Genomes and Genes
proprotein convertase 1
Summary: A CALCIUM-dependent endopeptidase that has specificity for cleavage at ARGININE that is near paired basic residues. It cleaves a variety of prohormones including PRO-OPIOMELANOCORTIN; PRORENIN; proenkephalins; prodynorphin; prosomatostatin; and PROINSULIN.
- Zhou Y, Lindberg I. Purification and characterization of the prohormone convertase PC1(PC3). J Biol Chem. 1993;268:5615-23 pubmed
- Benjannet S, Rondeau N, Paquet L, Boudreault A, Lazure C, Chretien M, et al. Comparative biosynthesis, covalent post-translational modifications and efficiency of prosegment cleavage of the prohormone convertases PC1 and PC2: glycosylation, sulphation and identification of the intracellular site of prosegment cleavage of PC1 . Biochem J. 1993;294 ( Pt 3):735-43 pubmed..In order to test the possibility that zymogen processing is performed by furin, we co-expressed this convertase with either pro-PC1 or pro-PC2. The data demonstrated the inability of furin to cleave either proenzyme. ..
- Breslin M, Lindberg I, Benjannet S, Mathis J, Lazure C, Seidah N. Differential processing of proenkephalin by prohormone convertases 1(3) and 2 and furin. J Biol Chem. 1993;268:27084-93 pubmed
- Hoshino A, Kowalska D, Jean F, Lazure C, Lindberg I. Modulation of PC1/3 activity by self-interaction and substrate binding. Endocrinology. 2011;152:1402-11 pubmed publisher..Our data suggest that enzyme oligomerization and peptide stabilization represent important contributing factors for the control of PC1/3 activity within secretory granules. ..
- Boudreault A, Gauthier D, Lazure C. Proprotein convertase PC1/3-related peptides are potent slow tight-binding inhibitors of murine PC1/3 and Hfurin. J Biol Chem. 1998;273:31574-80 pubmed..These results suggest that the proregion of PC1/3 is an important feature in regulating its activity. ..
- Qian Y, Devi L, Mzhavia N, Munzer S, Seidah N, Fricker L. The C-terminal region of proSAAS is a potent inhibitor of prohormone convertase 1. J Biol Chem. 2000;275:23596-601 pubmed..High concentrations of the inhibitory peptide quantitatively release the bound PC1. Taken together, these data support the proposal that proSAAS functions as an endogenous inhibitor of PC1. ..
- Morgan D, Wei S, Gomes I, Czyzyk T, Mzhavia N, Pan H, et al. The propeptide precursor proSAAS is involved in fetal neuropeptide processing and body weight regulation. J Neurochem. 2010;113:1275-84 pubmed publisher..This work suggests that proSAAS-derived peptides can inhibit PC1/3 in embryonic brain, but in the adult brain proSAAS peptides may function as neuropeptides that regulate body weight and potentially other behaviors. ..
- Zhu X, Zhou A, Dey A, Norrbom C, Carroll R, Zhang C, et al. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci U S A. 2002;99:10293-8 pubmed..The PC1/3-null mice are not obese. The basis for these phenotypic differences is an interesting topic for further study. These findings prove the importance of PC1/3 as a key neuroendocrine convertase. ..
- Goodman L, Gorman C. Autoproteolytic activation of the mouse prohormone convertase mPC1. Biochem Biophys Res Commun. 1994;201:795-804 pubmed..Additionally coexpression of a cleavage-site mutant (Arg110-Ala) with the substrate prorelaxin further demonstrated that autoproteolysis is required for the full activity of PC1. ..
- Hardiman A, Friedman T, Grunwald W, Furuta M, Zhu Z, Steiner D, et al. Endocrinomic profile of neurointermediate lobe pituitary prohormone processing in PC1/3- and PC2-Null mice using SELDI-TOF mass spectrometry. J Mol Endocrinol. 2005;34:739-51 pubmed..The results indicate that, in mice, both PC1/3 or PC2 enzyme activity are capable, but not required to correctly process pro-vasopressin or pro-oxytocin to their constituent active peptide hormones. ..
- Lankat Buttgereit B, Muller S, Schmidt H, Parhofer K, Gress T, Göke R. Knockdown of Pdcd4 results in induction of proprotein convertase 1/3 and potent secretion of chromogranin A and secretogranin II in a neuroendocrine cell line. Biol Cell. 2008;100:703-15 pubmed publisher..A) and Sg II (secretogranin II), and was accompanied by an up-regulation of intracellular PC1 (proprotein convertase 1/3)...
- Refaie S, Gagnon S, Gagnon H, Desjardins R, D Anjou F, D Orléans Juste P, et al. Disruption of proprotein convertase 1/3 (PC1/3) expression in mice causes innate immune defects and uncontrolled cytokine secretion. J Biol Chem. 2012;287:14703-17 pubmed publisherThe proprotein convertase 1/3 is expressed in the regulated secretory pathway of neural and endocrine cells. Its major function is in the post-translational processing and activation of precursor proteins...
- Pan H, Nanno D, Che F, Zhu X, Salton S, Steiner D, et al. Neuropeptide processing profile in mice lacking prohormone convertase-1. Biochemistry. 2005;44:4939-48 pubmed
- Choquet H, Stijnen P, Creemers J. Genetic and functional characterization of PCSK1. Methods Mol Biol. 2011;768:247-53 pubmed publisher..Sequencing efforts of larger cohorts of obese patients might reveal more variants conferring risk of obesity. ..
- Lee S, Prodhomme E, Lindberg I. Prohormone convertase 1 (PC1) processing and sorting: effect of PC1 propeptide and proSAAS. J Endocrinol. 2004;182:353-64 pubmed
- Lee S, Lee D, Sohn M, Yoon J. Overexpressed proprotein convertase 1/3 induces an epithelial-mesenchymal transition in airway epithelium. Eur Respir J. 2013;42:1379-90 pubmed publisher..Taken together, our data suggest that PC1/3 overexpression induces morphological and phenotypic epithelial-mesenchymal transition changes of airway epithelial cells and these changes may contribute to the pathogenesis of nasal polyps. ..
- Jackson R, Creemers J, Farooqi I, Raffin Sanson M, Varro A, Dockray G, et al. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest. 2003;112:1550-60 pubmedWe have previously described the only reported case of human proprotein convertase 1 (PC1) deficiency, in a female (Subject A) with obesity, hypogonadism, hypoadrenalism, and reactive hypoglycemia...
- Benzinou M, Creemers J, Choquet H, Lobbens S, Dina C, Durand E, et al. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat Genet. 2008;40:943-5 pubmed publisher..27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity. ..
- Creemers J, Choquet H, Stijnen P, Vatin V, Pigeyre M, Beckers S, et al. Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity. Diabetes. 2012;61:383-90 pubmed publisherNull mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity...
- Mbikay M, Sirois F, Nkongolo K, Basak A, Chretien M. Effects of rs6234/rs6235 and rs6232/rs6234/rs6235 PCSK1 single-nucleotide polymorphism clusters on proprotein convertase 1/3 biosynthesis and activity. Mol Genet Metab. 2011;104:682-7 pubmed publisherb>Proprotein convertase 1/3 (PC1/3) is one of the endoproteases initiating the proteolytic activation of prohormones and proneuropeptides in the secretory pathway...
- Farooqi S, O Rahilly S. Genetics of obesity in humans. Endocr Rev. 2006;27:710-18 pubmed
- Wen J, Chen Y, Song S, Ding J, Gao Y, Hu Q, et al. Paired box 6 (PAX6) regulates glucose metabolism via proinsulin processing mediated by prohormone convertase 1/3 (PC1/3). Diabetologia. 2009;52:504-13 pubmed publisher..It also provides an insight into the abnormal glucose metabolism caused by heterozygous PAX6 mutations in humans and mice. ..
- Lansac G, Dong W, Dubois C, Benlarbi N, Afonso C, Fournier I, et al. Lipopolysaccharide mediated regulation of neuroendocrine associated proprotein convertases and neuropeptide precursor processing in the rat spleen. J Neuroimmunol. 2006;171:57-71 pubmed..Collectively, these data clearly implicate PCs in immune responses, both innate and acquired. ..
- Creemers J, Pritchard L, Gyte A, Le Rouzic P, Meulemans S, Wardlaw S, et al. Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)83-132: interaction between AGRP83-132 and melanocortin receptors cannot be influenced by syndecan-3. Endocrinology. 2006;147:1621-31 pubmed..Because AGRP is cleaved before secretion, syndecan-3 must influence food intake independently of the MC4-R. ..
- Martin M, Lindberg I, Solorzano Vargas R, Wang J, Avitzur Y, Bandsma R, et al. Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology. 2013;145:138-148 pubmed publisherb>Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, ..
- Zhu X, Orci L, Carroll R, Norrbom C, Ravazzola M, Steiner D. Severe block in processing of proinsulin to insulin accompanied by elevation of des-64,65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3. Proc Natl Acad Sci U S A. 2002;99:10299-304 pubmed..These results confirm that PC1/3 plays a major role in processing proinsulin, but that its coordinated action with PC2 is necessary for the most efficient and complete processing of this prohormone. ..
- Apletalina E, Appel J, Lamango N, Houghten R, Lindberg I. Identification of inhibitors of prohormone convertases 1 and 2 using a peptide combinatorial library. J Biol Chem. 1998;273:26589-95 pubmed
- Jackson R, Creemers J, Ohagi S, Raffin Sanson M, Sanders L, Montague C, et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet. 1997;16:303-6 pubmed..In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents. ..
- Bicknell A. The tissue-specific processing of pro-opiomelanocortin. J Neuroendocrinol. 2008;20:692-9 pubmed publisher..This level of complexity has resulted in POMC becoming the archetypal model for prohormone processing, illustrating how a single protein combined with post-translational modification can have a diverse number of roles. ..
- Zhu X, Cao Y, Voogd K, Voodg K, Steiner D. On the processing of proghrelin to ghrelin. J Biol Chem. 2006;281:38867-70 pubmed
- Davidson H. (Pro)Insulin processing: a historical perspective. Cell Biochem Biophys. 2004;40:143-58 pubmed..of some of the key research projects leading to the identification of the central processing enzymes as proprotein convertase 1, proprotein convertase 2, and carboxypeptidase E...
- Wardman J, Zhang X, Gagnon S, Castro L, Zhu X, Steiner D, et al. Analysis of peptides in prohormone convertase 1/3 null mouse brain using quantitative peptidomics. J Neurochem. 2010;114:215-25 pubmed publisher..Analysis of these sites showed that while PC1/3 and PC2 have overlapping substrate preferences, there are particular cleavage site residues that distinguish peptides preferred by each PC. ..
- Dikeakos J, Mercure C, Lacombe M, Seidah N, Reudelhuber T. PC1/3, PC2 and PC5/6A are targeted to dense core secretory granules by a common mechanism. FEBS J. 2007;274:4094-102 pubmed..Analysis of the predicted structures formed by these three granule-sorting helices shows a correlation between their granule-sorting efficiency and the clustering of hydrophobic amino acids in their granule-targeting helices. ..
- Farooqi I, Volders K, Stanhope R, Heuschkel R, White A, Lank E, et al. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J Clin Endocrinol Metab. 2007;92:3369-73 pubmed..This case extends the clinical and molecular spectrum of human congenital PC1/3 deficiency. ..
- Seidah N, Marcinkiewicz M, Benjannet S, Gaspar L, Beaubien G, Mattei M, et al. Cloning and primary sequence of a mouse candidate prohormone convertase PC1 homologous to PC2, Furin, and Kex2: distinct chromosomal localization and messenger RNA distribution in brain and pituitary compared to PC2. Mol Endocrinol. 1991;5:111-22 pubmed..The genes coding for mPC1 and mPC2 map to the murine chromosomes 13 (band 13c) and 2 (2F3-2H2 region), respectively. ..
- Tateno T, Izumiyama H, Doi M, Akashi T, Ohno K, Hirata Y. Defective expression of prohormone convertase 1/3 in silent corticotroph adenoma. Endocr J. 2007;54:777-82 pubmed..Our data suggest that defective PC1/3 expression may lead to preferential production of unprocessed, biologically inactive ACTH variants in SCA. ..
- Kilimnik G, Kim A, Steiner D, Friedman T, Hara M. Intraislet production of GLP-1 by activation of prohormone convertase 1/3 in pancreatic ?-cells in mouse models of ß-cell regeneration. Islets. 2010;2:149-55 pubmed..Our study suggests an important role of ?-cells for ß-cell proliferation and further for the endocrine cell network within an islet. ..
- Garruti G, Cotecchia S, Giampetruzzi F, Giorgino F, Giorgino R. Neuroendocrine deregulation of food intake, adipose tissue and the gastrointestinal system in obesity and metabolic syndrome. J Gastrointestin Liver Dis. 2008;17:193-8 pubmed..Nonetheless, it was recently discovered that a mutation in the prohormone convertase 1/3 simultaneously produces severe gastrointestinal dysfunctions and obesity. ..
- Beinfeld M, Vishnuvardhan D, Blum A, Reynolds N, Fannous S, Kitagawa K, et al. Inhibition of prohormone convertase 1 (PC1) expression in cholecystokinin (CCK) expressing At-T20 cells decreased cellular content and secretion of CCK and caused a shift in molecular forms of CCK secreted. Peptides. 2006;27:905-10 pubmed..Stable expression of RNAi effectively decreased PC1 expression. The observed decrease in CCK seen with these RNAi treatments further supports a role for PC1 in CCK processing in these cells. ..
- Tzimas G, Chevet E, Jenna S, Nguyen D, Khatib A, Marcus V, et al. Abnormal expression and processing of the proprotein convertases PC1 and PC2 in human colorectal liver metastases. BMC Cancer. 2005;5:149 pubmed..In addition, the exclusive presence of 7B2 in metastatic tumors may represent a new target for early diagnosis, prognosis and/or treatment. ..
- Krajnik M, Schafer M, Sobanski P, Kowalewski J, Bloch Boguslawska E, Zylicz Z, et al. Enkephalin, its precursor, processing enzymes, and receptor as part of a local opioid network throughout the respiratory system of lung cancer patients. Hum Pathol. 2010;41:632-42 pubmed publisher..These findings encourage future studies to examine the functional role of local opioid peptides within the respiratory system...
- Portela Gomes G, Grimelius L, Stridsberg M. Prohormone convertases 1/3, 2, furin and protein 7B2 (Secretogranin V) in endocrine cells of the human pancreas. Regul Pept. 2008;146:117-24 pubmed
- Yongye A, Vivoli M, Lindberg I, Appel J, Houghten R, Martinez Mayorga K. Identification of a small molecule that selectively inhibits mouse PC2 over mouse PC1/3: a computational and experimental study. PLoS ONE. 2013;8:e56957 pubmed publisher..In addition, this new PC2 inhibitor is structurally different and of smaller size than those reported previously. This is advantageous for future studies where structural analogues can be built upon. ..
- Ftouhi N, Day R, Mbikay M, Chretien M, Seidah N. Gene organization of the mouse pro-hormone and pro-protein convertase PC1. DNA Cell Biol. 1994;13:395-407 pubmed..Using a 3' end probe specifically hybridizing with the 5-kb mRNA, we show that in the mouse pituitary neurointermediate lobe the 3-kb form is negatively regulated by dopamine, while the 5-kb form is not. ..
- Patriti A, Aisa M, Annetti C, Sidoni A, Galli F, Ferri I, et al. How the hindgut can cure type 2 diabetes. Ileal transposition improves glucose metabolism and beta-cell function in Goto-kakizaki rats through an enhanced Proglucagon gene expression and L-cell number. Surgery. 2007;142:74-85 pubmed..Moreover, these findings confirm at the preclinical level that IT is a surgical procedure of possible relevance in the therapy of type 2 diabetes in non-overweight and mildly obese patients. ..
- Jing E, Nillni E, Sanchez V, Stuart R, Good D. Deletion of the Nhlh2 transcription factor decreases the levels of the anorexigenic peptides alpha melanocyte-stimulating hormone and thyrotropin-releasing hormone and implicates prohormone convertases I and II in obesity. Endocrinology. 2004;145:1503-13 pubmed..Furthermore, this work supports a direct role for transcriptional control of neuropeptide processing enzymes in the etiology of adult-onset obesity. ..
- Marandi M, Mowla S, Tavallaei M, Yaghoobi M, Jafarnejad S. Proprotein convertases 1 and 2 (PC1 and PC2) are expressed in neurally differentiated rat bone marrow stromal stem cells (BMSCs). Neurosci Lett. 2007;420:198-203 pubmed..In conclusion, our results suggest that neurally differentiated BMSCs have acquired the functional machinery to process the precursor forms of proteins in both the constitutive and regulated pathways. ..
- Farooqi I. Genetic and hereditary aspects of childhood obesity. Best Pract Res Clin Endocrinol Metab. 2005;19:359-74 pubmed
- van Wamelen D, Aziz N, Zhao J, Balesar R, Unmehopa U, Roos R, et al. Decreased hypothalamic prohormone convertase expression in huntington disease patients. J Neuropathol Exp Neurol. 2013;72:1126-34 pubmed publisher..These changes might contribute to selective neuropathology underlying various clinical manifestations and may provide novel therapeutic targets in HD patients. ..
- Evans J, Fernando A, Ragolia L. Functional melanocortin-2 receptors are expressed by mouse aorta-derived mesenchymal progenitor cells. Mol Cell Endocrinol. 2012;355:60-70 pubmed publisher..These data demonstrate functional MC2-R expression in mouse aorta-derived mesenchymal progenitors and implicate both macrophage and mesenchymal cells as relevant sources of local POMC peptides. ..
- Mbikay M, Croissandeau G, Sirois F, Anini Y, Mayne J, Seidah N, et al. A targeted deletion/insertion in the mouse Pcsk1 locus is associated with homozygous embryo preimplantation lethality, mutant allele preferential transmission and heterozygous female susceptibility to dietary fat. Dev Biol. 2007;306:584-98 pubmedb>Proprotein convertase 1 (PC1) is a neuroendocrine proteinase involved in the proteolytic activation of precursors to hormones and neuropeptides...
- Peinado J, Li H, Johanning K, Lindberg I. Cleavage of recombinant proenkephalin and blockade mutants by prohormone convertases 1 and 2: an in vitro specificity study. J Neurochem. 2003;87:868-78 pubmed..Furthermore, glycosylated PE was less efficiently processed by PC2, indicating that glycosylation may serve as a mechanism to hinder processing. ..
- Cain B, Connolly K, Blum A, Vishnuvardhan D, Marchand J, Beinfeld M, et al. Distribution and colocalization of cholecystokinin with the prohormone convertase enzymes PC1, PC2, and PC5 in rat brain. J Comp Neurol. 2003;467:307-25 pubmed..These three enzymes may represent a redundant system to ensure production of biologically active CCK. ..
- Kurabuchi S, Tanaka S. Immunocytochemical localization of prohormone convertases PC1 and PC2 in the mouse thyroid gland and respiratory tract. J Histochem Cytochem. 2002;50:903-9 pubmed..These findings suggest that procalcitonin is proteolytically cleaved by PC2 alone or by PC2 together with PC1, and that the proCGRP is cleaved by PC1. ..
- Raverot G, Wierinckx A, Jouanneau E, Auger C, Borson Chazot F, Lachuer J, et al. Clinical, hormonal and molecular characterization of pituitary ACTH adenomas without (silent corticotroph adenomas) and with Cushing's disease. Eur J Endocrinol. 2010;163:35-43 pubmed publisher..65; P<0.05). Despite the absence of hypercortisolism, SCAs exhibit histological, biochemical and molecular corticotroph differentiation. SCA and MCA show hormonal and molecular similarities differentiating them from mCA. ..
- Kedees M, Grigoryan M, Guz Y, Teitelman G. Differential expression of glucagon and glucagon-like peptide 1 receptors in mouse pancreatic alpha and beta cells in two models of alpha cell hyperplasia. Mol Cell Endocrinol. 2009;311:69-76 pubmed publisher..In addition, they also suggest that the incretin could mediate alpha cell proliferation, inducing the development of alpha cell hyperplasia in Gcgr-/- mice. ..
- Perello M, Stuart R, Vaslet C, Nillni E. Cold exposure increases the biosynthesis and proteolytic processing of prothyrotropin-releasing hormone in the hypothalamic paraventricular nucleus via beta-adrenoreceptors. Endocrinology. 2007;148:4952-64 pubmed..In contrast, alpha-adrenoreceptors regulate TRH secretion but not proTRH biosynthesis and processing. Therefore, this study provides novel information on the molecular mechanisms of control of hypophysiotropic TRH biosynthesis. ..
- Salvas A, Benjannet S, Reudelhuber T, Chretien M, Seidah N. Evidence for proprotein convertase activity in the endoplasmic reticulum/early Golgi. FEBS Lett. 2005;579:5621-5 pubmed..This suggests that the convertases could cleave some substrates within the ER, possibly by displacing the inhibitory prosegment associated with them. ..
- Tatsumi K, Tanaka S, Takano T, Tahara S, Murakami Y, Takao T, et al. Frequent appearance of autoantibodies against prohormone convertase 1/3 and neuroendocrine protein 7B2 in patients with nonfunctioning pituitary macroadenoma. Endocrine. 2003;22:335-40 pubmed..These results suggest that autoantibodies against PC1/3 and 7B2 are novel tumor-associated autoantibodies and can be helpful in the diagnosis of clinically nonfunctioning pituitary macroadenoma. ..
- Dhanvantari S, Izzo A, Jansen E, Brubaker P. Coregulation of glucagon-like peptide-1 synthesis with proglucagon and prohormone convertase 1 gene expression in enteroendocrine GLUTag cells. Endocrinology. 2001;142:37-42 pubmed..01 vs. 12-h levels). Thus, PKA-induced secretion of GLP-1 from the L cell is followed by restoration of the cellular peptide levels through a PKA-mediated, CRE-dependent up-regulation of proglucagon and PC1 gene expression. ..
- Dai G, Smeekens S, Steiner D, McMurtry J, Kwok S. Characterization of multiple prohormone convertase PC1/3 transcripts in porcine ovary. Biochim Biophys Acta. 1995;1264:1-6 pubmed..Furthermore, five different polyadenylation sites have been observed. The utilization of these polyadenylation sites results in a length difference of 40-440 bp in the 3' untranslated regions of the transcripts. ..
- Aminzadeh M, Kim H, Layman L, Cheetham T. Rarer syndromes characterized by hypogonadotropic hypogonadism. Front Horm Res. 2010;39:154-67 pubmed publisher..Longer term therapy with sex steroid replacement is becoming even more important if improvements in life expectancy are to be matched by improvements in quality of life. ..
- Sato N, Ogawa Y. [Prohormone convertase 1 (PC1) gene mutation]. Nihon Rinsho. 2006;Suppl 3:249-53 pubmed
- Mzhavia N, Qian Y, Feng Y, Che F, Devi L, Fricker L. Processing of proSAAS in neuroendocrine cell lines. Biochem J. 2002;361:67-76 pubmed..In addition, the finding that the peptides are secreted via the regulated pathway is consistent with the proposal that they may function as neuropeptides. ..