Dynamic Evolution of the Cthrc1 Genes, a Newly Defined Collagen-Like Family

Abstract

Collagen triple helix repeat containing protein 1 (Cthrc1) is a secreted glycoprotein reported to regulate collagen deposition and to be linked to the Transforming growth factor β/Bone morphogenetic protein and the Wnt/planar cell polarity pathways. It was first identified as being induced upon injury to rat arteries and was found to be highly expressed in multiple human cancer types. Here, we explore the phylogenetic and evolutionary trends of this metazoan gene family, previously studied only in vertebrates. We identify Cthrc1 orthologs in two distant cnidarian species, the sea anemone Nematostella vectensis and the hydrozoan Clytia hemisphaerica, both of which harbor multiple copies of this gene. We find that Cthrc1 clade-specific diversification occurred multiple times in cnidarians as well as in most metazoan clades where we detected this gene. Many other groups, such as arthropods and nematodes, have entirely lost this gene family. Most vertebrates display a single highly conserved gene, and we show that the sequence evolutionary rate of Cthrc1 drastically decreased within the gnathostome lineage. Interestingly, this reduction coincided with the origin of its conserved upstream neighboring gene, Frizzled 6 (FZD6), which in mice has been shown to functionally interact with Cthrc1. Structural modeling methods further reveal that the yet uncharacterized C-terminal domain of Cthrc1 is similar in structure to the globular C1q superfamily domain, also found in the C-termini of collagens VIII and X. Thus, our studies show that the Cthrc1 genes are a collagen-like family with a variable short collagen triple helix domain and a highly conserved C-terminal domain structure resembling the C1q family.

The Role of CTHRC1 in Regulation of Multiple Signaling and Tumor Progression and Metastasis

“…Glycosylated protein CTHRC1 with a signal sequence is related to ECM and contains a variable short collagen-like motif. Intriguingly, CTHRC1 plays a role in inhibiting structural proteins, unlike other members of the collagen family [1,16]. Moreover, Leclair et al found that Cthrc1 cleaved at the N-terminus by plasmin shows better inhibition of collagen synthesis compared to full-length Cthrc1 in the PAC1 cell line [17].…”

A pan-cancer analysis of matrisome proteins reveals CTHRC1and LOXL2 as major ECM regulators across cancers

“…This study in carefully examining the role of the matrisome across cancers, has identified CTHRC1 and LOXL2 as major ECM regulators across cancers. Both play a role in collagen synthesis and assembly [23,28] by possibly interacting with POSTN, MMP13, SFRP4, COL11A1, COL10A1, COL1A1, ADAMTS12 and PPAPDCA1. This suggests the regulation of collagen could be a vital pan-cancer mediator of disease progression.…”

“…CTHRC1 and LOXL2 are both also known regulators of collagen synthesis and assembly [23,28]. Collagen makes up at least 30% of the total protein in the human body [29] and is highly aligned and anisotropic contributing to tumor cell survival and metastasis [30].…”

The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthritis

“…The human protein contains an N-terminal hydrophobic signal peptide of 30 amino acids in length that directs CTHRC1 for secretion, a short collagen triple helix repeat (CTHR) domain consisting of 12 repeats of the Gly-X-Y motif located between amino acids 57 and 93 [ 12 ], and a highly conserved C-terminal domain with structural homology to the globular C1q domain of collagens VIII and X domain ( Figure 1 ) [ 13 ]. The CTHR domain may promote CTHRC1 dimer or trimer formation and mediate interaction with a variety of ligands [ 12 , 13 ]. The domain structure of CTHRC1 is similar to that of adiponectin, which belongs to the C1q/tumor necrosis factor (TNF)-related protein superfamily [ 14 ].…”