Biology:WNT1-inducible-signaling pathway protein 1

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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]

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.[1][4][5][6]

Role in bone development

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

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 brain, breast, colon, and lung.[14][15][16][17] WISP-1 appears to inhibit metastasis[18][19] although expression of a WISP-1 splicing variant lacking the VWC domain appears to enhance the invasive characteristic of gastric carcinoma cells.[20]

References

  1. ↑ 1.0 1.1 1.2 "Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets". Nature Reviews. Drug Discovery 10 (12): 945–63. Dec 2011. doi:10.1038/nrd3599. PMID 22129992. 
  2. ↑ "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): 14717–22. Dec 1998. doi:10.1073/pnas.95.25.14717. PMID 9843955. Bibcode: 1998PNAS...9514717P. 
  3. ↑ "Entrez Gene: WISP1 WNT1 inducible signaling pathway protein 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8840. 
  4. ↑ "Functions and mechanisms of action of CCN matricellular proteins". The International Journal of Biochemistry & Cell Biology 41 (4): 771–83. Apr 2009. doi:10.1016/j.biocel.2008.07.025. PMID 18775791. 
  5. ↑ "The CCN family of proteins: structure-function relationships". Trends in Biochemical Sciences 33 (10): 461–73. Oct 2008. doi:10.1016/j.tibs.2008.07.006. PMID 18789696. 
  6. ↑ "All in the CCN family: essential matricellular signaling modulators emerge from the bunker". Journal of Cell Science 119 (Pt 23): 4803–10. Dec 2006. doi:10.1242/jcs.03270. PMID 17130294. 
  7. ↑ "WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair". The American Journal of Pathology 165 (3): 855–67. Sep 2004. doi:10.1016/S0002-9440(10)63348-2. PMID 15331410. 
  8. ↑ "WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity". Journal of Bone and Mineral Research 26 (1): 193–208. Jan 2011. doi:10.1002/jbmr.205. PMID 20684029. 
  9. ↑ "WISP-1 binds to decorin and biglycan". The Journal of Biological Chemistry 276 (50): 47599–607. Dec 2001. doi:10.1074/jbc.M108339200. PMID 11598131. 
  10. ↑ "WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase". Genes & Development 16 (1): 46–57. Jan 2002. doi:10.1101/gad.942902. PMID 11782444. 
  11. ↑ "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): 14414–27. May 2009. doi:10.1074/jbc.M809757200. PMID 19339243. 
  12. ↑ 12.0 12.1 "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): 772–87. Apr 2009. doi:10.1172/JCI33950. PMID 19287097. 
  13. ↑ "WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene". Genes & Development 14 (5): 585–95. Mar 2000. doi:10.1101/gad.14.5.585. PMID 10716946. 
  14. ↑ "Wnt activation is implicated in glioblastoma radioresistance". Laboratory Investigation 92 (3): 466–73. Mar 2012. doi:10.1038/labinvest.2011.161. PMID 22083670. 
  15. ↑ "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. Dec 2001. PMID 11751417. 
  16. ↑ "Overexpression of connective tissue growth factor WISP-1 in Chinese primary rectal cancer patients". World Journal of Gastroenterology 13 (28): 3878–82. Jul 2007. doi:10.3748/wjg.v13.i28.3878. PMID 17657846. 
  17. ↑ "Expression of Cyr61, CTGF, and WISP-1 correlates with clinical features of lung cancer". PLOS ONE 2 (6): e534. 2007. doi:10.1371/journal.pone.0000534. PMID 17579708. Bibcode: 2007PLoSO...2..534C.  open access
  18. ↑ "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): 289–96. Feb 1998. doi:10.1084/jem.187.3.289. PMID 9449709. 
  19. ↑ "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): 11465–70. Mar 2003. doi:10.1074/jbc.M210945200. PMID 12529380. 
  20. ↑ "A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in scirrhous gastric carcinoma". Oncogene 20 (39): 5525–32. Sep 2001. doi:10.1038/sj.onc.1204723. PMID 11571650. 




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