Disease relevance of ANTXR1

• The anthrax toxin receptors, ANTXR1 and ANTXR2, act as molecular clamps to prevent the protective antigen (PA) toxin subunit from forming pores until exposure to low pH [1].
• Notably, internalized LFn-Al and LFn-Lip protected cells that overexpressed anthrax receptor TEM8 from PA-induced, LF-independent toxicity, suggesting an independent mechanism for PA inhibition inside the cell [2].
• In this work, we expressed the ATR/TEM8 VWA domain as a fusion protein in Escherichia coli [3].
• TEM-7R (P = 0.05) and TEM-8 (P < 0.01) were significantly raised in breast cancer tissues compared with the levels detected in normal background tissues [4].
• RESULTS: TEM-1 (P = 0.01), TEM-7 (P = 0.04), TEM-7R (P = 0.03), TEM-8 (P = 0.001) significantly raised in colon cancer tissues compared with the levels detected in normal background tissues [5].

Psychiatry related information on ANTXR1

• Near stereopsis was best in the ATR arms, but this did not produce better near visual acuity or RSVP quality of life [6].
• We hypothesize that our patient has a contiguous gene syndrome and that the non-BPES-associated abnormalities (microcephaly, mild mental retardation, and growth delay) are the result of the deletion of the maternal ATR gene [7].

High impact information on ANTXR1

• LRP6 acts as a coreceptor with either TEM8 or CMG2, the two previously identified receptors for anthrax toxin [8].
• The receptor, termed ATR (anthrax toxin receptor), is a type I membrane protein with an extracellular von Willebrand factor A domain that binds directly to PA [9].
• Deletion of ATR mediated by the Cre recombinase caused the loss of ATR and ATRIP expression, loss of DNA damage checkpoint responses, and cell death [10].
• Thus, ATRIP and ATR are mutually dependent partners in cell cycle checkpoint signaling pathways [10].
• In this report we provide evidence that the ATM-Rad3-related protein ATR regulates phosphorylation of Ser-15 in DNA-damaged cells [11].

Chemical compound and disease context of ANTXR1

• The protective antigen (PA) subunit of anthrax toxin interacts with the integrin-like I domains of either of two cellular receptors, ANTXR1 or ANTXR2 [12].
• Selection of Anthrax Toxin Protective Antigen Variants That Discriminate between the Cellular Receptors TEM8 and CMG2 and Achieve Targeting of Tumor Cells [13].

Biological context of ANTXR1

• Both tracers retained high affinity to PA/ANTXR complexes and were readily internalized via receptor-mediated endocytosis [2].
• ATR-dependent phosphorylation of ATRIP in response to genotoxic stress [14].
• The serine 68 and 72 residues are important for the phosphorylation in vivo and are required exclusively for direct modification by ATR in vitro [14].
• METHODS: A ribozyme transgene (TEM-8) was cloned into a suitable mammalian expression vector (pc DNA 3.1-GFP-NT) and transfected into HECV cells [15].
• PI-kinase-related protein kinase ATR forms a complex with ATRIP and plays pivotal roles in maintaining genome integrity [14].

Anatomical context of ANTXR1

• The coordinate expression of TEM1, TEM5, and TEM8 on tumor endothelium in humans and mice makes these genes attractive targets for the development of antiangiogenic therapies [16].
• Finally, we show that the epithelial cells lining the small intestine strongly express ATR/TEM8 isoforms [17].
• Our results indicate that CMG2 transcripts are preferentially expressed over TEM8 transcripts in primary human and mouse macrophages as compared to immortalized cell lines [18].
• In this communication, we examined the expression of mRNA transcripts of TEM8 and CMG2 in primary human and mouse macrophages and mouse tissues by standard and quantitative real-time RT-PCR [18].
• Quantitative measurement of anthrax toxin receptor messenger RNA in primary mononuclear phagocytes [18].

Associations of ANTXR1 with chemical compounds

• Previously it was shown that the MIDAS threonine is essential for PA interaction with ANTXR1, a result consistent with the requirement that the I domain of that receptor adopts an open conformation for PA-binding [1] [12].
• The ATR/TEM8-PA interaction is mediated by the receptor's extracellular domain related to von Willebrand factor type A or integrin inserted domains (VWA/I domains) [19].
• For TEM8-associated toxin, these events can occur at close to neutral pH values, and they show relatively low sensitivity to ammonium chloride treatment in cells [20].
• UV transiently increased GSK-3beta activity, and this increase could be blocked by caffeine or by ATR small interfering RNA, indicating ATR-dependent activation of GSK-3beta. ser-114, located within the putative GSK-3beta target sequence, was phosphorylated by GSK-3beta upon UV exposure [21].
• It was previously shown that ATR is critical to fragile-site stability and that ATR-deficient cells have greatly elevated fragile-site expression (A. M. Casper, P. Nghiem, M. F. Arlt, and T. W. Glover, Cell 111:779-789, 2002) [22].

Regulatory relationships of ANTXR1

• Residues conserved between ANTXR2 and ANTXR1 that influence the ANTXR2-associated pH threshold of pore formation were also identified [1].

Other interactions of ANTXR1

• These studies distinguish CMG2 as a second anthrax toxin receptor and identify a potent antitoxin that may prove useful for the treatment of anthrax [19].
• Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor [19].
• An essential component of the ATR (ataxia telangiectasia-mutated and Rad3-related)-activating structure is single-stranded DNA [23].
• An ATR- and BRCA1-mediated Fanconi anemia pathway is required for activating the G2/M checkpoint and DNA damage repair upon rereplication [24].
• The accumulation of cells with rereplicated DNA is restored by the artificial induction of a G2-phase arrest even when ATR, BRCA1, or FANCA is absent [24].

Analytical, diagnostic and therapeutic context of ANTXR1

• Anthrax toxin receptor ATR/TEM8 VWA domain is responsible for the binding of protective antigen (PA) of B. anthracis, and thus an attractive target for structure-based drug therapies [3].
• The expression of TEMs (TEM-1 to TEM-8) was assessed using RT-PCR and their transcript levels were determined using real-time-quantitative PCR (Q-RT-PCR) [5].
• Immunoprecipitation studies of recombinant ATR reveal that catalytic activity of this polypeptide is required for DNA-stimulated phosphorylation of p53 on serine-15 [25].
• In the current study, the ATR protein was examined by gel filtration of protein extracts and was found to exist predominantly as part of a large protein complex [26].
• A kinase-inactivated form of the ATR gene was prepared by site-directed mutagenesis and was used in transfection experiments to probe the function of this complex [26].

References