WNT1-inducible-signaling pathway protein 1

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WNT1 inducible signaling pathway protein 1
Symbols WISP1 ; CCN4; WISP1c; WISP1i; WISP1tc
External IDs OMIM603398 MGI1197008 HomoloGene2883 GeneCards: WISP1 Gene
RNA expression pattern
PBB GE WISP1 206796 at tn.png
PBB GE WISP1 211312 s at tn.png
More reference expression data
Species Human Mouse
Entrez 8840 22402
Ensembl ENSG00000270132 ENSMUSG00000005124
UniProt O95388 O54775
RefSeq (mRNA) NM_001204869 NM_018865
RefSeq (protein) NP_001191798 NP_061353
Location (UCSC) Chr 8:
134.24 – 134.24 Mb
Chr 15:
66.89 – 66.92 Mb
PubMed search [1] [2]

WNT1-inducible-signaling pathway protein 1 (WISP-1),[1] also known as CCN4, is a matricellular protein that in humans is encoded by the WISP1 gene.[2][3]


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][4][5][6]

Role in bone development[edit]

WISP-1 promotes mesenchymal cell proliferation and osteoblastic differentiation, and represses chondrocytic differentiation.[7] WISP-1 binds BMP2 and enhances BMP2 function in osteogenesis.[8] These activities may be modulated by its direct binding to decorin and biglycan,[9] two members of a family of small leucine-rich proteoglycans present in the extracellular matrix of connective tissue.

Clinical significance[edit]

WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase,[10] and inhibits TNF-induced cell death in cardiomyocytes.[11] 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 pulmonary fibrosis and in a mouse model of bleomycin-induced lung fibrosis.[12] Orotracheal application of WISP-1 neutralizing antibodies to the lung ameliorates bleomycin-induced lung fibrosis,[12] raising the possibility that WISP-1 might be a potential target for anti-fibrotic therapy.[1]

Expression of WISP-1 promotes tumor growth,[13] and high WISP-1 expression correlates with advanced tumors of the breast, colon, and lung.[14][15][16] WISP-1 appears to inhibit metastasis[17][18] although expression of a WISP-1 splicing variant lacking the VWC domain appears to enhance the invasive characteristic of gastric carcinoma cells.[19]


  1. ^ a b c Jun JI, Lau LF (December 2011). "Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets". Nat Rev Drug Discov 10 (12): 945–63. doi:10.1038/nrd3599. PMID 22129992. 
  2. ^ 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 (Jan 1999). "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". Proc Natl Acad Sci U S A 95 (25): 14717–22. doi:10.1073/pnas.95.25.14717. PMC 24515. PMID 9843955. 
  3. ^ "Entrez Gene: WISP1 WNT1 inducible signaling pathway protein 1". 
  4. ^ Chen CC, Lau LF (April 2009). "Functions and mechanisms of action of CCN matricellular proteins". Int. J. Biochem. Cell Biol. 41 (4): 771–83. doi:10.1016/j.biocel.2008.07.025. PMC 2668982. PMID 18775791. 
  5. ^ Holbourn KP, Acharya KR, Perbal B (October 2008). "The CCN family of proteins: structure-function relationships". Trends Biochem. Sci. 33 (10): 461–73. doi:10.1016/j.tibs.2008.07.006. PMC 2683937. PMID 18789696. 
  6. ^ Leask A, Abraham DJ (December 2006). "All in the CCN family: essential matricellular signaling modulators emerge from the bunker". J. Cell. Sci. 119 (Pt 23): 4803–10. doi:10.1242/jcs.03270. PMID 17130294. 
  7. ^ French DM, Kaul RJ, D'Souza AL, Crowley CW, Bao M, Frantz GD, Filvaroff EH, Desnoyers L (September 2004). "WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair". Am. J. Pathol. 165 (3): 855–67. doi:10.1016/S0002-9440(10)63348-2. PMC 1618601. PMID 15331410. 
  8. ^ Ono M, Inkson CA, Kilts TM, Young MF (January 2011). "WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity". J. Bone Miner. Res. 26 (1): 193–208. doi:10.1002/jbmr.205. PMC 3179320. PMID 20684029. 
  9. ^ Desnoyers L, Arnott D, Pennica D (December 2001). "WISP-1 binds to decorin and biglycan". J. Biol. Chem. 276 (50): 47599–607. doi:10.1074/jbc.M108339200. PMID 11598131. 
  10. ^ 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 Dev. 16 (1): 46–57. doi:10.1101/gad.942902. PMC 155313. PMID 11782444. 
  11. ^ Venkatachalam K, Venkatesan B, Valente AJ, Melby PC, Nandish S, Reusch JE, Clark RA, Chandrasekar B (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". J. Biol. Chem. 284 (21): 14414–27. doi:10.1074/jbc.M809757200. PMC 2682890. PMID 19339243. 
  12. ^ a b Königshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, Rose F, Fink L, Seeger W, Schaefer L, Günther A, Eickelberg O (April 2009). "WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis". J. Clin. Invest. 119 (4): 772–87. doi:10.1172/JCI33950. PMC 2662540. PMID 19287097. 
  13. ^ Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ (March 2000). "WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene". Genes Dev. 14 (5): 585–95. PMC 316421. PMID 10716946. 
  14. ^ 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 Res. 61 (24): 8917–23. PMID 11751417. 
  15. ^ Tian C, Zhou ZG, Meng WJ, Sun XF, Yu YY, Li L, Luo HZ, Yang L, Zhou B, Gu J (July 2007). "Overexpression of connective tissue growth factor WISP-1 in Chinese primary rectal cancer patients". World J. Gastroenterol. 13 (28): 3878–82. PMID 17657846. 
  16. ^ Chen PP, Li WJ, Wang Y, Zhao S, Li DY, Feng LY, Shi XL, Koeffler HP, Tong XJ, Xie D (2007). "Expression of Cyr61, CTGF, and WISP-1 correlates with clinical features of lung cancer". PLoS ONE 2 (6): e534. doi:10.1371/journal.pone.0000534. PMC 1888724. PMID 17579708. 
  17. ^ Hashimoto Y, Shindo-Okada N, Tani M, Nagamachi Y, Takeuchi K, Shiroishi T, Toma H, Yokota J (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". J. Exp. Med. 187 (3): 289–96. doi:10.1084/jem.187.3.289. PMC 2212122. PMID 9449709. 
  18. ^ 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". J. Biol. Chem. 278 (13): 11465–70. doi:10.1074/jbc.M210945200. PMID 12529380. 
  19. ^ Tanaka S, Sugimachi K, Saeki H, Kinoshita J, Ohga T, Shimada M, Maehara Y, Sugimachi K (September 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. PMID 11571650.