The dark sides of capillary morphogenesis gene 2

Ecole Polytechnique Fédérale de Lausanne, Institute of Global Health, Lausanne, Switzerland.
The EMBO Journal (Impact Factor: 10.43). 11/2011; 31(1):3-13. DOI: 10.1038/emboj.2011.442
Source: PubMed


Capillary morphogenesis gene 2 (CMG2) is a type I membrane protein involved in the homeostasis of the extracellular matrix. While it shares interesting similarities with integrins, its exact molecular role is unknown. The interest and knowledge about CMG2 largely stems from the fact that it is involved in two diseases, one infectious and one genetic. CMG2 is the main receptor of the anthrax toxin, and knocking out this gene in mice renders them insensitive to infection with Bacillus anthracis spores. On the other hand, mutations in CMG2 lead to a rare but severe autosomal recessive disorder in humans called Hyaline Fibromatosis Syndrome (HFS). We will here review what is known about the structure of CMG2 and its ability to mediate anthrax toxin entry into cell. We will then describe the limited knowledge available concerning the physiological role of CMG2. Finally, we will describe HFS and the consequences of HFS-associated mutations in CMG2 at the molecular and cellular level.


Available from: Francoise Gisou van der Goot
  • Source
    • "Furthermore, TEM8 and CMG2 receptors play a role in epithelial and endothelial cell functions, so that mutations of TEM8 and CMG2 lead to very rare diseases, whose pathological mechanism is still largely unknown (Deuquet et al., 2011). TEM8 is involved in the regulation of expression of vascular endothelial growth factor receptors (VEGFRs), playing a role in angiogenesis that, in turn, is detrimental in cancer progression (Deuquet et al., 2011). CMG2 is involved in the regulation cytoskeleton structure and might have a role in cancer spreading (Cryan and Rogers, 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Anthrax toxin comprises three different proteins, jointly acting to exert toxic activity: a non-toxic protective agent (PA), toxic edema factor (EF), and lethal factor (LF). Binding of PA to anthrax receptors promotes oligomerization of PA, binding of EF and LF, and then endocytosis of the complex. Homomeric forms of PA, complexes of PA bound to LF and to the endogenous receptor capillary morphogenesis gene 2 (CMG2) were analyzed. In this work, we characterized protein–protein interfaces (PPIs) and identified key residues at PPIs of complexes, by means of a protein contact network (PCN) approach. Flexibility and global and local topological properties of each PCN were computed. The vulnerability of each PCN was calculated using different node removal strategies, with reference to specific PCN topological descriptors, such as participation coefficient, contact order, and degree. The participation coefficient P, the topological descriptor of the node's ability to intervene in protein inter-module communication, was the key descriptor of PCN vulnerability of all structures. High P residues were localized both at PPIs and other regions of complexes, so that we argued an allosteric mechanism in protein–protein interactions. The identification of residues, with key role in the stability of PPIs, has a huge potential in the development of new drugs, which would be designed to target not only PPIs but also residues localized in allosteric regions of supramolecular complexes.
    Frontiers in Bioengineering and Biotechnology 10/2015; 3(1 Pt 1). DOI:10.3389/fbioe.2015.00170
  • Source
    • "ANTXR2 is not associated with AS in the Han Chinese,49 and the minor allele frequency was too low to analyze this in Koreans. Anthrax toxin-receptor 2 could potentially affect new bone formation, as it is a membrane-bound molecule that can interact with low-density lipoprotein receptor-related protein (LRP)-6.50 LRP6 is an important surface receptor in the Wnt/β–catenin pathway, and thus can affect osteoblastic activity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ankylosing spondylitis (AS) is a complex disease involving multiple risk factors, both genetic and environmental. AS patients are predominantly young men, and the disease is characterized by inflammation and ankylosis, mainly at the cartilage-bone interface and enthesis. HLA-B27 has been known to be the major AS-susceptibility gene for more than 40 years. Despite advances made in the past few years, progress in the search for non-human leukocyte antigen susceptibility genes has been hampered by the heterogeneity of the disease. Compared to other complex diseases, such as inflammatory bowel disease (IBD), fewer susceptibility loci have been identified in AS. Furthermore, non-major histocompatibility-complex susceptibility loci discovered, such as ERAP1 and IL23R, are likely contributors to joint inflammation. Identification and confirmation of functional variants remains a significant challenge of investigations involving genome-wide association studies (GWAS). It remains unclear why none of the AS-susceptibility genes identified in GWAS appear to be directly involved in the ankylosing process. Numerous reviews have recently been published on the genetics of AS. Therefore, aside from a brief summary of what AS GWAS has successfully achieved thus far, this review will focus on directions that could address unanswered questions raised by GWAS.
    The Application of Clinical Genetics 05/2014; 7:105-15. DOI:10.2147/TACG.S37325
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The outcome of exposure to infectious microbes or their toxins is influenced by both microbial and host genes. Some host genes encode defense mechanisms, whereas others assist pathogen functions. Genomic analyses have associated host gene mutations with altered infectious disease susceptibility, but evidence for causality is limited. Here we demonstrate that human genetic variation affecting capillary morphogenesis gene 2 (CMG2), which encodes a host membrane protein exploited by anthrax toxin as a principal receptor, dramatically alters toxin sensitivity. Lymphoblastoid cells derived from a HapMap Project cohort of 234 persons of African, European, or Asian ancestry differed in sensitivity mediated by the protective antigen (PA) moiety of anthrax toxin by more than four orders of magnitude, with 99% of the cohort showing a 250-fold range of sensitivity. We find that relative sensitivity is an inherited trait that correlates strongly with CMG2 mRNA abundance in cells of each ethnic/geographical group and in the combined population pool (P = 4 × 10(-11)). The extent of CMG2 expression in transfected murine macrophages and human lymphoblastoid cells affected anthrax toxin binding, internalization, and sensitivity. A CMG2 single-nucleotide polymorphism (SNP) occurring frequently in African and European populations independently altered toxin uptake, but was not statistically associated with altered sensitivity in HapMap cell populations. Our results reveal extensive human diversity in cell lethality dependent on PA-mediated toxin binding and uptake, and identify individual differences in CMG2 expression level as a determinant of this diversity. Testing of genomically characterized human cell populations may offer a broadly useful strategy for elucidating effects of genetic variation on infectious disease susceptibility.
    Proceedings of the National Academy of Sciences 02/2012; 109(8):2972-7. DOI:10.1073/pnas.1121006109 · 9.67 Impact Factor
Show more