Plasma membrane translocation of REDD1 governed by GPCRs contributes to mTORC1 activation
| Autor: | Jeremy C. Simpson, Sandra Lecat, Muriel Hachet-Haas, Hans W. D. Matthes, Rainer Pepperkok, Jean-Luc Galzi, Jan De Mey, Keltouma El Baghdadi, Grégory Michel |
|---|---|
| Přispěvatelé: | Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Biotechnologie des interactions macromoléculaires (BIM), European Molecular Biology Laboratory [Heidelberg] (EMBL), University College Dublin [Dublin] (UCD), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7) |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
chemistry
metabolism [SDV]Life Sciences [q-bio] Molecular Sequence Data G-protein-coupled receptors Chromosomal translocation mTORC1 [CHIM.THER]Chemical Sciences/Medicinal Chemistry Biology Mechanistic Target of Rapamycin Complex 1 Protein Sorting Signals Bioluminescence resonance energy transfer Receptor tyrosine kinase 03 medical and health sciences 0302 clinical medicine Calmodulin Sciences du Vivant [q-bio]/Biologie cellulaire [CHIM]Chemical Sciences Humans Protein Interaction Domains and Motifs Amino Acid Sequence Calcium Signaling PI3K/AKT/mTOR pathway 030304 developmental biology G protein-coupled receptor Adaptor Proteins Signal Transducing 0303 health sciences Effector Kinase TOR Serine-Threonine Kinases Cell Membrane REDD1 Proteins Cell Biology Receptors Neurokinin-2 [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences Cell biology Enzyme Activation Protein Transport HEK293 Cells Calmodulin Pathway 030220 oncology & carcinogenesis Multiprotein Complexes biology.protein mTOR [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology Ca 2+ biological phenomena cell phenomena and immunity Transcription Factors |
| Zdroj: | Journal of Cell Science Journal of Cell Science, Company of Biologists, 2014, 127 (4), pp.773-787. ⟨10.1242/jcs.136432⟩ |
| ISSN: | 0021-9533 1477-9137 |
| DOI: | 10.1242/jcs.136432⟩ |
| Popis: | The mTORC1 kinase promotes cell growth in response to growth factors by activation of receptor tyrosine kinase. It is regulated by the cellular energy level and the availability of nutrients. mTORC1 activity is also inhibited by cellular stresses through overexpression of REDD1 (regulated in development and DNA damage responses). We report the identification of REDD1 in a fluorescent live-imaging screen aimed at discovering new proteins implicated in G-protein-coupled receptor signaling, based on translocation criteria. Using a sensitive and quantitative plasma membrane localization assay based on bioluminescent resonance energy transfer, we further show that a panel of endogenously expressed GPCRs, through a Ca(2+)/calmodulin pathway, triggers plasma membrane translocation of REDD1 but not of its homolog REDD2. REDD1 and REDD2 share a conserved mTORC1-inhibitory motif characterized at the functional and structural level and differ most in their N-termini. We show that the N-terminus of REDD1 and its mTORC1-inhibitory motif participate in the GPCR-evoked dynamic interaction of REDD1 with the plasma membrane. We further identify REDD1 as a novel effector in GPCR signaling. We show that fast activation of mTORC1 by GPCRs correlates with fast and maximal translocation of REDD1 to the plasma membrane. Overexpression of functional REDD1 leads to a reduction of mTORC1 activation by GPCRs. By contrast, depletion of endogenous REDD1 protein unleashes mTORC1 activity. Thus, translocation to the plasma membrane appears to be an inactivation mechanism of REDD1 by GPCRs, which probably act by sequestering its functional mTORC1-inhibitory motif that is necessary for plasma membrane targeting. journal article research support, non-u.s. gov't 2014 Feb 15 2013 12 11 imported |
| Databáze: | OpenAIRE |
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