Anthrax toxin: structures, functions and tumour targeting

Liu, Shihui; Schubert, Rebecca L.; Bugge, Thomas H.; Leppla, Stephen H.

doi:10.1517/eobt.3.5.843.21229

Cited by 21 publications

(33 citation statements)

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“…These studies were extended to human cell lines which represent several phenotypes known to be targeted by anthrax; the effect of cell differentiation on the receptor parameters was also measured. Our results are considered in light of recent findings, which suggest a mechanism for cell type-specific susceptibility to LT based upon differential display of PA-specific receptors; the implications of these results for recent work on the use of PA as a mechanism for targeted drug delivery [4,5] are also discussed.…”

Section: Introductionmentioning

confidence: 70%

“…However, we have quantitatively confirmed that a variety of cell types are able to specifically bind PA and that cells targeted by LT have significantly increased PA binding, presumably resulting from greater display of PA-specific receptors. Furthermore, the generality of PA binding needs to be considered in studies that use PA as a cell specific delivery vehicle for cancer therapies [4], which supports the extensive efforts to create engineered PA molecules (bearing altered protease cleavage sites) to specifically target tumor cells with chemotherapeutic agents [5].…”

Section: Discussionmentioning

confidence: 99%

“…PA-mediated internalization of LF and EF occurs following PA heptamerization on the cell surface and pH-dependent pore formation within the endosome (reviewed in [2]). Quantification of the affinity and number of endogenous PA-specific receptors is important for understanding the role of PA in anthrax virulence and its potential as a pharmaceutical delivery agent [3][4][5]. Previous studies have measured the binding affinity of PA to non-human mammalian cells [6,7] and purified receptors [8], but information on PA binding to human cells is lacking.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative analysis of the effect of cell type and cellular differentiation on protective antigen binding to human target cells

Deshpande¹,

Hammon²,

Sanders³

et al. 2006

FEBS Letters

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We quantitatively measured protective antigen (PA) binding to human cells targeted by anthrax lethal toxin (LT). Affinities were less than 50 nM for all cells, but differentiated cells (macrophages and neutrophils) had significantly increased PA binding and endothelial cells demonstrated the most binding. Combined with the function of such cells, this suggests that PA receptors interact with the extracellular matrix and that differentiation increases the number of PA-specific receptors, which supports previously observed differentiation-induced LT susceptibility. Our results quantifiably confirm that the generality of PA binding will complicate its use as a tumor targeting agent.

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Section: Introductionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quantitative analysis of the effect of cell type and cellular differentiation on protective antigen binding to human target cells

Deshpande¹,

Hammon²,

Sanders³

et al. 2006

FEBS Letters

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“…Anthrax-protective antigen-P63 oligomerizes to form a ring-shaped heptamer (Santelli et al, 2004). A heptamer prepore binds anthrax lethal factor and edema factor and delivers them into the intracellular milieu, where they exert their toxic effect (Liu et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

et al. 2006

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Invasion-promoting membrane type-1 matrix metalloproteinase (MT1-MMP) functions in cancer cells as an oncogene and as a mediator of proteolytic events on the cell surface. To exert its functional activity, MT1-MMP requires proteolytic removal of the prodomain sequence. There are two potential furin cleavage motifs, R 89 -R-P-R-C 93 and R 108 -R-K-R-Y 112 , in the prodomain sequence of MT1-MMP. Our data suggest an important role of furin and related proprotein convertases (PCs) in mediating both the activation of MT1-MMP and the levels of functionally active MT1-MMP at the surface of cancer cells. We have determined that the peptide sequence that spans the first cleavage site is susceptible to furin and PC5/6, whereas the second sequence is susceptible to furin and also to PC5/6, PC7 and PACE4. In the structure of the MT1-MMP proenzyme, the R 89 -R-P-R-C 93 site, however, is inaccessible to PCs. Our studies also demonstrated a direct functional link between the activation and the uptake rate of the proenzyme and the enzyme of MT1-MMP. Thus, the uptake rate of the latent MT1-MMP proenzyme noticeably exceeded that of the active enzyme. We conclude that furin and related PCs are the essential components of the specialized cellular machinery that controls the levels of the functionally active, mature, MT1-MMP enzyme on the cell surface to continually support the potency of pericellular proteolysis.

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“…Anthrax toxin is a 3-part toxin consisting of protective antigen (PA, 83 kDa), edema factor (EF, 90 kDa), and lethal factor (LF, 89 kDa) (2)(3)(4). These 3 proteins are individually nontoxic, but can assemble on the cell surface to form toxic complexes.…”

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confidence: 99%

Capillary morphogenesis protein-2 is the major receptor mediating lethality of anthrax toxin in vivo

Liu

Crown²,

Miller-Randolph³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Anthrax toxin, a major virulence factor of Bacillus anthracis, gains entry into target cells by binding to either of 2 von Willebrand factor A domain-containing proteins, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). The wide tissue expression of TEM8 and CMG2 suggest that both receptors could play a role in anthrax pathogenesis. To explore the roles of TEM8 and CMG2 in normal physiology, as well as in anthrax pathogenesis, we generated TEM8-and CMG2-null mice and TEM8/ CMG2 double-null mice by deleting TEM8 and CMG2 transmembrane domains. TEM8 and CMG2 were found to be dispensable for mouse development and life, but both are essential in female reproduction in mice. We found that the lethality of anthrax toxin for mice is mostly mediated by CMG2 and that TEM8 plays only a minor role. This is likely because anthrax toxin has approximately 11-fold higher affinity for CMG2 than for TEM8. Finally, the CMG2-null mice are also shown to be highly resistant to B. anthracis spore infection, attesting to the importance of both anthrax toxin and CMG2 in anthrax infections.edema toxin ͉ lethal toxin ͉ tumor endothelium marker-8 B acillus anthracis is a Gram-positive, rod-shaped, sporeforming bacterium, and the causative agent of anthrax. Anthrax toxin is the major virulence factor for this organism and responsible for its lethal effects in the host. Although treatment with antibiotics to eliminate the bacteria can be life-saving at the earlier stages of anthrax disease, once enough toxin has been produced, the disease is often lethal despite treatment. Thus, countermeasures that block toxin or limit its effects are essential at later stages of disease (1). Therefore, a detailed understanding of the interaction between anthrax toxin and the host is needed as a basis for developing improved interventions.Anthrax toxin is a 3-part toxin consisting of protective antigen (PA, 83 kDa), edema factor (EF, 90 kDa), and lethal factor (LF, 89 kDa) (2-4). These 3 proteins are individually nontoxic, but can assemble on the cell surface to form toxic complexes. To intoxicate host mammalian cells, PA binds to its cellular receptors, tumor endothelium marker-8 [TEM8, also named anthrax toxin receptor 1 (ANTXR1)] and capillary morphogenesis protein-2 [CMG2, also named anthrax toxin receptor 2 (ANTXR2)] (5, 6) with the involvement of a coreceptor LRP6 (7,8) and is then proteolytically processed to the active form, cell-surface bound PA63. PA63 spontaneously oligomerizes to form a heptamer that binds and delivers LF and EF into the cytosol. EF, which combines with PA to form edema toxin (ET), is a calmodulin-dependent adenylate cyclase that elevates intracellular cAMP levels, thereby causing diverse effects including impairment of phagocytosis and death of experimental animals (9, 10). LF, which combines with PA to form lethal toxin (LT), is a zinc-dependent metalloproteinase that cleaves and inactivates the mitogen-activated protein kinase kinases (MEKs) 1-4, 6, and 7 (11-13), blocking the ERK, p38, and Jun...

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Anthrax toxin: structures, functions and tumour targeting

Cited by 21 publications

References 0 publications

Quantitative analysis of the effect of cell type and cellular differentiation on protective antigen binding to human target cells

Quantitative analysis of the effect of cell type and cellular differentiation on protective antigen binding to human target cells

Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

Capillary morphogenesis protein-2 is the major receptor mediating lethality of anthrax toxin in vivo

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