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WNT1-inducible-signaling pathway protein 1

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CCN4
Identifiers
AliasesCCN4, WISP1c, WISP1i, WISP1tc, WNT1 inducible signaling pathway protein 1, WISP1-OT1, WISP1-UT1, cellular communication network factor 4, WISP1
External IDsOMIM: 603398; MGI: 1197008; HomoloGene: 2883; GeneCards: CCN4; OMA:CCN4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

8840

22402

Ensembl

ENSG00000104415

ENSMUSG00000005124

UniProt

O95388

O54775

RefSeq (mRNA)

NM_001204869
NM_001204870
NM_003882
NM_080838

NM_018865

RefSeq (protein)

NP_001191798
NP_001191799
NP_003873
NP_543028

NP_061353

Location (UCSC)Chr 8: 133.19 – 133.23 MbChr 15: 66.76 – 66.8 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

Structure

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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]

Role in bone development

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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.

Clinical significance

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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.

Cancer

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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]

Pulmonary fibrosis

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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]

Cardiac fibrosis

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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]

Myocardial injury

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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]

Intimal thickening

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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]

Atherosclerosis

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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]

Aortic aneurysm

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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]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000104415 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000005124 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c Jun JI, Lau LF (December 2011). "Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets". Nature Reviews. Drug Discovery. 10 (12): 945–963. doi:10.1038/nrd3599. PMC 3663145. PMID 22129992.
  6. ^ Brigstock DR, Goldschmeding R, Katsube KI, Lam SC, Lau LF, Lyons K, et al. (April 2003). "Proposal for a unified CCN nomenclature". Molecular Pathology. 56 (2): 127–128. doi:10.1136/mp.56.2.127. PMC 1187305. PMID 12665631.
  7. ^ Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, et al. (December 1998). "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. Bibcode:1998PNAS...9514717P. doi:10.1073/pnas.95.25.14717. PMC 24515. PMID 9843955.
  8. ^ "Entrez Gene: WISP1 WNT1 inducible signaling pathway protein 1".
  9. ^ Chen CC, Lau LF (April 2009). "Functions and mechanisms of action of CCN matricellular proteins". The International Journal of Biochemistry & Cell Biology. 41 (4): 771–783. doi:10.1016/j.biocel.2008.07.025. PMC 2668982. PMID 18775791.
  10. ^ Holbourn KP, Acharya KR, Perbal B (October 2008). "The CCN family of proteins: structure-function relationships". Trends in Biochemical Sciences. 33 (10): 461–473. doi:10.1016/j.tibs.2008.07.006. PMC 2683937. PMID 18789696.
  11. ^ Leask A, Abraham DJ (December 2006). "All in the CCN family: essential matricellular signaling modulators emerge from the bunker". Journal of Cell Science. 119 (Pt 23): 4803–4810. doi:10.1242/jcs.03270. PMID 17130294. S2CID 334940.
  12. ^ French DM, Kaul RJ, D'Souza AL, Crowley CW, Bao M, Frantz GD, et al. (September 2004). "WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair". The American Journal of Pathology. 165 (3): 855–867. doi:10.1016/S0002-9440(10)63348-2. PMC 1618601. PMID 15331410.
  13. ^ Ono M, Inkson CA, Kilts TM, Young MF (January 2011). "WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity". Journal of Bone and Mineral Research. 26 (1): 193–208. doi:10.1002/jbmr.205. PMC 3179320. PMID 20684029.
  14. ^ Desnoyers L, Arnott D, Pennica D (December 2001). "WISP-1 binds to decorin and biglycan". The Journal of Biological Chemistry. 276 (50): 47599–47607. doi:10.1074/jbc.M108339200. PMID 11598131.
  15. ^ a b c Liu H, Dong W, Lin Z, Lu J, Wan H, Zhou Z, et al. (August 2013). "CCN4 regulates vascular smooth muscle cell migration and proliferation". Molecules and Cells. 36 (2): 112–118. doi:10.1007/s10059-013-0012-2. PMC 3887954. PMID 23807044.
  16. ^ a b c d Williams H, Mill CA, Monk BA, Hulin-Curtis S, Johnson JL, George SJ (July 2016). "Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration". Arteriosclerosis, Thrombosis, and Vascular Biology. 36 (7): 1417–1424. doi:10.1161/ATVBAHA.116.307626. PMID 27199447.
  17. ^ Liu H, Dong W, Lin Z, Lu J, Wan H, Zhou Z, et al. (August 2013). "CCN4 regulates vascular smooth muscle cell migration and proliferation". Molecules and Cells. 36 (2): 112–118. doi:10.1007/s10059-013-0012-2. PMC 3887954. PMID 23807044.
  18. ^ a b c d Mill C, Monk BA, Williams H, Simmonds SJ, Jeremy JY, Johnson JL, et al. (November 2014). "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. doi:10.1161/ATVBAHA.114.303922. PMID 25212236.
  19. ^ a b c Williams H, Wadey KS, Frankow A, Blythe HC, Forbes T, Johnson JL, et al. (September 2021). "Aneurysm severity is suppressed by deletion of CCN4". Journal of Cell Communication and Signaling. 15 (3): 421–432. doi:10.1007/s12079-021-00623-5. PMC 8222476. PMID 34080128.
  20. ^ a b Li Z, Williams H, Jackson ML, Johnson JL, George SJ (June 2024). "WISP-1 Regulates Cardiac Fibrosis by Promoting Cardiac Fibroblasts' Activation and Collagen Processing". Cells. 13 (11): 989. doi:10.3390/cells13110989. PMC 11172092. PMID 38891121.
  21. ^ Chiang KC, Yeh CN, Chung LC, Feng TH, Sun CC, Chen MF, et al. (March 2015). "WNT-1 inducible signaling pathway protein-1 enhances growth and tumorigenesis in human breast cancer". Scientific Reports. 5 (1): 8686. Bibcode:2015NatSR...5E8686C. doi:10.1038/srep08686. PMC 4346832. PMID 25732125.
  22. ^ Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ (March 2000). "WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene". Genes & Development. 14 (5): 585–595. doi:10.1101/gad.14.5.585. PMC 316421. PMID 10716946.
  23. ^ Kim Y, Kim KH, Lee J, Lee YA, Kim M, Lee SJ, et al. (March 2012). "Wnt activation is implicated in glioblastoma radioresistance". Laboratory Investigation; A Journal of Technical Methods and Pathology. 92 (3): 466–473. doi:10.1038/labinvest.2011.161. PMID 22083670.
  24. ^ Xie D, Nakachi K, Wang H, Elashoff R, Koeffler HP (December 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): 8917–8923. PMID 11751417.
  25. ^ Tian C, Zhou ZG, Meng WJ, Sun XF, Yu YY, Li L, et al. (July 2007). "Overexpression of connective tissue growth factor WISP-1 in Chinese primary rectal cancer patients". World Journal of Gastroenterology. 13 (28): 3878–3882. doi:10.3748/wjg.v13.i28.3878. PMC 4611224. PMID 17657846.
  26. ^ Chen PP, Li WJ, Wang Y, Zhao S, Li DY, Feng LY, et al. (June 2007). "Expression of Cyr61, CTGF, and WISP-1 correlates with clinical features of lung cancer". PLOS ONE. 2 (6): e534. Bibcode:2007PLoSO...2..534C. doi:10.1371/journal.pone.0000534. PMC 1888724. PMID 17579708. Open access icon
  27. ^ Hashimoto Y, Shindo-Okada N, Tani M, Nagamachi Y, Takeuchi K, Shiroishi T, et al. (February 1998). "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. doi:10.1084/jem.187.3.289. PMC 2212122. PMID 9449709.
  28. ^ Soon LL, Yie TA, Shvarts A, Levine AJ, Su F, Tchou-Wong KM (March 2003). "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. doi:10.1074/jbc.M210945200. PMID 12529380.
  29. ^ Tanaka S, Sugimachi K, Saeki H, Kinoshita J, Ohga T, Shimada M, et al. (September 2001). "A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in scirrhous gastric carcinoma". Oncogene. 20 (39): 5525–5532. doi:10.1038/sj.onc.1204723. PMID 11571650. S2CID 19149969.
  30. ^ a b Königshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, et al. (April 2009). "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. doi:10.1172/JCI33950. PMC 2662540. PMID 19287097.
  31. ^ Su F, Overholtzer M, Besser D, Levine AJ (January 2002). "WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase". Genes & Development. 16 (1): 46–57. doi:10.1101/gad.942902. PMC 155313. PMID 11782444.
  32. ^ Venkatachalam K, Venkatesan B, Valente AJ, Melby PC, Nandish S, Reusch JE, et al. (May 2009). "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. doi:10.1074/jbc.M809757200. PMC 2682890. PMID 19339243.
  33. ^ Bentzon JF, Otsuka F, Virmani R, Falk E (June 2014). "Mechanisms of plaque formation and rupture". Circulation Research. 114 (12): 1852–1866. doi:10.1161/CIRCRESAHA.114.302721. PMID 24902970.
  34. ^ Williams H, Simmonds S, Bond A, Somos A, Li Z, Forbes T, et al. (October 2024). "CCN4 (WISP-1) reduces apoptosis and atherosclerotic plaque burden in an ApoE mouse model". Atherosclerosis. 397: 118570. doi:10.1016/j.atherosclerosis.2024.118570. PMID 39276419.
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