title: The extracellular regulated kinase-1 (ERK1) controls regulated alpha-secretase-mediated processing, promoter transactivation, and mRNA levels of the cellular prion protein.
abstract: The α-secretases A disintegrin and metalloprotease 10 (ADAM10) and ADAM17 trigger constitutive and regulated processing of the cellular prion protein (PrP(c)) yielding N1 fragment. The latter depends on protein kinase C (PKC)-coupled M1/M3 muscarinic receptor activation and subsequent phosphorylation of ADAM17 on its intracytoplasmic threonine 735. Here we show that regulated PrP(c) processing and ADAM17 phosphorylation and activation are controlled by the extracellular-regulated kinase-1/MAP-ERK kinase (ERK1/MEK) cascade. Thus, reductions of ERK1 or MEK activities by dominant-negative analogs, pharmacological inhibition, or genetic ablation all impair N1 secretion, whereas constitutively active proteins increase N1 recovery in the conditioned medium. Interestingly, we also observed an ERK1-mediated enhanced expression of PrP(c). We demonstrate that the ERK1-associated increase in PrP(c) promoter transactivation and mRNA levels involve transcription factor AP-1 as a downstream effector. Altogether, our data identify ERK1 as an important regulator of PrP(c) cellular homeostasis and indicate that this kinase exerts a dual control of PrP(c) levels through transcriptional and post-transcriptional mechanisms.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire and Institut de Neuro-Médecine Moléculaire, Unité Mixte de Recherche, 6097 Centre National de la Recherche Scientifique/Université de Nice-Sophia-Antipolis, Equipe labellisée Fondation pour la Recherche Médicale, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France.
authors.forename: Moustapha
authors.initials: M
authors.lastname: Cissé
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire and Institut de Neuro-Médecine Moléculaire, Unité Mixte de Recherche, 6097 Centre National de la Recherche Scientifique/Université de Nice-Sophia-Antipolis, Equipe labellisée Fondation pour la Recherche Médicale, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Duplan
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire and Institut de Neuro-Médecine Moléculaire, Unité Mixte de Recherche, 6097 Centre National de la Recherche Scientifique/Université de Nice-Sophia-Antipolis, Equipe labellisée Fondation pour la Recherche Médicale, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France.
authors.forename: Marie-Victoire
authors.initials: MV
authors.lastname: Guillot-Sestier
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire and Institut de Neuro-Médecine Moléculaire, Unité Mixte de Recherche, 6097 Centre National de la Recherche Scientifique/Université de Nice-Sophia-Antipolis, Equipe labellisée Fondation pour la Recherche Médicale, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Rumigny
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire and Institut de Neuro-Médecine Moléculaire, Unité Mixte de Recherche, 6097 Centre National de la Recherche Scientifique/Université de Nice-Sophia-Antipolis, Equipe labellisée Fondation pour la Recherche Médicale, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bauer
authors.affiliation: Institute of Developmental Biology and Cancer, Unité Mixte de Recherche, 6543 Centre National de la Recherche Scientifique/Université de Nice-Sophia-Antipolis, Centre Antoine Lacassagne, 06189 Nice, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Pagès
authors.affiliation: Institute of Clinical Pharmacology and Toxicology, Charité-Universitaetsmedizin Berlin, Campus Mitte, Luisenstrasse 10-11, 10117 Berlin, Germany, and.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Orzechowski
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Slack
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire and Institut de Neuro-Médecine Moléculaire, Unité Mixte de Recherche, 6097 Centre National de la Recherche Scientifique/Université de Nice-Sophia-Antipolis, Equipe labellisée Fondation pour la Recherche Médicale, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France,. Electronic address: checler@ipmc.cnrs.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire and Institut de Neuro-Médecine Moléculaire, Unité Mixte de Recherche, 6097 Centre National de la Recherche Scientifique/Université de Nice-Sophia-Antipolis, Equipe labellisée Fondation pour la Recherche Médicale, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France,. Electronic address: mbbvc@mahidol.ac.th.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincent
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D043643:Receptor, Muscarinic M1 / Q000235:genetics / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D018621:PrPC Proteins; D012333:RNA, Messenger; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D018808:Transcription Factor AP-1; D048052:Mitogen-Activated Protein Kinase 3; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse