Aminopeptidase N in arterial hypertension

Danziger, Robert S.

doi:10.1007/s10741-007-9061-y

Cited by 58 publications

(54 citation statements)

References 92 publications

(42 reference statements)

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“…4 shows the representative spectra that were confidently assigned by one search engine but not the other. Aminopeptidase N (CD13), present in various brain structures (52), was identified with three unique glycopeptides with good Mascot scores of 61, 54, and 50, respectively. In Sequest, the corresponding scores for the three peptides were XCorr 3.29 (R2gNATLVNEADKLR2S, 2ϩ, p 4.8eϪ8, ⌬Cn 0.029 where gN is deamidated Asn), XCorr 3.969 (R2FTCgNQTTDVIIIHSK2K, 3ϩ, p 1.0eϪ9, ⌬Cn 0.030), and XCorr 4.882 (K2SGQEDHYWLDVEKgNQSAK2F, 3ϩ, p 1.77eϪ06, ⌬Cn 0.011), respectively.…”

Section: Resultsmentioning

confidence: 99%

Simultaneous Characterization of Glyco- and Phosphoproteomes of Mouse Brain Membrane Proteome with Electrostatic Repulsion Hydrophilic Interaction Chromatography

Zhang

Guo

et al. 2010

Molecular & Cellular Proteomics

101

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Characterization of glyco-and phosphoproteins as well as their modification sites poses many challenges, the greatest being loss of their signals during mass spectrometric detection due to substoichiometric amounts and the ion suppression effect caused by peptides of high abundance. We report here an optimized protocol using electrostatic repulsion hydrophilic interaction chromatography for the simultaneous enrichment of glyco-and phosphopeptides from mouse brain membrane protein digest. With this protocol, we successfully identified 544 unique glycoproteins and 922 glycosylation sites, which were significantly higher than those from the commonly used hydrazide chemistry method (192 glycoproteins and 345 glycosylation sites). Moreover, a total of 383 phosphoproteins and 915 phosphorylation sites were recovered from the sample, suggesting that this protocol has the potential to enrich both glycopeptides and phosphopeptides simultaneously. Of the total 995 glycosylation sites identified from both methods, 96% were considered new as they were either annotated as putative or not documented in the newly released Swiss-Prot database. Thus, this study could be of significant value in complementing the current glycoprotein database and provides a unique opportunity to study the complex interaction of two different post-translational modifications in health and disease without being affected by interexperimental variations. Molecular & Cellular Proteomics 9:635-647, 2010.

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Section: Resultsmentioning

confidence: 99%

Simultaneous Characterization of Glyco- and Phosphoproteomes of Mouse Brain Membrane Proteome with Electrostatic Repulsion Hydrophilic Interaction Chromatography

Zhang

Guo

et al. 2010

Molecular & Cellular Proteomics

101

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“…Identification of APN substrates implicated in tumor growth and metastasis is another required next step. A number of cytokines, growth factors, and extracellular matrix molecules implicated in angiogenesis have been reported as putative APN substrates (46)(47)(48)(49)(50)(51)(52)(53)(54)(55), and testing their possible roles in the models presented here will be the focus of future studies.…”

Section: Discussionmentioning

confidence: 99%

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

Guzman-Rojas

Rangel

Salameh

et al. 2012

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

115

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Processes that promote cancer progression such as angiogenesis require a functional interplay between malignant and nonmalignant cells in the tumor microenvironment. The metalloprotease aminopeptidase N (APN; CD13) is often overexpressed in tumor cells and has been implicated in angiogenesis and cancer progression. Our previous studies of APN-null mice revealed impaired neoangiogenesis in model systems without cancer cells and suggested the hypothesis that APN expressed by nonmalignant cells might promote tumor growth. We tested this hypothesis by comparing the effects of APN deficiency in allografted malignant (tumor) and nonmalignant (host) cells on tumor growth and metastasis in APNnull mice. In two independent tumor graft models, APN activity in both the tumors and the host cells cooperate to promote tumor vascularization and growth. Loss of APN expression by the host and/ or the malignant cells also impaired lung metastasis in experimental mouse models. Thus, cooperation in APN expression by both cancer cells and nonmalignant stromal cells within the tumor microenvironment promotes angiogenesis, tumor growth, and metastasis.lung cancer | melanoma | proteolytic activity | shRNA | tumorigenesis A minopeptidase N (APN, CD13; EC 3.4.11.2) is a widely expressed type II membrane-bound metalloprotease (1, 2). It functions in the enzymatic cleavage of peptides, in endocytosis, and as a signaling molecule and has been implicated in the regulation of complex and diverse processes, including cell migration, cell survival, viral uptake, and angiogenesis (3). APN has also been linked specifically to cancer, having been identified as a cellsurface marker for malignant myeloid cells (4-7) and reaching high levels of expression in association with the progression of tumors, including breast, ovarian, and prostate cancer (8-14). Indeed, vascular endothelial growth factor (VEGF), a key angiogenesis regulator, induces the expression of APN at an early stage of tumor growth (15), again highlighting the role of this enzyme in angiogenesis, a process crucial for sustained growth of most solid tumors (16). Studies of bestatin, a CD13 inhibitor and antiangiogenic agent, also suggest that APN enzymatic activity is relevant for tumorigenesis (17,18). Nevertheless, the substrates of APN in the context of angiogenesis are still unknown. The only well-defined substrate is angiotensin III in the renin-angiotensin pathway, in which APN cleaves the NH 2 -terminal arginine residue of angiotensin III to form angiotensin IV. Consistent with several lines of evidence, we have previously identified APN as a target for inhibition of tumor vascularization and growth (18)(19)(20).Tumor growth relies on a complex microenvironment in which malignant cells cooperate with various other cell types: endothelial cells of the blood and lymphatic circulation, mesenchymal stromal cells/cancer-associated fibroblasts, and a variety of bone marrow-derived cells such as myeloid-derived suppressor cells and lymphocytes (21, 22). Some of these cell populations c...

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“…For the stress study, 5 animals were maintained in their original home cages as control whereas 5 animals were randomly selected and placed individually inside plastic cyl- [42], bradykinins [42], endorphins [42] AlaAP; PSAP/EC 3.4.11.14/ Ala-␤-NNap/soluble enkephalins [12] LeuAP/EC 3.4.11.1/Leu-␤-NNap/soluble, membrane enkephalins [17], angiotensin II [20], substance P [19], dynorphins [18] NSAP/EC 3.4.11.-/Leu-␤-NNap/soluble enkephalins [12] P-LeuAP; oxytocinase/ EC 3.4.11.3/Leu-␤-NNap + L-methionine 20 mM/ membrane, soluble?…”

Section: Methodsmentioning

confidence: 99%

Stress Influences Brain Enkephalinase, Oxytocinase and Angiotensinase Activities: A New Hypothesis

et al. 2009

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Brain enkephalin and oxytocin are anxiolytic agents involved in the response mechanism to stress. Degrading enzymes such as enkephalinase and oxytocinase could also be associated with this response. The effect of acute immobilization stress on enkephalinase and oxytocinase activities was determined in the soluble and membrane fractions of the medial prefrontal cortex, hippocampus and amygdala using alanyl- and leucyl-beta-naphthylamide as substrates, the latter in the presence and absence of 20 mML-methionine. No change in aminopeptidase activities was observed in the prefrontal cortex of stressed rats. In contrast, enkephalinase activity decreased in the soluble fraction of the hippocampus but increased in the membrane fraction. In the amygdala, soluble oxytocinase and membrane enkephalinase activities decreased in stressed animals. These results show that acute immobilization stress affects differentially enkephalinase and oxytocinase activities depending on the fraction and brain region analyzed. A reduction in the activity of soluble enkephalinase in the hippocampus and soluble oxytocinase as well as membrane enkephalinase in the amygdala may suggest higher availability/longer action of enkephalin and oxytocin at these locations. This may explain the relative importance of these enzymatic activities in the anxiolytic properties proposed for enkephalins and oxytocin in the hippocampus and amygdala during stress conditions. This interpretation is not applicable to membrane enkephalinase activity in the hippocampus. However, alanyl-beta-naphthylamide hydrolyzing activity not only measures enkephalinase activity, it also reflects the angiotensinase-induced metabolism of angiotensin III to angiotensin IV. Therefore, our results may also mirror an increase in the formation of Ang IV in hippocampus and a decrease in the amygdala in acute stress. In conclusion, aminopeptidase activities in the hippocampus and amygdala may affect enkephalin, oxytocin and angiotensin III metabolism during acute immobilization stress and therefore be involved in the anxiolytic response.

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Aminopeptidase N in arterial hypertension

Cited by 58 publications

References 92 publications

Simultaneous Characterization of Glyco- and Phosphoproteomes of Mouse Brain Membrane Proteome with Electrostatic Repulsion Hydrophilic Interaction Chromatography

Simultaneous Characterization of Glyco- and Phosphoproteomes of Mouse Brain Membrane Proteome with Electrostatic Repulsion Hydrophilic Interaction Chromatography

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

Stress Influences Brain Enkephalinase, Oxytocinase and Angiotensinase Activities: A New Hypothesis

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