CTHRC1 (Collagen Triple Helix Repeat Containing 1)

2008-11-01   Renee J LeClair , Tahir Durmus , Volkhard Lindner 

Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA

Identity

HGNC
LOCATION
8q22.3
LOCUSID
ALIAS
-

DNA/RNA

Description

CTHRC1 spans 4 exons and is a 1.2 kb transcript.

Proteins

Expression

The expression patterns of Cthrc1 during murine embryonic development and in postnatal tissues have been characterized with in situ hybridization and immunohistochemistry (see Durmus et al., 2007 for a complete review). Cthrc1 expression levels are induced in the adventitia and intimal smooth muscle after balloon catheter injury of arteries. Additionally, Cthrc1 is highly expressed in cartilage and developing bones as well as in myofibroblasts during skin wound healing. Indirect evidence for the expression of Cthrc1 by hair cells of the inner ear has been reported in a Cthrc1 mutant mouse with a beta-galactosidase expression construct replacing the first exon of Cthrc1. Expression of Cthrc1 is increased in fibroblasts and chondrocytic cells in response to TGF-beta family members including BMP4, BMP2 and TGF-beta. Cthrc1 is also upregulated during tumorigenesis and metastasis; its role during this process is unknown.

Localisation

CTHRC1 has a signal peptide that targets it to the ER-Golgi pathway for secretion. In the extracellular environment the molecule is sensitive to cleavage by proteases such as plasmin. While CTHRC1 is abundant in cartilage matrix, the CTHRC1 protein has been observed in the cytoplasm of select cell types such as certain neuronal populations and parafollicular cells of the thyroid gland despite the presence of the signal peptide.

Function

CTHRC1 has been linked to major signaling pathways such as Wnt and TGF-beta. The ability of CTHRC1 to inhibit TGF-beta signaling via a reduction in Smad 2/Smad 3 phosphorylation has been demonstrated both in vivo and in vitro models. This inhibition translates into a reduction in collagen type I deposition during vascular remodeling.
Characterization of Cthrc1 deficient mice indicated that the gene is not essential for normal development. Evidence from in vitro studies suggested that Cthrc1 may play a role in the Planar Cell Polarity (PCP) pathway of non-canonical Wnt signaling. Combinatorial mutations in both Cthrc1 alleles and a single allele of Vangl2, a gene previously shown to be involved in noncanonical Wnt signaling, resulted in animals lacking proper orientation of inner and outer ear hair cells. Further biochemical analysis showed Cthrc1 associated with several of the Frizzled family of receptors suggesting it may stabilize the receptor ligand complex on the cell surface. Cthrc1 deficient mice also demonstrated a reduction in bone density that was attributable to a reduction in osteoblast number and coverage. Mechanistically, it is unclear how this occurs but was shown to be due to a reduction in osteoblast proliferation rather than an increase in osteoclasts.

Homology

CTHRC1 is a unique protein, displaying an extremely high level of conservation among vertebrates, but showing very little homology to other currently known proteins. Structurally, it contains a short collagen-like motif similar to the collagen domains present in the C1q/tumor necrosis factor-a-related proteins (CTRPs). Both CTHRC1 and CTRP members share a conserved and post-translationally modified lysine residue present in the collagen domain, but currently there are no data to suggest that the collagen domain of CTHRC1 leads to trimerization.

Implicated in

Entity name
Breast cancer
Disease
Lobular carcinoma and invasive ductal carcinoma
Prognosis
Undetermined. Suggested that CTHRC1 expression in these tumors is associated with cancer tissue invasion and metastasis.
Entity name
Solid cancers
Disease
Melanomas, cancers of the rectum, small intestine, colon, liver, lung, ovary, breast, thyroid gland and cervix.
Prognosis
CTHRC1 is upregulated in solid tumors. Linked expression levels to prognosis is undetermined.

Bibliography

Pubmed IDLast YearTitleAuthors
166784982006Expression analysis of the novel gene collagen triple helix repeat containing-1 (Cthrc1).Durmus T et al
184210232008Differential gene expression profiling in HELLP syndrome placentas.Kang BY et al
186061352008Leading Wnt down a PCP path: Cthrc1 acts as a coreceptor in the Wnt-PCP pathway.Kelley MW et al
187798652008Cthrc1 is a positive regulator of osteoblastic bone formation.Kimura H et al
176629152007The role of collagen triple helix repeat containing 1 in injured arteries, collagen expression, and transforming growth factor beta signaling.LeClair R et al
173221742007Cthrc1 is a novel inhibitor of transforming growth factor-beta signaling and neointimal lesion formation.LeClair RJ et al
184676472008Intracellular localization of Cthrc1 characterizes differentiated smooth muscle.Leclair RJ et al
156185382005Collagen triple helix repeat containing 1, a novel secreted protein in injured and diseased arteries, inhibits collagen expression and promotes cell migration.Pyagay P et al
167780982006Aberrant expression of collagen triple helix repeat containing 1 in human solid cancers.Tang L et al
173890372007Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis.Turashvili G et al
181827192007[Construction of a subtracted cDNA library of chronic intermittent hypoxia rabbit liver by suppression subtractive hybridization].Wu YT et al
186061382008Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex.Yamamoto S et al

Other Information

Locus ID:

NCBI: 115908
MIM: 610635
HGNC: 18831
Ensembl: ENSG00000164932

Variants:

dbSNP: 115908
ClinVar: 115908
TCGA: ENSG00000164932
COSMIC: CTHRC1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000164932ENST00000330295Q96CG8
ENSG00000164932ENST00000415886E7EVQ5
ENSG00000164932ENST00000520337Q96CG8
ENSG00000164932ENST00000520880E5RK99

Expression (GTEx)

0
50
100
150
200
250
300

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
156185382005Collagen triple helix repeat containing 1, a novel secreted protein in injured and diseased arteries, inhibits collagen expression and promotes cell migration.75
167780982006Aberrant expression of collagen triple helix repeat containing 1 in human solid cancers.62
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.59
247261402014CTHRC1 acts as a prognostic factor and promotes invasiveness of gastrointestinal stromal tumors by activating Wnt/PCP-Rho signaling.36
239229812013Overexpression of CTHRC1 in hepatocellular carcinoma promotes tumor invasion and predicts poor prognosis.34
225909772012CTHRC1 is upregulated by promoter demethylation and transforming growth factor-β1 and may be associated with metastasis in human gastric cancer.33
245041722014Collagen triple helix repeat containing 1 (CTHRC1) acts via ERK-dependent induction of MMP9 to promote invasion of colorectal cancer cells.33
217916902011Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma.30
232228132013Collagen triple helix repeat containing-1 promotes pancreatic cancer progression by regulating migration and adhesion of tumor cells.30
252382602014Overexpression of collagen triple helix repeat containing 1 (CTHRC1) is associated with tumour aggressiveness and poor prognosis in human non-small cell lung cancer.24

Citation

Renee J LeClair ; Tahir Durmus ; Volkhard Lindner

CTHRC1 (Collagen Triple Helix Repeat Containing 1)

Atlas Genet Cytogenet Oncol Haematol. 2008-11-01

Online version: http://atlasgeneticsoncology.org/gene/40193/cthrc1