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WISP3 (WNT-1 inducible signaling pathway protein 3)

Written2005-03Celina G Kleer, Lei Ding
Department of Pathology, 2G332 University Hospital, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0054, USA

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Wnt1 signaling pathway protein 3
LocusID (NCBI) 8838
Atlas_Id 469
Location 6q21  [Link to chromosome band 6q21]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


Description 5 exons spanning 967kb of genomic
Transcription Alternative splicing generates at least three transcript variants, their sizes are 1212bp, 1307 bp and 1068 bp


Description WISP3 contains four conserved cysteine-rich domains: insulin-like growth factor-binding domain, von Willebrand factor type C module, thrombospondin domain and C-terminal cystine knot-like domain. It has three isoforms: 1) variant 1, 354 aa, 39292 Da; 2) variant 2, 331 aa, This variant differs from variant 1 in two regions. It has an alternate 5' end which results in a different N-terminus. It also uses two alternative donor and acceptor sites in the middle coding region which result in a few internal aa differences between variant 1 and 2. 3) variant 3, 372 aa, This variant differs in the 5' UTR and CDS, compared to variant 1. The resulting protein is longer and has a distinct N-terminus, compared to variant 1.
Expression Predominant expression in adult kidney and testis and fetal kidney. Weaker expression found in placenta, ovary, prostate and small intestine. Also expressed in skeletally-derived cells such as synoviocytes and articular cartilage chondrocytes.
Localisation Secreted (Probable).
Function It is a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the connective tissue growth factor (CTGF) family and may be downstream in the WNT1 signaling pathway that is relevant to malignant transformation. It is over-expressed in colon tumors. It is essential for normal postnatal skeletal growth and cartilage homeostasis. It acts as a putative growth regulator contributing to the inflammatory breast cancer by regulating tumor cell growth, invasion and angiogenesis.
Homology Wnt1-inducible signaling proteins


Germinal Various types of mutations have been described, dispersed throughout the gene, including nucleotide substitutions, small deletions and small insertions. There are patients who are compound heterozygous, heterozygous or homozygous. The mutations cause progressive pseudorheumatoid dysplasia.
Somatic Somatic mutations that cause reading frameshifts at a polyadenosine tract within the WISP3 coding sequence have been observed at higher-than-expected rates in gastrointestinal tumors from patients with mutations in the mismatch repair pathway.

Implicated in

Entity Arthropathy, progressive pseudorheumatoid, of childhood
Disease Mutations in the WISP3 gene result in an arthropathy of childhood beginning at about age 3-8. Usually several joints were affected with pain and soft tissue swelling. The proximal interphalangeal joints of the hand were most commonly affected and the hips and elbows next most often involved.
Entity Inflammatory breast cancer
Oncogenesis Loss of WISP3 is one of the key genetic alterations in the development of IBC.
Entity Rheumatoid arthritis
Entity Colon cancer
Oncogenesis Frameshifts, non-sense mutations and non-synonymous changes involving cysteines or affect a splice-donor site.


The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.
Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A
Genome research. 2003 ; 13 (10) : 2265-2270.
PMID 12975309
Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia.
Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Furga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV, Rezai-Delui H, Legius E, Le Merrer M, Al-Alami J, Bahabri SA, Warman ML
Nature genetics. 1999 ; 23 (1) : 94-98.
PMID 10471507
WISP3 (CCN6) is a secreted tumor-suppressor protein that modulates IGF signaling in inflammatory breast cancer.
Kleer CG, Zhang Y, Pan Q, Merajver SD
Neoplasia (New York, N.Y.). 2004 ; 6 (2) : 179-185.
PMID 15140407
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.
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
Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (25) : 14717-14722.
PMID 9843955
WISP3-dependent regulation of type II collagen and aggrecan production in chondrocytes.
Sen M, Cheng YH, Goldring MB, Lotz MK, Carson DA
Arthritis and rheumatism. 2004 ; 50 (2) : 488-497.
PMID 14872491
Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.
Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Mammalian Gene Collection Program Team, Marra MA
Proceedings of the National Academy of Sciences of the United States of America. 2002 ; 99 (26) : 16899-16903.
PMID 12477932
Variant WISPs as targets for gastrointestinal carcinomas.
Tanaka S, Sugimachi K, Shimada M, Maehara Y, Sugimachi K
Gastroenterology. 2002 ; 123 (1) : 392-393.
PMID 12105881
WNT1 inducible signaling pathway protein 3, WISP-3, a novel target gene in colorectal carcinomas with microsatellite instability.
Thorstensen L, Diep CB, Meling GI, Aagesen TH, Ahrens CH, Rognum TO, Lothe RA
Gastroenterology. 2001 ; 121 (6) : 1275-1280.
PMID 11729105
A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype.
van Golen KL, Davies S, Wu ZF, Wang Y, Bucana CD, Root H, Chandrasekharappa S, Strawderman M, Ethier SP, Merajver SD
Clinical cancer research : an official journal of the American Association for Cancer Research. 1999 ; 5 (9) : 2511-2519.
PMID 10499627


This paper should be referenced as such :
Kleer, CG ; Ding, L
WISP3 (wnt-1 inducible signaling pathway protein 3)
Atlas Genet Cytogenet Oncol Haematol. 2005;9(2):145-146.
Free journal version : [ pdf ]   [ DOI ]

External links

Atlas Explorer : (Salamanque)
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
BioGPS (Tissue expression)8838
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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