WNT1-inducible-signaling pathway protein 1 explained

WNT1-inducible-signaling pathway protein 1 (WISP-1),[1] is a member of the CCN protein family and should correctly be referred to as CCN4 as suggested by the International CCN Society.[2] It is a matricellular protein that in humans is encoded by the WISP1 gene.[3] [4]

Structure

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.[1] [5] [6] [7]

Role in bone development

CCN4/WISP-1 promotes mesenchymal cell proliferation and osteoblastic differentiation, and represses chondrocytic differentiation.[8] WISP-1 binds BMP2 and enhances BMP2 function in osteogenesis.[9] These activities may be modulated by its direct binding to decorin and biglycan,[10] two members of a family of small leucine-rich proteoglycans present in the extracellular matrix of connective tissue.

Clinical significance

In cells CCN4 has a range of actions including stimulating cell migration[11] [12] and cell proliferation[13] and is a pro-survival factor.[14] These effects appear to be conserved across a range of cell types including vascular smooth muscle cells, monocytes,[15] fibroblasts[16] and cancer cell lines.[17] The effects are also preserved across species from mouse and rat to human cells studied in vitro.

Cancer

Expression of CCN4 promotes tumor growth,[18] and high CCN4 expression correlates with advanced tumors of the brain, breast, colon, and lung.[19] [20] [21] [22] CCN4 appears to inhibit metastasis[23] [24] although expression of a CCN4 splicing variant lacking the VWC domain appears to enhance the invasive characteristic of gastric carcinoma cells.[25]

Pulmonary fibrosis

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.[26]

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.

Cardiac fibrosis

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.

Myocardial injury

CCN4 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase,[27] and inhibits TNF-induced cell death in cardiomyocytes.[28]

Intimal thickening

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.

Atherosclerosis

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.[29] 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.[30]

Aortic aneurysm

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.

Notes and References

  1. Jun JI, Lau LF . Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets . Nature Reviews. Drug Discovery . 10 . 12 . 945–963 . December 2011 . 22129992 . 3663145 . 10.1038/nrd3599 .
  2. Brigstock DR, Goldschmeding R, Katsube KI, Lam SC, Lau LF, Lyons K, Naus C, Perbal B, Riser B, Takigawa M, Yeger H . Proposal for a unified CCN nomenclature . Molecular Pathology . 56 . 2 . 127–128 . April 2003 . 12665631 . 1187305 . 10.1136/mp.56.2.127 .
  3. Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M, Watanabe C, Cohen RL, Melhem MF, Finley GG, Quirke P, Goddard AD, Hillan KJ, Gurney AL, Botstein D, Levine AJ . WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors . Proceedings of the National Academy of Sciences of the United States of America . 95 . 25 . 14717–14722 . December 1998 . 9843955 . 24515 . 10.1073/pnas.95.25.14717 . free . 1998PNAS...9514717P .
  4. Web site: Entrez Gene: WISP1 WNT1 inducible signaling pathway protein 1.
  5. Chen CC, Lau LF . Functions and mechanisms of action of CCN matricellular proteins . The International Journal of Biochemistry & Cell Biology . 41 . 4 . 771–783 . April 2009 . 18775791 . 2668982 . 10.1016/j.biocel.2008.07.025 .
  6. Holbourn KP, Acharya KR, Perbal B . The CCN family of proteins: structure-function relationships . Trends in Biochemical Sciences . 33 . 10 . 461–473 . October 2008 . 18789696 . 2683937 . 10.1016/j.tibs.2008.07.006 .
  7. Leask A, Abraham DJ . All in the CCN family: essential matricellular signaling modulators emerge from the bunker . Journal of Cell Science . 119 . Pt 23 . 4803–4810 . December 2006 . 17130294 . 10.1242/jcs.03270 . 334940 .
  8. French DM, Kaul RJ, D'Souza AL, Crowley CW, Bao M, Frantz GD, Filvaroff EH, Desnoyers L . WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair . The American Journal of Pathology . 165 . 3 . 855–867 . September 2004 . 15331410 . 1618601 . 10.1016/S0002-9440(10)63348-2 .
  9. Ono M, Inkson CA, Kilts TM, Young MF . WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity . Journal of Bone and Mineral Research . 26 . 1 . 193–208 . January 2011 . 20684029 . 3179320 . 10.1002/jbmr.205 .
  10. Desnoyers L, Arnott D, Pennica D . WISP-1 binds to decorin and biglycan . The Journal of Biological Chemistry . 276 . 50 . 47599–47607 . December 2001 . 11598131 . 10.1074/jbc.M108339200 . free .
  11. Liu H, Dong W, Lin Z, Lu J, Wan H, Zhou Z, Liu Z . CCN4 regulates vascular smooth muscle cell migration and proliferation . Molecules and Cells . 36 . 2 . 112–118 . August 2013 . 23807044 . 3887954 . 10.1007/s10059-013-0012-2 .
  12. Williams H, Mill CA, Monk BA, Hulin-Curtis S, Johnson JL, George SJ . Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration . Arteriosclerosis, Thrombosis, and Vascular Biology . 36 . 7 . 1417–1424 . July 2016 . 27199447 . 10.1161/ATVBAHA.116.307626 .
  13. Liu H, Dong W, Lin Z, Lu J, Wan H, Zhou Z, Liu Z . CCN4 regulates vascular smooth muscle cell migration and proliferation . Molecules and Cells . 36 . 2 . 112–118 . August 2013 . 23807044 . 3887954 . 10.1007/s10059-013-0012-2 .
  14. Mill C, Monk BA, Williams H, Simmonds SJ, Jeremy JY, Johnson JL, George SJ . Wnt5a-induced Wnt1-inducible secreted protein-1 suppresses vascular smooth muscle cell apoptosis induced by oxidative stress . Arteriosclerosis, Thrombosis, and Vascular Biology . 34 . 11 . 2449–2456 . November 2014 . 25212236 . 10.1161/ATVBAHA.114.303922 .
  15. Williams H, Wadey KS, Frankow A, Blythe HC, Forbes T, Johnson JL, George SJ . September 2021 . Aneurysm severity is suppressed by deletion of CCN4 . Journal of Cell Communication and Signaling . 15 . 3 . 421–432 . 10.1007/s12079-021-00623-5 . 8222476 . 34080128.
  16. Li Z, Williams H, Jackson ML, Johnson JL, George SJ . WISP-1 Regulates Cardiac Fibrosis by Promoting Cardiac Fibroblasts' Activation and Collagen Processing . Cells . 13 . 11 . 989 . June 2024 . 38891121 . 11172092 . 10.3390/cells13110989 . free .
  17. Chiang KC, Yeh CN, Chung LC, Feng TH, Sun CC, Chen MF, Jan YY, Yeh TS, Chen SC, Juang HH . WNT-1 inducible signaling pathway protein-1 enhances growth and tumorigenesis in human breast cancer . Scientific Reports . 5 . 1 . 8686 . March 2015 . 25732125 . 4346832 . 10.1038/srep08686 . 2015NatSR...5E8686C .
  18. Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ . WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene . Genes & Development . 14 . 5 . 585–595 . March 2000 . 10716946 . 316421 . 10.1101/gad.14.5.585 .
  19. Kim Y, Kim KH, Lee J, Lee YA, Kim M, Lee SJ, Park K, Yang H, Jin J, Joo KM, Lee J, Nam DH . Wnt activation is implicated in glioblastoma radioresistance . Laboratory Investigation; A Journal of Technical Methods and Pathology . 92 . 3 . 466–473 . March 2012 . 22083670 . 10.1038/labinvest.2011.161 . free .
  20. Xie D, Nakachi K, Wang H, Elashoff R, Koeffler HP . Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features . Cancer Research . 61 . 24 . 8917–8923 . December 2001 . 11751417 .
  21. Tian C, Zhou ZG, Meng WJ, Sun XF, Yu YY, Li L, Luo HZ, Yang L, Zhou B, Gu J . Overexpression of connective tissue growth factor WISP-1 in Chinese primary rectal cancer patients . World Journal of Gastroenterology . 13 . 28 . 3878–3882 . July 2007 . 17657846 . 4611224 . 10.3748/wjg.v13.i28.3878 . free .
  22. Chen PP, Li WJ, Wang Y, Zhao S, Li DY, Feng LY, Shi XL, Koeffler HP, Tong XJ, Xie D . Expression of Cyr61, CTGF, and WISP-1 correlates with clinical features of lung cancer . PLOS ONE . 2 . 6 . e534 . June 2007 . 17579708 . 1888724 . 10.1371/journal.pone.0000534 . 2007PLoSO...2..534C . free .
  23. Hashimoto Y, Shindo-Okada N, Tani M, Nagamachi Y, Takeuchi K, Shiroishi T, Toma H, Yokota J . 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 . The Journal of Experimental Medicine . 187 . 3 . 289–296 . February 1998 . 9449709 . 2212122 . 10.1084/jem.187.3.289 .
  24. Soon LL, Yie TA, Shvarts A, Levine AJ, Su F, Tchou-Wong KM . Overexpression of WISP-1 down-regulated motility and invasion of lung cancer cells through inhibition of Rac activation . The Journal of Biological Chemistry . 278 . 13 . 11465–11470 . March 2003 . 12529380 . 10.1074/jbc.M210945200 . free .
  25. Tanaka S, Sugimachi K, Saeki H, Kinoshita J, Ohga T, Shimada M, Maehara Y, Sugimachi K . A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in scirrhous gastric carcinoma . Oncogene . 20 . 39 . 5525–5532 . September 2001 . 11571650 . 10.1038/sj.onc.1204723 . 19149969 .
  26. Königshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, Rose F, Fink L, Seeger W, Schaefer L, Günther A, Eickelberg O . WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis . The Journal of Clinical Investigation . 119 . 4 . 772–787 . April 2009 . 19287097 . 2662540 . 10.1172/JCI33950 .
  27. Su F, Overholtzer M, Besser D, Levine AJ . WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase . Genes & Development . 16 . 1 . 46–57 . January 2002 . 11782444 . 155313 . 10.1101/gad.942902 .
  28. Venkatachalam K, Venkatesan B, Valente AJ, Melby PC, Nandish S, Reusch JE, Clark RA, Chandrasekar B . 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 . The Journal of Biological Chemistry . 284 . 21 . 14414–14427 . May 2009 . 19339243 . 2682890 . 10.1074/jbc.M809757200 . free .
  29. Bentzon JF, Otsuka F, Virmani R, Falk E . Mechanisms of plaque formation and rupture . Circulation Research . 114 . 12 . 1852–1866 . June 2014 . 24902970 . 10.1161/CIRCRESAHA.114.302721 .
  30. 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 . CCN4 (WISP-1) reduces apoptosis and atherosclerotic plaque burden in an ApoE mouse model . Atherosclerosis . 397 . 118570 . October 2024 . 39276419 . 10.1016/j.atherosclerosis.2024.118570 . free .

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