WISP3 (WNT-1 inducible signaling pathway protein 3)

2005-03-01   Celina G Kleer , Lei Ding 

Department of Pathology, 2G332 University Hospital, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0054, USA

Identity

HGNC
LOCATION
6q21
LOCUSID
ALIAS
LIBC,PPAC,PPD,PPRD,WISP-3,WISP3

DNA/RNA

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

Proteins

Atlas Image

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

Mutations

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 name
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 name
Inflammatory breast cancer
Oncogenesis
Loss of WISP3 is one of the key genetic alterations in the development of IBC.
Entity name
Rheumatoid arthritis
Oncogenesis
Frameshifts, non-sense mutations and non-synonymous changes involving cysteines or affect a splice-donor site.

Bibliography

Pubmed IDLast YearTitleAuthors
129753092003The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.Clark HF et al
104715071999Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia.Hurvitz JR et al
151404072004WISP3 (CCN6) is a secreted tumor-suppressor protein that modulates IGF signaling in inflammatory breast cancer.Kleer CG et al
98439551998WISP 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 et al
148724912004WISP3-dependent regulation of type II collagen and aggrecan production in chondrocytes.Sen M et al
124779322002Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.Strausberg RL et al
121058812002Variant WISPs as targets for gastrointestinal carcinomas.Tanaka S et al
117291052001WNT1 inducible signaling pathway protein 3, WISP-3, a novel target gene in colorectal carcinomas with microsatellite instability.Thorstensen L et al
104996271999A 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 et al

Citation

Celina G Kleer ; Lei Ding

WISP3 (WNT-1 inducible signaling pathway protein 3)

Atlas Genet Cytogenet Oncol Haematol. 2005-03-01

Online version: http://atlasgeneticsoncology.org/gene/469/wisp3-(wnt-1-inducible-signaling-pathway-protein-3)