Atlas of Genetics and Cytogenetics in Oncology and Haematology

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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

(Note : for Links provided by Atlas : click)


Alias_symbol (synonym)CCN6
Other aliasPPD
Wnt1 signaling pathway protein 3
LocusID (NCBI) 8838
Atlas_Id 469
Location 6q21  [Link to chromosome band 6q21]
Location_base_pair Starts at 112054168 and ends at 112069684 bp from pter ( according to hg19-Feb_2009)  [Mapping WISP3.png]
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 ]
On line version :

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Ovary: Epithelial tumors

External links

HGNC (Hugo)WISP3   12771
Entrez_Gene (NCBI)WISP3  8838  WNT1 inducible signaling pathway protein 3
AliasesCCN6; LIBC; PPAC; PPD; 
GeneCards (Weizmann)WISP3
Ensembl hg19 (Hinxton)ENSG00000112761 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000112761 [Gene_View]  ENSG00000112761 [Sequence]  chr6:112054168-112069684 [Contig_View]  WISP3 [Vega]
ICGC DataPortalENSG00000112761
TCGA cBioPortalWISP3
Genatlas (Paris)WISP3
SOURCE (Princeton)WISP3
Genetics Home Reference (NIH)WISP3
Genomic and cartography
GoldenPath hg38 (UCSC)WISP3  -     chr6:112054168-112069684 +  6q21   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)WISP3  -     6q21   [Description]    (hg19-Feb_2009)
EnsemblWISP3 - 6q21 [CytoView hg19]  WISP3 - 6q21 [CytoView hg38]
Mapping of homologs : NCBIWISP3 [Mapview hg19]  WISP3 [Mapview hg38]
OMIM208230   603400   
Gene and transcription
Genbank (Entrez)AB075040 AF100781 AF143679 AY358349 AY358350
RefSeq transcript (Entrez)NM_003880 NM_130396 NM_198239
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)WISP3
Cluster EST : UnigeneHs.558428 [ NCBI ]
CGAP (NCI)Hs.558428
Alternative Splicing GalleryENSG00000112761
Gene ExpressionWISP3 [ NCBI-GEO ]   WISP3 [ EBI - ARRAY_EXPRESS ]   WISP3 [ SEEK ]   WISP3 [ MEM ]
Gene Expression Viewer (FireBrowse)WISP3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8838
GTEX Portal (Tissue expression)WISP3
Human Protein AtlasENSG00000112761-WISP3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO95389   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO95389  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO95389
Splice isoforms : SwissVarO95389
Domaine pattern : Prosite (Expaxy)CTCK_2 (PS01225)    IGFBP_N_1 (PS00222)    IGFBP_N_2 (PS51323)    TSP1 (PS50092)   
Domains : Interpro (EBI)Cys_knot_C    Glyco_hormone_CN    Growth_fac_rcpt_cys_sf    IGFBP-like    IGFBP_CNN    Insulin_GF-bd_Cys-rich_CS    TSP1_rpt    TSP1_rpt_sf   
Domain families : Pfam (Sanger)Cys_knot (PF00007)    IGFBP (PF00219)   
Domain families : Pfam (NCBI)pfam00007    pfam00219   
Domain families : Smart (EMBL)CT (SM00041)  IB (SM00121)  TSP1 (SM00209)  
Conserved Domain (NCBI)WISP3
DMDM Disease mutations8838
Blocks (Seattle)WISP3
Human Protein Atlas [tissue]ENSG00000112761-WISP3 [tissue]
Peptide AtlasO95389
IPIIPI00022051   IPI00419732   IPI00383246   IPI00412939   IPI00917794   IPI00515003   IPI01010374   
Protein Interaction databases
IntAct (EBI)O95389
Ontologies - Pathways
Ontology : AmiGOregulation of cell growth  integrin binding  insulin-like growth factor binding  extracellular space  endoplasmic reticulum  cell adhesion  signal transduction  signal transduction  cell-cell signaling  growth factor activity  heparin binding  regulation of signaling receptor activity  negative regulation of cell death  
Ontology : EGO-EBIregulation of cell growth  integrin binding  insulin-like growth factor binding  extracellular space  endoplasmic reticulum  cell adhesion  signal transduction  signal transduction  cell-cell signaling  growth factor activity  heparin binding  regulation of signaling receptor activity  negative regulation of cell death  
NDEx NetworkWISP3
Atlas of Cancer Signalling NetworkWISP3
Wikipedia pathwaysWISP3
Orthology - Evolution
GeneTree (enSembl)ENSG00000112761
Phylogenetic Trees/Animal Genes : TreeFamWISP3
Homologs : HomoloGeneWISP3
Homology/Alignments : Family Browser (UCSC)WISP3
Gene fusions - Rearrangements
Fusion : QuiverWISP3
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerWISP3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)WISP3
Exome Variant ServerWISP3
ExAC (Exome Aggregation Consortium)ENSG00000112761
GNOMAD BrowserENSG00000112761
Varsome BrowserWISP3
Genetic variants : HAPMAP8838
Genomic Variants (DGV)WISP3 [DGVbeta]
DECIPHERWISP3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisWISP3 
ICGC Data PortalWISP3 
TCGA Data PortalWISP3 
Broad Tumor PortalWISP3
OASIS PortalWISP3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICWISP3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDWISP3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch WISP3
DgiDB (Drug Gene Interaction Database)WISP3
DoCM (Curated mutations)WISP3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)WISP3 (select a term)
NCG5 (London)WISP3
Cancer3DWISP3(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM208230    603400   
Genetic Testing Registry WISP3
NextProtO95389 [Medical]
Target ValidationWISP3
Huge Navigator WISP3 [HugePedia]
snp3D : Map Gene to Disease8838
BioCentury BCIQWISP3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD8838
Chemical/Pharm GKB GenePA37374
Clinical trialWISP3
canSAR (ICR)WISP3 (select the gene name)
PubMed57 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 12 18:18:13 CEST 2018

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