title: 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: 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.
authors.affiliation: From the INSERM 1062, INRA 1260, Aix-Marseille Université, Faculté de médecine, F-13385, Marseille, France.
authors.forename: Imène
authors.initials: I
authors.lastname: Kara
authors.affiliation: From the INSERM 1062, INRA 1260, Aix-Marseille Université, Faculté de médecine, F-13385, Marseille, France.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Poggi
authors.affiliation: From the INSERM 1062, INRA 1260, Aix-Marseille Université, Faculté de médecine, F-13385, Marseille, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Bonardo
authors.affiliation: From the INSERM 1062, INRA 1260, Aix-Marseille Université, Faculté de médecine, F-13385, Marseille, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Govers
authors.affiliation: From the INSERM 1062, INRA 1260, Aix-Marseille Université, Faculté de médecine, F-13385, Marseille, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Landrier
authors.affiliation: Nuolan Net, 1098 Amsterdam, The Netherlands.
authors.forename: Sun
authors.initials: S
authors.lastname: Tian
authors.affiliation: the Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors.forename: Ingo
authors.initials: I
authors.lastname: Leibiger
authors.affiliation: the Institut de Pharmacologie de Sherbrooke, Département de Chirurgie/Urologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada, and.
authors.forename: Robert
authors.initials: R
authors.lastname: Day
authors.affiliation: the Laboratory of Biochemical Neuroendocrinology Center for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: John W M
authors.initials: JW
authors.lastname: Creemers
authors.affiliation: From the INSERM 1062, INRA 1260, Aix-Marseille Université, Faculté de médecine, F-13385, Marseille, France, franck.peiretti@univ-amu.fr.
authors.forename: Franck
authors.initials: F
authors.lastname: Peiretti
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D049109:Cell Proliferation; D045683:Furin / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D051379:Mice; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D007335:Insulin-Like Growth Factor II; D011972:Receptor, Insulin; C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D045683:Furin
keywords: Cell Signaling; Furin; Insulin; Insulin Receptor; Insulin-like Growth Factor (IGF); Metabolic Signaling; Mitogenic Signaling; Proprotein Convertase