Antxr2Edit
ANTXR2, also known as capillary morphogenesis gene 2 (CMG2), is a cell-surface receptor that plays a dual role in human biology: it serves as one of the receptors for Bacillus anthracis protective antigen (PA), enabling the intracellular delivery of the toxin components edema factor (EF) and lethal factor (LF); and it participates in normal vascular development and basement membrane interactions. CMG2/ANTXR2 binds components of the extracellular matrix, most notably collagen IV and laminin, and is essential for proper capillary morphogenesis. Mutations in ANTXR2 cause rare hyaline storage disorders in infancy and skeletal dysplasias later in life, highlighting the gene’s importance beyond infectious disease biology.
Gene and protein
ANTXR2 is encoded by the ANTXR2 gene and is commonly referred to by its protein alias CMG2. The protein features an extracellular von Willebrand factor A (vWA) domain containing a metal-ion–dependent adhesion site (MIDAS), which mediates ligand binding to extracellular matrix components. It is a single-pass type I transmembrane protein with a cytoplasmic tail that participates in interactions with the cytoskeleton and signaling pathways. The extracellular domain's affinity for basement membrane components underlies CMG2’s role in angiogenesis and tissue remodeling, while the transmembrane and cytoplasmic portions link extracellular cues to intracellular responses.
Antxr2/CMG2 is expressed in endothelial cells and other tissues during development, where it contributes to basement-membrane integrity and capillary formation. Its interaction with collagen IV and laminin anchors endothelial cells to the vascular basement membrane, supporting vessel stabilization and morphogenesis. In addition to its normal physiological roles, the receptor’s properties have made it a useful tool in targeted therapies and research on receptor-mediated delivery systems.
ANTXR1 refers to a related receptor in the same family, with overlap and distinctions in tissue distribution and function. The CMG2/ANTXR2 axis is often discussed alongside other ECM-binding receptors in the broader context of vascular biology and tumor angiogenesis. For mechanistic context, readers may also consult von Willebrand factor A domain and MIDAS.
Anthrax toxin receptor and entry mechanism
The receptor function of CMG2/ANTXR2 is most widely known for its role in Bacillus anthracis pathogenesis. PA binds to CMG2 on the surface of susceptible cells, where PA is proteolytically activated by furin and then oligomerizes to form a prepore that can bind EF or LF. The toxin complex is subsequently endocytosed, and acidification of the endosome triggers translocation of EF and LF into the cytosol, where EF increases intracellular cAMP and LF disrupts signaling pathways such as MAPK cascades. This receptor-mediated entry is a canonical example of a host receptor that bacteria co-opt to deliver virulence factors.
Organisms and components involved in this process include protective antigen, Bacillus anthracis, endocytosis, and the intracellular consequences of toxin delivery. The PA–CMG2 interaction, including the structural features of the vWA/MIDAS region and the subsequent conformational changes, has been a major focus of structural biology and host–pathogen interaction studies. For broader toxin biology, see anthrax toxin and the individual toxin components LF and EF.
Physiological and developmental roles
Beyond its role as an anthrax receptor, CMG2/ANTXR2 contributes to normal vascular development and tissue maintenance. By binding basement-m membrane constituents, CMG2 helps anchor endothelial cells during capillary morphogenesis and contributes to the stability of developing vasculature. In animal models and human tissue, CMG2 activity supports endothelial cell–matrix interactions necessary for proper vessel formation and remodeling.
The dual identity of ANTXR2—as a physiological mediator of angiogenesis and as a receptor for a major biotoxin—highlights a recurring theme in biology: evolution has repurposed existing receptor–ligand interactions for defense against disease and for normal development. Related ECM interactions involve collagen IV and laminin, and the broader context includes basement membranes, perivascular cells, and the signals that regulate vessel maturation.
Medical significance
Mutations in ANTXR2 cause rare hereditary disorders characterized by abnormal connective tissue deposition and skeletal anomalies. Infantile systemic hyalinosis (ISH) and geroderma osteodysplasticum (GOD) are two primary examples. These conditions reflect dysregulated matrix deposition and defective ECM–cell interactions, often resulting in subcutaneous nodules, joint contractures, bone abnormalities, and skin changes. The disorders underscore CMG2/ANTXR2’s essential role in maintaining connective tissue architecture and vascular integrity from infancy onward.
In oncology and other disease contexts, CMG2/ANTXR2 is of interest because of its role in endothelial cell biology and tissue remodeling. Some tumors exhibit up-regulated CMG2 expression in their vasculature, making the receptor a potential target for anti-angiogenic strategies or for selective drug delivery systems that exploit receptor-mediated internalization. Research into CMG2-targeted approaches includes exploring peptide ligands, antibody fragments, or novel delivery platforms that leverage the receptor’s ECM-binding properties.
Research directions, therapeutics, and policy considerations
Because CMG2/ANTXR2 is a gateway for anthrax toxin entry, understanding its structure and binding properties informs biodefense strategies and medical countermeasure development. The same receptor has inspired interest in targeted therapies that exploit receptor-mediated uptake for cancer and other diseases, including engineered toxin delivery systems in preclinical settings and research into ECM-targeted therapies that modulate angiogenesis.
From a policy and science-management perspective, debates surround the balance between biodefense preparedness and regulatory oversight of dual-use research. Proponents emphasize enabling robust national security postures, rapid countermeasure development, and private-sector innovation. Critics argue for appropriate safeguards to minimize unintended consequences, balancing scientific progress with public safety and ethical considerations. In this space, ANTXR2/CMG2 serves as a case study in how a single host receptor can influence both pathogen-based risk and therapeutic opportunity, shaping conversations about funding priorities, regulatory frameworks, and the responsible advancement of biotechnology.