1. The Paired Basic Amino Acid-cleaving Enzyme 4 (PACE4) Is Involved in the Maturation of Insulin Receptor Isoform B: an opportunity to reduce the specific insulin receptor-dependent effects of insulin-like growth factor 2 (IGF2)
- Author
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Kara, Imène, Poggi, Marjorie, Bonardo, Bernadette, Govers, Roland, Landrier, Jean-François, Tian, Sun, Leibiger, Ingo, Day, Robert, Creemers, John W. M., Peiretti, Franck, peiretti, franck, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Amsterdam, The Netherlands, Karolinska Institutet [Stockholm], Université de Sherbrooke (UdeS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), INSERM, INRA, Aix-Marseille Universite, Ministere de la Recherche et de l'Enseignement Superieur, Prostate Cancer Canada [D2013-8, 2012-951, TAG2014-02], Canadian Cancer Society Research Institute [701590], and Fonds Wetenschappelijk Onderzoek (FWO) Vlaanderen
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animal structures ,MESH: Receptor, Insulin ,Insulin-like Growth Factor (IGF) ,viruses ,Insulin Receptor ,MESH: Furin ,Mitogenic Signaling ,MESH: Insulin-Like Growth Factor II ,Cell Signaling ,MESH: Cell Proliferation ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: Serine Endopeptidases ,MESH: Mice ,health care economics and organizations ,Furin ,MESH: Humans ,MESH: Immunoblotting ,MESH: Real-Time Polymerase Chain Reaction ,Metabolic Signaling ,Proprotein Convertase ,humanities ,MESH: 3T3-L1 Cells ,MESH: HEK293 Cells ,MESH: HeLa Cells ,MESH: Proprotein Convertases - Abstract
International audience; Background: The insulin receptor exists as two isoforms: IRA and IRB. Results: IRA and IRB are similarly matured by furin, but when furin activity is reduced, IRB is matured by PACE4. Conclusion: Proprotein convertase inhibition can selectively reduce IRA maturation and its signaling. Significance: This can be considered as a new opportunity to target IRA signaling in cancer. Gaining the full activity of the insulin receptor (IR) requires the proteolytic cleavage of its proform by intra-Golgi furin-like activity. In mammalian cells, IR is expressed as two isoforms (IRB and IRA) that are responsible for insulin action. However, only IRA transmits the growth-promoting and mitogenic effects of insulin-like growth factor 2. Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation. Therefore, in situations of impaired furin activity, the proteolytic maturation of IRB is greater than that of IRA, and accordingly, the amount of phosphorylated IRB is also greater than that of IRA. We highlight the ability of a particular proprotein convertase inhibitor to effectively reduce the maturation of IRA and its associated mitogenic signaling without altering the signals emanating from IRB. In conclusion, the selective PACE4-dependent maturation of IRB occurs when furin activity is reduced; accordingly, the pharmacological inhibition of furin reduces IRA maturation and its mitogenic potential without altering the insulin effects.
- Published
- 2015
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