Processing of pro‐islet amyloid polypeptide (proIAPP) by the prohormone convertase PC2

Badman, Michael K.; Shennan, K. I. J.; Jermany, Joanne L.; Docherty, Kevin; Clark, Anne

doi:10.1016/0014-5793(95)01460-8

Cited by 57 publications

(39 citation statements)

References 28 publications

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“…Therefore, in PC2 null mice, cleavage at the NH 2 -terminus is completely blocked (since only PC2 can cleave at this site) and cleavage at the COOH-terminus is mediated by PC1/3 and is normal, whereas in PC1/3 null mice, cleavage at the COOH-terminus is impaired (since PC1/3 preferentially cleaves at this site) but proIAPP is still processed to IAPP by the action of PC2 at both cleavage sites. These data are in agreement with earlier in vitro studies that suggested that PC2 can process proIAPP at its COOH-terminal cleavage site (30,31). Interestingly, the lack of active PC1/3 in PC1/3 Ϫ/Ϫ islets was not accompanied by a compensatory increase in PC2 protein levels, implying that normal levels of PC2 are enough to process proIAPP at both sites.…”

Section: Discussionsupporting

confidence: 92%

“…The mechanism(s) by which proIAPP, the IAPP precursor molecule, is processed in vivo is still not completely understood, but it is likely that the prohormone convertases PC1/3 and PC2, which are responsible for processing proinsulin to insulin and C-peptide (18,21,27,29), also mediate proIAPP processing (24,30,31). We have previously shown that mice lacking PC2 are unable to process proIAPP at its NH 2 -terminal cleavage site, indicating that PC2 is essential for proIAPP processing at the NH 2 -terminus in vivo (24).…”

Section: Discussionmentioning

confidence: 99%

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Role of β-Cell Prohormone Convertase (PC)1/3 in Processing of Pro-Islet Amyloid Polypeptide

et al. 2004

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1Islet amyloid polypeptide (IAPP) (amylin), the major component of islet amyloid, is produced by cleavage at the COOH-and NH 2 -termini of its precursor, proIAPP, likely by the ␤-cell prohormone convertases (PC) 1/3 and PC2. Mice lacking PC2 can process proIAPP at its COOH-but not its NH 2 -terminal cleavage site, suggesting that PC1/3 is capable of initiating proIAPP cleavage at its COOH-terminus. To determine the precise role of PC1/3 in proIAPP processing, Western blot analysis was performed on islets isolated from mice lacking PC1/3 (PC1/3 ؊/؊ ). These islets contained not only fully processed IAPP as in PC1/3 ؉/؉ islets, but also elevated levels of a COOH-terminally unprocessed intermediate form, suggesting impaired processing at the COOHterminus. Next, GH3 cells that do not normally express proIAPP or detectable levels of PC1/3 or PC2 were cotransduced with adenoviruses expressing rat proIAPP and either PC2 or PC1/3. As expected, in GH3 cells transduced to express only proIAPP, no processing was observed. Coexpression of proIAPP and PC2 resulted in production of mature IAPP, whereas in cells that coexpressed proIAPP and PC1/3 only a 6-kDa intermediate was produced. We conclude that PC1/3 is important for processing of proIAPP at the COOHterminus, but in its absence, PC2 can initiate complete processing of proIAPP to IAPP by cleaving the precursor at either its NH 2 -or COOH-terminal cleavage sites.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Role of β-Cell Prohormone Convertase (PC)1/3 in Processing of Pro-Islet Amyloid Polypeptide

et al. 2004

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“…This relative abundance of IAPP precursors might result from a combination of increased rates of synthesis (present data) and a saturation of the IAPP processing activity [21,23]. This would be expected to lead to the release of a higher proportion of precursor-and intermediate forms, similar to the relative hypersecretion of proinsulin from tissue with a higher proportion of this precursor [24].…”

Section: Discussionmentioning

confidence: 95%

Prolonged exposure of pancreatic beta cells to raised glucose concentrations results in increased cellular content of islet amyloid polypeptide precursors

et al. 1999

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Islet amyloid polypeptide (IAPP) is a 37 amino acid peptide that is produced by pancreatic beta cells following synthesis of (pre)pro-IAPP and proteolytic cleavage at dibasic lys-arg residues [1]. The peptide is the predominant component of the amyloid deposits which are often observed in pancreatic islets of non-insulin dependent diabetic patients [2,3]. Formation of amyloid fibrils appears dependent on an amyloidogenic region (amino acids 20±29) in the IAPP-amino acid sequence, known to be present in the human peptide [4,5]. Overproduction and increased secretion of IAPP have been suggested to be predisposing conditions [6,7] but their relation to amyloid formation is not yet understood [8]. Newly diagnosed patients with Type II (non-insulin-dependent) diabetes have increased circulating concentrations of IAPP-like immunoreactivity, containing high MW IAPP-like peptides [9]. Islet amyloid polypeptide precursors also seem to be present in the amyloid deposits, as documented by their immunocytochemical reactivity for a flanking peptide sequence of pro-IAPP [10]. It is still not clear to which extent precursor forms are present in islet beta cells and whether continuously raised glucose concentrations ± as occurring in non-insulin dependent diabetes ± can increase their abundance, intra-and extracellu- Diabetologia (1999) Summary Most non-insulin dependent diabetic patients have amyloid deposits in their pancreatic islets. It is not known whether chronic hyperglycaemia contributes to the formation of amyloid fibrils from the islet amyloid polypeptide that is produced by the pancreatic beta cells. Since islet amyloid exhibits islet amyloid polypeptide precursors immunoreactivity, we examined whether sustained in vitro exposure to raised glucose increases the abundance of these precursors in human beta cells. After 6 days stimulation with 20 mmol/l glucose the cellular content of insulin but not islet amyloid polypeptide was decreased leading to an increase in the ratio of the latter over insulin (3.0 ± 0.6 vs 1.8 ± 0.3 after 6 mmol/l glucose culture, p < 0.05). Similar changes occurred in rat beta cells cultured for 3 days in the presence of 20 mmol/1 glucose plus 3-isobutyl-1-methylxanthine. Western blot analysis of cellular islet amyloid polypeptide after prolonged exposure to high glucose indicated the presence of higher proportions of its precursor-and intermediate forms. In human beta cells cultured in 20 mmol/l glucose, the major form corresponds to an intermediate species which exhibits an immunoreactivity for the N-flanking peptide, as is also the case in islet amyloid. We concluded that prolonged in vitro exposure of beta cells to raised glucose concentrations increases the relative proportion of islet amyloid polypeptide over insulin, as well as of its precursors over the mature form of islet amyloid polypeptide. [Diabetologia (1999)

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“…This impairment in the initial step in proIAPP processing might be due to impaired action of PC3 in these mice, possibly because of substrate inhibition of the enzyme by the accumulation of the NH 2 -terminal proIAPP conversion intermediate. Alternatively, it is possible that PC2 may also contribute to processing of proIAPP at the COOH-terminal cleavage site, as has been suggested by in vitro studies (15,21).…”

Section: Discussionmentioning

confidence: 98%

The Prohormone Convertase Enzyme 2 (PC2) Is Essential for Processing Pro-Islet Amyloid Polypeptide at the NH2-Terminal Cleavage Site

et al. 2001

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Impaired processing of pro-islet amyloid polypeptide (proIAPP), the precursor of the ␤-cell peptide islet amyloid polypeptide (IAPP) (amylin), has been implicated in islet amyloid formation in type 2 diabetes. The prohormone convertase enzymes PC3 (also known as PC1) and PC2 are localized to ␤-cell secretory granules with proIAPP and proinsulin and are responsible for proinsulin processing. To determine whether PC2 might be essential for proIAPP processing, we performed Western blot analysis of freshly isolated islets from normal mice and mice lacking active PC2. As expected, the primary species of IAPP immunoreactivity in islets from wild-type mice was fully processed (4-kDa) IAPP, with only small amounts of the 8-kDa precursor (unprocessed proIAPP) present. Islets from heterozygous PC2 null mice were identical to wild-type animals, suggesting that half the normal complement of PC2 is sufficient for normal proIAPP processing. By contrast, in islets from homozygous PC2 null mice, the predominant IAPP-

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Processing of pro‐islet amyloid polypeptide (proIAPP) by the prohormone convertase PC2

Cited by 57 publications

References 28 publications

Role of β-Cell Prohormone Convertase (PC)1/3 in Processing of Pro-Islet Amyloid Polypeptide

Role of β-Cell Prohormone Convertase (PC)1/3 in Processing of Pro-Islet Amyloid Polypeptide

Prolonged exposure of pancreatic beta cells to raised glucose concentrations results in increased cellular content of islet amyloid polypeptide precursors

The Prohormone Convertase Enzyme 2 (PC2) Is Essential for Processing Pro-Islet Amyloid Polypeptide at the NH2-Terminal Cleavage Site

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