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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)

Abstract : 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.
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Imène Kara, Marjorie Poggi, Bernadette Bonardo, Roland Govers, Jean-François Landrier, et al.. 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). Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2015, 290 (5), pp.2812 - 2821. ⟨10.1074/jbc.M114.592543⟩. ⟨inserm-01478251⟩

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