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Rebecca McGirr, Leonardo Guizzetti and Savita Dhanvantari

L cells, and by the primary and secondary structures of proglucagon. The prohormone processing enzyme carboxypeptidase E (CPE) is expressed in both alpha and L cells, while PC1/3 is found in L cells and PC2 in alpha cells. Several lines of evidence

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L Friis-Hansen, KA Lacourse, LC Samuelson and JJ Holst

The maturation of many peptide hormones is attenuated in carboxypeptidase E (CPE)-deficient fat/fat mice, leading to a slowly developing, adult-onset obesity with mild diabetes. To determine the contribution of the hormones generated from the proglucagon precursor to this phenotype, we studied the tissue-specific processing of glucagon and glucagon-like peptide-1 (GLP-1) in these mice. In all tissues examined there was a great reduction in mature amidated GLP-1. Furthermore, a lack of CPE attenuates prohormone convertase processing of proglucagon in both the pancreas and the intestine. These findings suggest that defects in proglucagon processing together with other endocrine malfunctions could contribute to the diabetic and obesity phenotype in fat/fat mice.

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EH Leiter

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S Wei, Y Feng, FY Che, H Pan, N Mzhavia, LA Devi, AA McKinzie, N Levin, WG Richards and LD Fricker

ProSAAS is a neuroendocrine peptide precursor that potently inhibits prohormone convertase 1 in vitro. To explore the function of proSAAS and its derived peptides, transgenic mice were created which express proSAAS using the beta-actin promoter. The body weight of transgenic mice was normal until approximately 10-12 weeks, and then increased 30-50% over wild-type littermates. Adult transgenic mice had a fat mass approximately twice that of wild-type mice, and fasting blood glucose levels were slightly elevated. In the pituitary, the levels of several fully processed peptides in transgenic mice were not reduced compared with wild-type mice, indicating that the proSAAS transgene did not affect prohormone convertase 1 activity in this tissue. Because the inhibitory potency of proSAAS-derived peptides towards prohormone convertase 1 is much greater in the absence of carboxypeptidase E activity, the proSAAS transgene was also expressed in carboxypeptidase E-deficient Cpe (fat/fat) mice. Although the transgenic mice were born in the expected frequency, 21 of 22 proSAAS transgenic Cpe (fat/fat) mice died between 11 and 26 weeks of age, presumably due to greatly elevated blood glucose. The levels of several pituitary peptides were significantly reduced in the proSAAS transgenic Cpe (fat/fat) mice relative to non-transgenic Cpe (fat/fat) mice, suggesting that the transgene inhibited prohormone convertase 1 in these mice. Taken together, these results are consistent with a role for proSAAS-derived peptides as neuropeptides that influence body weight independently of their function as inhibitors of prohormone convertase 1.

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PC Guest, SM Abdel-Halim, DJ Gross, A Clark, V Poitout, R Amaria, CG Ostenson and JC Hutton

The biosynthesis and processing of proinsulin was investigated in the diabetic Goto-Kakizaki (GK) rat. Immunofluorescence microscopy comparing GK and Wistar control rat pancreata revealed marked changes in the distribution of alpha-cells and pronounced beta-cell heterogeneity in the expression patterns of insulin, prohormone convertases PC1, PC2, carboxypeptidase E (CPE) and the PC-binding proteins 7B2 and ProSAAS. Western blot analyses of isolated islets revealed little difference in PC1 and CPE expression but PC2 immunoreactivity was markedly lower in the GK islets. The processing of the PC2-dependent substrate chromogranin A was reduced as evidenced by the appearance of intermediates. No differences were seen in the biosynthesis and post-translational modification of PC1, PC2 or CPE following incubation of islets in 16.7 mM glucose, but incubation in 3.3 mM glucose resulted in decreased PC2 biosynthesis in the GK islets. The rates of biosynthesis, processing and secretion of newly synthesized (pro)insulin were comparable. Circulating insulin immunoreactivity in both Wistar and GK rats was predominantly insulin 1 and 2 in the expected ratios with no (pro)insulin evident. Thus, the marked changes in islet morphology and PC2 expression did not impact the rate or extent of proinsulin processing either in vitro or in vivo in this experimental model.

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Kikuko Hotta, Masahiro Hosaka, Atsushi Tanabe and Toshiyuki Takeuchi

Letters 248 133 – 137 . Hosaka M Watanabe T Sakai Y Kato T Takeuchi T 2005 Interaction between secretogranin III and carboxypeptidase E facilitates prohormone sorting within secretory granules . Journal of Cell Science 118 4785

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Xiaoqin Shi, Xinyu Li, Yi Hou, Xuemei Cao, Yuyao Zhang, Heng Wang, Hongyin Wang, Chuan Peng, Jibin Li, Qifu Li, Chaodong Wu and Xiaoqiu Xiao

after refeeding. α-MSH was produced from POMC through a series of enzymatic cleavage including type 1 and type 2 prohormone convertase (PC1 and PC2) and carboxypeptidase E (CPE) ( Nillni 2016 ) ( Fig. 5B ). To test if changes in POMC expression and

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Niamh X Cawley, Guida Portela-Gomes, Hong Lou and Y Peng Loh

-basic residue cleavage site and that carboxypeptidase E-like activity from the N2a conditioned media likely removed the extended basic residues to generate authentic glucagon. This processing pattern would be consistent with yapsin 1 specificity because both the

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Anaies Nazarians-Armavil, Jennifer A Chalmers, Claire B Lee, Wenqing Ye and Denise D Belsham

following treatment, insulin significantly increased Pomc transcript levels ( Fig. 3 D) and slightly decreased Insr ( Ir ) mRNA expression ( Fig. 3 E). There were no significant differences in gene expression of IRS1, IRS2, carboxypeptidase E (CPE

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Lorraine O’Driscoll, Patrick Gammell, Eadaoin McKiernan, Eoin Ryan, Per Bendix Jeppesen, Sweta Rani and Martin Clynes

-secreting structures similar to pancreatic islets. Science 292 1389 –1394. Marzban L , Soukhatcheva G & Verchere CB 2005 Role of carboxypeptidase E in processing of pro-islet amyloid polypeptide in β-cells. Endocrinology 146 1808