Download Gene Section CTHRC1 (Collagen Triple Helix Repeat Containing 1)

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CTHRC1 (Collagen Triple Helix Repeat Containing 1)
Renee J LeClair, Tahir Durmus, Volkhard Lindner
Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA (RJLC, TD,
VL)
Published in Atlas Database: November 2008
Online updated version : http://AtlasGeneticsOncology.org/Genes/CTHRC1ID40193ch8q22.html
DOI: 10.4267/2042/44579
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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.
Identity
Other names: NMTC1
HGNC (Hugo): CTHRC1
Location: 8q22.3
DNA/RNA
Description
Localisation
CTHRC1 spans 4 exons and is a 1.2 kb transcript.
CTHRC1 has a signal peptide that targets it to the ERGolgi 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.
Protein
Description
Collagen Triple Helix Repeat Containing-1, CTHRC1,
is a 30kDa secreted protein that has the ability to inhibit
collagen matrix synthesis. CTHRC1 is glycosylated
and retains a signal sequence consistent with it being
secreted from the cell. Activity of the protein is reliant
on removal of the propeptide and while CTHRC1 does
not contain a predictable consensus propeptide
cleavage site, there is direct evidence demonstrating the
ability of plasmin to cleave the secreted protein at
residues E46 and R96.
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
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
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
719
CTHRC1 (Collagen Triple Helix Repeat Containing 1)
LeClair R, et al.
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.
inhibits collagen expression and promotes cell migration. Circ
Res. 2005 Feb 4;96(2):261-8
Homology
LeClair R, Lindner V. The role of collagen triple helix repeat
containing 1 in injured arteries, collagen expression, and
transforming growth factor beta signaling. Trends Cardiovasc
Med. 2007 Aug;17(6):202-5
Durmus T, LeClair RJ, Park KS, Terzic A, Yoon JK, Lindner V.
Expression analysis of the novel gene collagen triple helix
repeat containing-1 (Cthrc1). Gene Expr Patterns. 2006
Oct;6(8):935-40
Tang L, Dai DL, Su M, Martinka M, Li G, Zhou Y. Aberrant
expression of collagen triple helix repeat containing 1 in human
solid cancers. Clin Cancer Res. 2006 Jun 15;12(12):3716-22
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.
LeClair RJ, Durmus T, Wang Q, Pyagay P, Terzic A, Lindner
V. Cthrc1 is a novel inhibitor of transforming growth factor-beta
signaling and neointimal lesion formation. Circ Res. 2007 Mar
30;100(6):826-33
Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova
M, Ehrmann J, Klein J, Fridman E, Skarda J, Srovnal J,
Hajduch M, Murray P, Kolar Z. Novel markers for differentiation
of lobular and ductal invasive breast carcinomas by laser
microdissection and microarray analysis. BMC Cancer. 2007
Mar 27;7:55
Wu YT, Liu RH, Yang Y, Luo YQ, Rong Y. [Construction of a
subtracted cDNA library of chronic intermittent hypoxia rabbit
liver by suppression subtractive hybridization]. Zhong Nan Da
Xue Xue Bao Yi Xue Ban. 2007 Dec;32(6):1013-9
Implicated in
Breast cancer
Kang BY, Tsoi S, Zhu S, Su S, Kay HH. Differential gene
expression profiling in HELLP syndrome placentas. Reprod
Sci. 2008 Apr;15(3):285-94
Disease
Lobular carcinoma and invasive ductal carcinoma.
Prognosis
Undetermined. Suggested that CTHRC1 expression in
these tumors is associated with cancer tissue invasion
and metastasis.
Kelley MW. Leading Wnt down a PCP path: Cthrc1 acts as a
coreceptor in the Wnt-PCP pathway. Dev Cell. 2008
Jul;15(1):7-8
Kimura H, Kwan KM, Zhang Z, Deng JM, Darnay BG,
Behringer RR, Nakamura T, de Crombrugghe B, Akiyama H.
Cthrc1 is a positive regulator of osteoblastic bone formation.
PLoS One. 2008 Sep 9;3(9):e3174
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.
Leclair RJ, Wang Q, Benson MA, Prudovsky I, Lindner V.
Intracellular localization of Cthrc1 characterizes differentiated
smooth muscle. Arterioscler Thromb Vasc Biol. 2008
Jul;28(7):1332-8
Yamamoto S, Nishimura O, Misaki K, Nishita M, Minami Y,
Yonemura S, Tarui H, Sasaki H. Cthrc1 selectively activates
the planar cell polarity pathway of Wnt signaling by stabilizing
the Wnt-receptor complex. Dev Cell. 2008 Jul;15(1):23-36
References
This article should be referenced as such:
Pyagay P, Heroult M, Wang Q, Lehnert W, Belden J, Liaw L,
Friesel RE, Lindner V. Collagen triple helix repeat containing 1,
a novel secreted protein in injured and diseased arteries,
LeClair R, Durmus T, Lindner V. CTHRC1 (Collagen Triple
Helix Repeat Containing 1). Atlas Genet Cytogenet Oncol
Haematol. 2009; 13(10):719-720.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
720