Inhibition of Alanyl Aminopeptidase Induces MAP-Kinase p42/ERK2 in the Human T Cell Line KARPAS-299

Lendeckel, Uwe; Kähne, Thilo; Arndt, Marco; Frank, Karin; Ansorge, Siegfried

doi:10.1006/bbrc.1998.9585

Cited by 32 publications

(20 citation statements)

References 42 publications

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“…In accordance with the other inhibitors tested it is concluded that AP-M (EC 3.4.11.2) is the major exopeptidase affecting the LVV-H7 degradation in EDTA plasma. AP-M, which is also termed alanyl-AP [35], CD13 [25] or AP-N [29,32,36], preferentially cleaves alanine residues, but also other amino acids due to its low specificity. This enzyme is a ubiquitous exopeptidase anchored in plasma membranes but also found in soluble forms in human plasma [37][38][39][40][41].…”

Section: Incubation Of Lvv-h7 In Plasmamentioning

confidence: 99%

Comparative in vitro degradation of the human hemorphin LVV‐H7 in mammalian plasma analysed by capillary zone electrophoresis and mass spectrometry

John¹,

Schulz²,

Forssmann

2007

Biopharm & Drug Disp

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The human hemorphin LVV-H7 (L32VVYPWTQRF41) is a hemoglobin-beta, -gamma, -delta or -epsilon chain derived cationic decapeptide of the micro-opioid receptor binding family. It exhibits potential pharmacological value relevant, for example, for blood pressure regulation, learning performance and Alzheimer's disease. The regulatory potency is strictly dependent on the length of the amino acid sequence which is sensitive towards proteinases from tissues and plasma. To analyse LVV-H7 in vitro degradation in mammalian plasma, a novel multi-component quantitative capillary zone electrophoretic (CZE) procedure was applied, combined with qualitative metabolite profiling by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). In all types of plasma, LVV-H7 was N-terminally truncated generating four metabolites (M1-M4) with an intact C-terminus: M1 (V33VYPWTQRF41), M2 (V34YPWTQRF41), M3 (Y35PWTQRF41) and M4 (W37TQRF41). In EDTA plasma these degradation products were detected exclusively, whereas in citrate and heparin plasma four further metabolites appeared resulting from additional C-terminal cleavage of the dipeptide R40F41: M5 (L32VVYPWTQ39), M6 (V33VYPWTQ39), M7 (V34YPWTQ39) and M8 (Y35PWTQ39). In the presence of selective proteinase inhibitors aminopeptidase M and angiotensin-converting enzyme (for N- and C-terminal truncation, respectively) were identified as plasma enzymes responsible for hemorphin degradation. Furthermore, striking inter-mammalian species distinctions were detected revealing strongly differing degradation velocities but similar metabolite patterns.

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Section: Incubation Of Lvv-h7 In Plasmamentioning

confidence: 99%

Comparative in vitro degradation of the human hemorphin LVV‐H7 in mammalian plasma analysed by capillary zone electrophoresis and mass spectrometry

John¹,

Schulz²,

Forssmann

2007

Biopharm & Drug Disp

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“…These data correlate with a previous proposal (17) for other aminopeptidases of the M1 family (45). Interestingly, human APN/CD13 (aminopeptidase N), a zincbinding type 2 transmembrane ectopeptidase of 150 kDa (family M1) that is selectively expressed in endothelial cells and participates in angiogenesis (46), has also been localized in the nuclear fraction (47) and is involved in cell proliferation (48,49).…”

Section: Discussionmentioning

confidence: 99%

Aminopeptidase N1 (EtAPN1), an M1 Metalloprotease of the Apicomplexan Parasite Eimeria tenella, Participates in Parasite Development

et al. 2014

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Aminopeptidases N are metalloproteases of the M1 family that have been reported in numerous apicomplexan parasites, including Plasmodium, Toxoplasma, Cryptosporidium, and Eimeria. While investigating the potency of aminopeptidases as therapeutic targets against coccidiosis, one of the most important avian diseases caused by the genus Eimeria, we identified and characterized Eimeria tenella aminopeptidase N1 (EtAPN1). Its inhibition by bestatin and amastatin, as well as its reactivation by divalent ions, is typical of zinc-dependent metalloproteases. EtAPN1 shared a similar sequence, three-dimensional structure, and substrate specificity and similar kinetic parameters with A-M1 from Plasmodium falciparum (PfA-M1), a validated target in the treatment of malaria. EtAPN1 is synthesized as a 120-kDa precursor and cleaved into 96-, 68-, and 38-kDa forms during sporulation. Further, immunolocalization assays revealed that, similar to PfA-M1, EtAPN1 is present during the intracellular life cycle stages in both the parasite cytoplasm and the parasite nucleus. The present results support the hypothesis of a conserved role between the two aminopeptidases, and we suggest that EtAPN1 might be a valuable target for anticoccidiosis drugs.

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“…Several groups have previously reported that anticatalytic antibodies or peptide inhibitors for APN markedly inhibited the invasive potential of rodent and human tumor cells [16][17][18][19]. Since this protease exerts some influence independent of its enzymatic domain [14,15,22,23], we decided to employ the antisense strategy for APN inhibition. Antisense RNA blocks APN expression at an early stage of mRNA maturation.…”

Section: Discussionmentioning

confidence: 99%

“…Cell cycle control and cell differentiation of macrophage/monocyte [12], and mitogenic activation of lymphocytes [13] have been found to be associated with surface APN activity. Furthermore, APN serves as a virus receptor for the corona virus [14], and has recently been reported to be involved in signal transduction with p42/ERK2 MAP kinase in a human T cell line [15].…”

Section: Introductionmentioning

confidence: 99%

Untitled

Kido

Krueger

Haeckel

et al. 2003

Clinical and Experimental Metastasis

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Aminopeptidase N (APN/CD13), a Zn2+-dependent ectopeptidase, is localized on the cell surface and functions as a transmembrane protein. Increased expression and activity of APN have been postulated to correlate with the aggressive behavior of several tumor types. In this study, the osteosarcoma cell line MNNG/HOS was stably transfected with an expression vector capable of expressing the antisense transcript of APN. Four stably transfected clones, the control clones and parental cells were characterized. Stable integration of the antisense vector was confirmed by PCR analysis of genomic DNA. Competitive RT-PCR revealed that mRNA expression of antisense-transfectants was decreased to approximately 37% of the control cell line. The activity assay showed that the enzymatic activity of APN was inhibited to approximately 51% of the control cell line. Antisense-transfection had no influence on the cellular proliferation measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, on the motility in Transwell chambers, and on the adhesive potential to collagen I. However, an in vitro invasion assay revealed a significant decrease in the number of cells that migrated through a reconstituted membrane (51% of the control cell line). The adhesive potential to Matrigel was also affected (73% of the control cell line). Furthermore, under in vivo conditions, a reduced potency to metastasize to the lung was shown in an experimental metastasis assay in nude mice. These findings demonstrate that APN plays an active role in the cellular attachment and proteolytic degradation of the extracellular matrix in the metastatic process of osteosarcomas.

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Inhibition of Alanyl Aminopeptidase Induces MAP-Kinase p42/ERK2 in the Human T Cell Line KARPAS-299

Cited by 32 publications

References 42 publications

Comparative in vitro degradation of the human hemorphin LVV‐H7 in mammalian plasma analysed by capillary zone electrophoresis and mass spectrometry

Comparative in vitro degradation of the human hemorphin LVV‐H7 in mammalian plasma analysed by capillary zone electrophoresis and mass spectrometry

Aminopeptidase N1 (EtAPN1), an M1 Metalloprotease of the Apicomplexan Parasite Eimeria tenella, Participates in Parasite Development

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