TEM8 has also been described to be overexpressed in breast cancer [12], gall bladder carcinomas [13], and prostate cancer [14]. by the plasmid pXO1 and form bipartite combinations. The combination of LF and PA generates lethal toxin (LT), while EF combined with PA comprises edema toxin (ET). LT and ET cause anthrax and the disease-related symptoms. In mouse experiments, the lethality of both LT and ET has been shown [6], while the three toxin components (PA, LF, and EF) are not individually toxic [1]. The main role of the poly–d-glutamic acid capsule is to facilitate initiation of an infection, while the symptoms of anthrax disease are due to septicemia, which is the result of the toxin production (reviewed in [3]). PA, LF, and EF have been studied in great detail and this has resulted in detailed knowledge of their molecular mechanisms of action. LF and EF can only access host cells through delivery by PA (Figure 1). PA binds to either of its two known cell surface receptors, tumor endothelial marker 8 (TEM8 or ANTXR1) or capillary morphogenesis gene 2 (CMG2 or ANTXR2). Results indicate that CMG2 is the major receptor responsible for in vivo toxicity in mice [7,8]. Cell surface binding of PA results in its oligomerization, which generates binding sites for LF and EF [9,10]. In recent years, the molecular mechanisms of the anthrax toxin intoxication process has been studied in great detail and is understood very well (reviewed in [11]). The first step of the uptake mechanism is the binding of PA to TEM8 or CMG2. Both receptors are transmembrane proteins and ubiquitously expressed. TEM8 has also been described to be overexpressed in breast cancer [12], gall bladder carcinomas [13], and prostate cancer [14]. CMG2 might play a role in parturition as the knock-out of CMG2 in mice resulted in the inability of pregnant mice to give birth [15]. A deposition of collagen was found in the myometrium of the mice, resulting in loss of smooth muscles. In human patients, mutations of CMG2 are connected to two autosomal recessive disorders, Juvenile Hyaline Fibromatosis and Infantile Systemic Hyalinosis. Both diseases are characterized by excess hyaline material deposition in connective tissues. The role of CMG2 and TEM8 in healthy individuals remains unclear. In a valuable study, Liu et al. described the role of tissue-specific CMG2-knockouts in mice and the effect of LT Darusentan or ET in these mice [6]. As a result, LT acts specifically on cardiomyocytes and vascular smooth muscle cells expressing CMG2, while ET acts mainly on CMG2-positive hepatocytes. According to this study, the role of TEM8 as an AT receptor is negligible for intoxication by LT and ET in mice. Open in a separate window Figure 1 Anthrax toxin activation mechanism. Anthrax toxin protective antigen (PA) is cleaved by furin (1) to enable binding to either of its two known cell surface receptors (2), tumor endothelial marker 8 (TEM8 or ANTXR1) or capillary morphogenesis gene 2 (CMG2 or ANTXR2). PA oligomerizes (3) and the two effector molecules of anthrax toxin, lethal factor (LF) and edema factor (EF), bind to the PA oligomer. If PA forms an octamer, up to four effector molecules can bind at the intersection of PA molecules and internalize by receptor-mediated endocytosis (4); acidification Darusentan in endosomes results in pore formation by PA (5); LF and EF partly unfold and Darusentan the unfolded in the host by affecting signaling pathways and modulating immunologic responses. ET injected in high doses is lethal in mice and induces hemorrhaging lesions in many organs MLL3 accompanied by both hypotension and bradycardia [27]. However, while ET manifests massive immunomodulatory effects in immune cells, such as macrophages and B cells [28], it induces no acute cytotoxic effect on a number of cell types, such as dendritic cells, T-cells, macrophages, neutrophils, and human microvascular endothelial cells [29,30,31,32,33]. LF is a zinc metalloproteinase that cleaves mitogen-activated protein kinase kinases (MAPKKs) in their exotoxin A (PE) [45]. PE is an ADP-ribosylating exotoxin from flagellin) was efficiently delivered to the cytosol of mouse macrophages by PA [85] and flagellin activated the inflammasome in the macrophages. LFn was also combined with -lactamase to generate a screening and visualization system based on AT [86,87,88,89]. The combination of PA and LFn–lactamase has been successfully Darusentan used to characterize the protease specificity for uPA-activated and MMP-activated PA and to identify inhibitors for the uptake of AT by.