View source for WNT1-inducible-signaling pathway protein 1

{{Infobox_gene}}
'''WNT1-inducible-signaling pathway protein 1''' (WISP-1),<ref name="Jun_Lau_2011">{{cite journal | vauthors = Jun JI, Lau LF | title = Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 12 | pages = 945–63 | date = Dec 2011 | pmid = 22129992 | doi = 10.1038/nrd3599 | pmc = 3663145 }}</ref> also known as  '''CCN4''', is a [[matricellular protein]] that in humans is encoded by the ''WISP1'' [[gene]].<ref name="pmid9843955">{{cite journal | vauthors = 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 | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 25 | pages = 14717–22 | date = Dec 1998 | pmid = 9843955 | pmc = 24515 | doi = 10.1073/pnas.95.25.14717 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: WISP1 WNT1 inducible signaling pathway protein 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8840| accessdate = }}</ref>

== 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 ([[insulin-like growth factor-binding protein|IGFBP]]), von Willebrand type C repeats ([[Von Willebrand factor type C domain|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]], [[cell migration|migration]], [[cell proliferation|proliferation]], [[cell differentiation|differentiation]], and survival.<ref name="Jun_Lau_2011"/><ref name="pmid18775791">{{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 = 771–83 | date = Apr 2009 | pmid = 18775791 | pmc = 2668982 | doi = 10.1016/j.biocel.2008.07.025 }}</ref><ref name="pmid18789696">{{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 = 461–73 | date = Oct 2008 | pmid = 18789696 | pmc = 2683937 | doi = 10.1016/j.tibs.2008.07.006 }}</ref><ref name="pmid17130294">{{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 = 4803–10 | date = Dec 2006 | pmid = 17130294 | doi = 10.1242/jcs.03270 }}</ref>

== Role in bone development ==

WISP-1 promotes [[mesenchymal]] cell proliferation and [[osteoblastic]] differentiation, and represses [[chondrocyte|chondrocytic]] differentiation.<ref name="pmid15331410">{{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 = 855–67 | date = Sep 2004 | pmid = 15331410 | pmc = 1618601 | doi = 10.1016/S0002-9440(10)63348-2 }}</ref> WISP-1 binds [[bone morphogenetic protein 2|BMP2]] and enhances BMP2 function in [[osteogenesis]].<ref name="pmid20684029">{{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 = Jan 2011 | pmid = 20684029 | pmc = 3179320 | doi = 10.1002/jbmr.205 }}</ref> These activities may be modulated by its direct binding to [[decorin]] and [[biglycan]],<ref name="pmid11598131">{{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 = 47599–607 | date = Dec 2001 | pmid = 11598131 | doi = 10.1074/jbc.M108339200 }}</ref> two members of a family of small leucine-rich [[proteoglycan]]s 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|Akt kinase]],<ref name="pmid11782444">{{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 = Jan 2002 | pmid = 11782444 | pmc = 155313 | doi = 10.1101/gad.942902 }}</ref> and inhibits [[TNF]]-induced cell death in cardiomyocytes.<ref name="pmid19339243">{{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 = 14414–27 | date = May 2009 | pmid = 19339243 | pmc = 2682890 | doi = 10.1074/jbc.M809757200 }}</ref> 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.<ref name="Königshoff_2009">{{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 = 772–87 | date = Apr 2009 | pmid = 19287097 | pmc = 2662540 | doi = 10.1172/JCI33950 }}</ref> Orotracheal application of WISP-1 neutralizing antibodies to the lung ameliorates [[bleomycin]]-induced lung fibrosis,<ref name="Königshoff_2009"/> raising the possibility that WISP-1 might be a potential target for anti-fibrotic therapy.<ref name="Jun_Lau_2011"/>

Expression of WISP-1 promotes tumor growth,<ref name="pmid10716946">{{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 = 585–95 | date = Mar 2000 | pmid = 10716946 | pmc = 316421 | doi =  }}</ref> and high WISP-1 expression correlates with advanced tumors of the brain, breast, colon, and lung.<ref>{{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 | volume = 92 | issue = 3 | pages = 466–73 | date = Mar 2012 | pmid = 22083670 | doi = 10.1038/labinvest.2011.161 }}</ref><ref name="pmid11751417">{{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 = 8917–23 | date = Dec 2001 | pmid = 11751417 | doi =  }}</ref><ref name="pmid17657846">{{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 = 3878–82 | date = Jul 2007 | pmid = 17657846 | doi = 10.3748/wjg.v13.i28.3878 }}</ref><ref name="pmid17579708">{{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 | year = 2007 | pmid = 17579708 | pmc = 1888724 | doi = 10.1371/journal.pone.0000534 }} {{open access}}</ref> WISP-1 appears to inhibit [[metastasis]]<ref name="pmid9449709">{{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 = 289–96 | date = Feb 1998 | pmid = 9449709 | pmc = 2212122 | doi = 10.1084/jem.187.3.289 }}</ref><ref name="pmid12529380">{{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 = 11465–70 | date = Mar 2003 | pmid = 12529380 | doi = 10.1074/jbc.M210945200 }}</ref> although expression of a WISP-1 splicing variant lacking the VWC domain appears to enhance the invasive characteristic of [[gastric carcinoma]] cells.<ref name="pmid11571650">{{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 = 5525–32 | date = Sep 2001 | pmid = 11571650 | doi = 10.1038/sj.onc.1204723 }}</ref>
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== References ==
{{reflist|33em}}

[[Category:CCN proteins]]