{cite journal | vauthors = Bentzon JF, Otsuka F, Virmani R, Falk E | title = Mechanisms of plaque formation and rupture | journal = Circulation Research | volume = 114 | issue = 12 | pages = 1852–1866 | date = June 2014 | pmid = 24902970 | doi = 10.1161/CIRCRESAHA.114.302721 }} 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.{{cite journal | vauthors = Williams H, Simmonds S, Bond A, Somos A, Li Z, Forbes T, Bianco R, Dugdale C, Brown Z, Rice H, Herman A, Johnson J, George S | title = CCN4 (WISP-1) reduces apoptosis and atherosclerotic plaque burden in an ApoE mouse model | journal = Atherosclerosis | volume = 397 | pages = 118570 | date = October 2024 | pmid = 39276419 | doi = 10.1016/j.atherosclerosis.2024.118570 | doi-access = free | pmc = 7617386 }}

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.{{Clear}}

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Category:CCN proteins