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      Plasma levels of the proprotein convertase furin and incidence of diabetes and mortality

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          Abstract

          Background

          Diabetes mellitus is linked to premature mortality of virtually all causes. Furin is a proprotein convertase broadly involved in the maintenance of cellular homeostasis; however, little is known about its role in the development of diabetes mellitus and risk of premature mortality.

          Objectives

          To test if fasting plasma concentration of furin is associated with the development of diabetes mellitus and mortality.

          Methods

          Overnight fasted plasma furin levels were measured at baseline examination in 4678 individuals from the population‐based prospective Malmö Diet and Cancer Study. We studied the relation of plasma furin levels with metabolic and hemodynamic traits. We used multivariable Cox proportional hazards models to investigate the association between baseline plasma furin levels and incidence of diabetes mellitus and mortality during 21.3–21.7 years follow‐up.

          Results

          An association was observed between quartiles of furin concentration at baseline and body mass index, blood pressure and plasma concentration of glucose, insulin, LDL and HDL cholesterol (|0.11| ≤ β ≤ |0.31|, <  0.001). Plasma furin (hazard ratio [ HR] per one standard deviation increment of furin) was predictive of future diabetes mellitus (727 events; HR = 1.24, CI = 1.14–1.36, <  0.001) after adjustment for age, sex, body mass index, systolic and diastolic blood pressure, use of antihypertensive treatment, alcohol intake and fasting plasma level of glucose, insulin and lipoproteins cholesterol. Furin was also independently related to the risk of all‐cause mortality (1229 events; HR = 1.12, CI = 1.05–1.19, =  0.001) after full multivariable adjustment.

          Conclusion

          Individuals with high plasma furin concentration have a pronounced dysmetabolic phenotype and elevated risk of diabetes mellitus and premature mortality.

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          Most cited references21

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          Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins.

          Limited endoproteolysis of inactive precursor proteins at sites marked by paired or multiple basic amino acids is a widespread process by which biologically active peptides and proteins are produced within the secretory pathway in eukaryotic cells. The identification of a novel family of endoproteases homologous with bacterial subtilisins and yeast Kex2p has accelerated progress in understanding the complex mechanisms underlying the production of the bioactive materials. Seven distinct proprotein convertases of this family (furin, PC2, PC1/PC3, PC4, PACE4, PC5/PC6, LPC/PC7/PC8/SPC7) have been identified in mammalian species, some having isoforms generated via alternative splicing. The family has been shown to be responsible for conversion of precursors of peptide hormones, neuropeptides, and many other proteins into their biologically active forms. Furin, the first proprotein convertase to be identified, has been most extensively studied. It has been shown to be expressed in all tissues and cell lines examined and to be mainly localized in the trans-Golgi network, although some proportion of the furin molecules cycle between this compartment and the cell surface. This endoprotease is capable of cleaving precursors of a wide variety of proteins, including growth factors, serum proteins, including proteases of the blood-clotting and complement systems, matrix metalloproteinases, receptors, viral-envelope glycoproteins and bacterial exotoxins, typically at sites marked by the consensus Arg-Xaa-(Lys/Arg)-Arg sequence. The present review covers the structure and function of mammalian subtilisin/Kex2p-like proprotein convertases, focusing on furin (EC 3.4.21.85).
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            The proprotein convertase furin in tumour progression.

            Proprotein convertases are proteases that have been implicated in the activation of a wide variety of proteins. These proteins are generally synthesised as precursor proteins and require limited proteolysis for conversion into their mature bioactive counterparts. Many of these proteins, including metalloproteases, growth factors and their receptors or adhesion molecules, have been shown to facilitate tumour formation and progression. Hence, this review will focus on the proprotein convertase furin and its role in cancer. The expression of furin has been confirmed in a large spectrum of cancers such as head and neck squamous cell carcinoma, breast cancer and rhabdomyosarcoma. Functional studies modulating furin activity uncovered its importance for the processing of many cancer-related substrates and strongly indicate that high furin activity promotes the malignant phenotype of cancer cells. In this review, we summarise the expression and function of furin in different cancer types, discuss its role in processing cancer-related proproteins and give examples of potential therapeutic approaches that take advantage of the proteolytic activity of furin in cancer cells.
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              Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin.

              We have examined the role of Furin in postimplantation-stage mouse embryos by analyzing both the expression pattern of fur mRNA and the developmental consequences of a loss-of-function mutation at the fur locus. At early stages (day 7.5), fur mRNA is abundant in extraembryonic endoderm and mesoderm, anterior visceral endoderm, and in precardiac mesoderm. 1 day later fur is expressed throughout the heart tube and in the lateral plate mesoderm, notochordal plate and definitive gut endoderm. Embryos lacking Furin die between days 10.5 and 11.5, presumably due to hemodynamic insufficiency associated with severe ventral closure defects and the failure of the heart tube to fuse and undergo looping morphogenesis. Morphogenesis of the yolk sac vasculature is also abnormal, although blood islands and endothelial precursors form. Analysis of cardiac and endodermal marker genes shows that while both myocardial precursors and definitive endoderm cells are specified, their numbers and migratory properties are compromised. Notably, mutant embryos fail to undergo axial rotation, even though Nodal and eHand, two molecular markers of left-right asymmetry, are appropriately expressed. Overall, the present data identify Furin as an important activator of signals responsible for ventral closure and embryonic turning.
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                Author and article information

                Contributors
                celine.fernandez@med.lu.se
                olle.melander@med.lu.se
                Journal
                J Intern Med
                J. Intern. Med
                10.1111/(ISSN)1365-2796
                JOIM
                Journal of Internal Medicine
                John Wiley and Sons Inc. (Hoboken )
                0954-6820
                1365-2796
                02 July 2018
                October 2018
                : 284
                : 4 ( doiID: 10.1111/joim.2018.284.issue-4 )
                : 377-387
                Affiliations
                [ 1 ] Department of Clinical Sciences Lund University Malmö Sweden
                [ 2 ] Faculty of Health Sciences School of Pharmacy University of Eastern Finland Kuopio Finland
                [ 3 ] Division of Pharmacology and Pharmacotherapy Drug Research Program University of Helsinki Helsinki Finland
                Author notes
                [*] [* ] Correspondence: Céline Fernandez or Olle Melander, Department of Clinical Sciences, Hypertension and Cardiovascular Disease, Clinical Research Center, Box 50332, 202 13 Malmö, Sweden.

                (fax: +4640391222; e‐mails: celine.fernandez@ 123456med.lu.se (CF) or olle.melander@ 123456med.lu.se (OM)).

                Article
                JOIM12783
                10.1111/joim.12783
                6175079
                29888466
                2373614c-027f-4138-a536-d21ee65817f9
                © 2018 The Authors Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 2, Tables: 4, Pages: 11, Words: 6608
                Product
                Funding
                Funded by: Albert Påhlsson Research Foundation
                Funded by: Crafoord Research Foundation
                Funded by: Ernhold Lundström Research Foundation
                Funded by: Royal Physiographic Society of Lund
                Funded by: Åke Wiberg Foundation
                Funded by: Knut and Alice Wallenberg Foundation
                Funded by: Göran Gustafsson Foundation
                Funded by: Swedish Heart‐ and Lung Foundation
                Funded by: Swedish Research Council
                Funded by: Novo Nordisk Foundation, Region Skåne and Skåne University Hospital
                Funded by: European Research Council
                Award ID: 649021
                Funded by: Region Skåne
                Funded by: Swedish Diabetes Foundation
                Funded by: Novo Nordic Foundation
                Funded by: Linneus Foundation for the Lund University Diabetes Center
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                joim12783
                October 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.0 mode:remove_FC converted:08.10.2018

                Internal medicine
                diabetes mellitus,furin,mortality,population‐based cohort,risk prediction
                Internal medicine
                diabetes mellitus, furin, mortality, population‐based cohort, risk prediction

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