Abstract
The anthrax toxin receptors—capillary morphogenesis gene 2 (CMG2) and tumor endothelial marker 8 (TEM8)—were identified almost 20 years ago, although few studies have moved beyond their roles as receptors for the anthrax toxins to address their physiological functions. In the last few years, insight into their endogenous roles has come from two rare diseases: hyaline fibromatosis syndrome, caused by mutations in CMG2, and growth retardation, alopecia, pseudo-anodontia, and optic atrophy (GAPO) syndrome, caused by loss-of-function mutations in TEM8. Although CMG2 and TEM8 are highly homologous at the protein level, the difference in disease symptoms points to variations in the physiological roles of the two anthrax receptors. Here, we focus on the similarities between these receptors in their ability to regulate extracellular matrix homeostasis, angiogenesis, cell migration, and skin elasticity. In this way, we shed light on how mutations in these two related proteins cause such seemingly different diseases and we highlight the existing knowledge gaps that could form the focus of future studies.
Highlights
In the early 2000s, two newly discovered proteins—capillary morphogenesis gene 2 (CMG2) and tumor endothelial marker 8 (TEM8)—were demonstrated to be anthrax toxin receptors (ANTXRs)[1,2]
What has helped to drive research into their endogenous roles is that both receptors are associated with recessive autosomal diseases: mutations in CMG2 lead to hyaline fibromatosis syndrome (HFS), whereas mutations in TEM8 result in growth retardation, alopecia, pseudo-anodontia, and optic atrophy (GAPO) syndrome[5,6,7]
In recent years, significant progress has been made in understanding the functions of CMG2 and TEM8 in vertebrates
Summary
In the early 2000s, two newly discovered proteins—capillary morphogenesis gene 2 (CMG2) and tumor endothelial marker 8 (TEM8)—were demonstrated to be anthrax toxin receptors (ANTXRs)[1,2]. For CMG2, there are mixed reports of the effect of its overexpression on cancer progression; some show that lower CMG2 correlated with a more aggressive soft-tissue sarcoma[58] and breast cancer[59], and others reveal that higher CMG2 resulted in a worse survival rate in patients with gastric cancer[60] and glioblastoma[61] These studies link these proteins to angiogenesis, mechanistic explanations of the cancer-related roles of ANTXRs are still lacking. Hu et al recently showed that fibroblasts isolated from older mice deficient in TEM8 have an increased expression of ColI, fibronectin, and the connective tissue growth factor (CTGF)[75] They argue for a cell-autonomous mechanism wherein TEM8 targets CTGF to regulate ECM production, meaning that TEM8-lacking cells have higher CTGF, a higher ECM production that leads to fibrosis[75]. Double-KO mice are viable but produce no pups when mated[76], suggesting that the receptors have non-redundant roles in fertility, embryonic development, or parturition
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