Prohormone convertase-1 is essential for conversion of chromogranin A to pancreastatin

Udupi, Vidyavathi; Lee, Heung Man; Kurosky, Alexander; Greeley, George H.

doi:10.1016/s0167-0115(99)00061-0

Cited by 28 publications

(18 citation statements)

References 28 publications

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“…In contrast, plasma CgA was elevated in 10 (83%) while PST was abnormally elevated in 50% of this group. We could therefore identify no overall effect of PPIs on PST (no differences in PPI-treated and non-treated controls), which presumably reflects the heterogeneity in secretion of this peptide family following prohormone cleavage (Udupi et al 1999). While others have identified correlations between CgA and PST (Syversen et al 1994), we could identify no statistically significant relationship; this is consistent with previous assays (Stronge et al 2008, O'Dorisio et al 2010.…”

Section: Discussionsupporting

confidence: 86%

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A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection

Modlin

Drozdov

Alaimo

et al. 2014

Endocrine-Related Cancer

103

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A critical requirement in neuroendocrine tumor (NET) management is a sensitive, specific and reproducible blood biomarker test. We evaluated a PCR-based 51 transcript signature (NETest) and compared it to chromogranin A (CgA), pancreastatin (PST) and neurokinin A (NKA). The multigene signature was evaluated in two groups: i) a validation set of 40 NETs and controls and ii) a prospectively collected group of NETs (nZ41, 61% small intestinal, 50% metastatic, 44% currently treated and 41 age-sex matched controls). Samples were analyzed by a two-step PCR (51 marker genes) protocol and ELISAs for CgA, PST and NKA. Sensitivity comparisons included c 2 , non-parametric measurements, ROC curves and predictive feature importance (PFAI) analyses. NETest identified 38 of 41 NETs. Performance metrics were: sensitivity 92.8%, specificity 92.8%, positive predictive value 92.8% and negative predictive value 92.8%. Single analyte ELISA metrics were: CgA 76, 59, 65, and 71%; PST 63, 56, 59, and 61% and NKA 39, 93, 84, and 60%. The AUCs (ROC analysis) were: NETest: 0.96G0.025, CgA: 0.67G0.06, PST 0.56G0.06, NKA: 0.66G0.06. NETest significantly outperformed single analyte tests (area differences: 0.284-0.403, Z-statistic 4.85-5.9, P!0.0001). PFAI analysis determined NETest had most value (69%) in diagnosis (CgA (13%), PST (9%), and NKA (9%)). Test data were consistent with the validation set (NETest O95% sensitivity and specificity, AUC Z0.98 vs single analytes: 59-67% sensitivity, AUCs: 0.58-0.63). The NETest is significantly more sensitive and efficient (O93%) than single analyte assays (CgA, PST or NKA) in NET diagnosis. Blood-based multigene analytic measurement will facilitate early detection of disease recurrence and can predict therapeutic efficacy.

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Section: Discussionsupporting

confidence: 86%

“…Pancreastatin (PST) is a derivative of CgA that inhibits both pancreatic insulin and exocrine secretion, and may stimulate gastric acid secretion (Udupi et al 1999). It is elevated in 58-81% of NETs (Stridsberg et al 1995, Calhoun et al 2003 and does not appear to be elevated by PPI use (Raines et al 2012).…”

Section: Introductionmentioning

confidence: 99%

A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection

Modlin

Drozdov

Alaimo

et al. 2014

Endocrine-Related Cancer

103

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“…3), revealed a major catestatin form (bovine chromogranin A 332-364 ) cleaved, as expected, at dibasic sites: KRLEGEEE-EEEDPDRSMRLSFRARGYGFRGPGLQLRR. Recognition of dibasic recognition sites by prohormone convertases is well described in chromogranin A; we (28) and others (29) have shown that chromogranin A is a substrate in vivo for prohormone convertases 1 and 2 as well as furin. Chromogranin B and secretogranin II are also cleaved by prohormone convertases (30).…”

Section: -4)mentioning

confidence: 60%

Formation of the Catecholamine Release-inhibitory Peptide Catestatin from Chromogranin A

Taylor¹,

Taupenot²,

Mahata³

et al. 2000

Journal of Biological Chemistry

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We conclude that catestatin is cleaved extensively in vivo, and the peptide is released by exocytosis. In chromaffin granules, the major form of catestatin is cleaved at dibasic sites, while smaller carboxyl-terminal forms also occur. Knowledge of cleavage sites of catestatin from chromogranin A may provide a useful starting point in analysis of the relationship between structure and function for this peptide.Chromogranin A, the major soluble protein in catecholamine storage vesicles, not only stabilizes the core of such vesicles (1) but also serves as a prohormone cleaved into several biologically active peptides, including the insulin release-inhibitory fragments pancreastatin (2) and ␤-granin (3-5), the vasodilator vasostatin (6, 7), and the parathyroid hormone release-inhibitory parastatin (8). Recently we described an additional chromogranin A fragment, catestatin (bovine chromogranin A 344 -364), which acts specifically as a potent (IC 50 ϳ200 -400 nM) nicotinic cholinergic antagonist to inhibit catecholamine release (9, 10), suggesting a novel autocrine feedback mechanism controlling sympathochromaffin exocytosis. Initial studies of catestatin relied on synthetic peptides (10); hence, the existence of the peptide in vivo remains unexplored, as do its precise cleavage sites from chromogranin A.In this study, we explored processing of the catestatin region of chromogranin A in secretory granules of chromaffin cells and sympathetic nerves, as well as in human pheochromocytomas. We documented catestatin cleavage from chromogranin A and determined the precise endogenous cleavage sites bounding catestatin in bovine and human chromaffin granules by chromatographic separations coupled with amino-terminal amino acid sequencing, immunoprecipitation, and matrix-assisted laser desorption ionization (MALDI) 1 mass spectrometry. We confirmed catestatin's regulated secretion by chromaffin cells. A major form of catestatin was processed at dibasic sites (bovine chromogranin A 332-364 or human chromogranin A 340 -372 ), while a smaller form was also identified (bovine chromogranin A 343-362 ). Both larger and smaller size forms were synthesized; each displayed specific antagonism of nicotinic cholinergicstimulated catecholamine release, while the smaller form had greater potency of inhibition. MATERIALS AND METHODS Preparation of TissueFractions-All preparative steps on tissues or protein fractions were conducted at 0 -4°C. Bovine adrenal medullary chromaffin granules were prepared by centrifugation on 0.3 M/1.6 M sucrose density step gradients, as described previously (10). After granule hypotonic lysis and centrifugal removal of granule membranes, the soluble proteins and peptides in the supernatant were size-fractionated on a 2.6 ϫ 80-cm Sephacryl S-300 column (Amersham Pharmacia Biotech), eluting with the volatile buffer 0.3 M ammonium acetate, pH 6.5, as described previously (11). The buffer was removed by lyophilization before further studies. In some experiments, bovine chromaffin granule proteins/peptides (200 l c...

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“…Seven-hundred and twenty microliters of apelin ELISA buffer were added to all samples for apelin determinations. For the second method, apelin immunoreactivity was extracted using a standard protein extraction method (43,44). In brief, pancreatic samples were homogenized in lysis buffer containing 60 mM DTT, 1 mM PMSF, and Complete Mini Protease Inhibitor Fig.…”

Section: Apelin Elisamentioning

confidence: 99%

Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice

Rastellini

Han

Bhatia

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Prohormone convertase-1 is essential for conversion of chromogranin A to pancreastatin

Cited by 28 publications

References 28 publications

A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection

A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection

Formation of the Catecholamine Release-inhibitory Peptide Catestatin from Chromogranin A

Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice

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