A TAT-DEF-Elk-1 peptide regulates the cytonuclear trafficking of Elk-1 and controls cytoskeleton dynamics.
The transcription factor Elk-1 plays a key role in cell differentiation, proliferation and apoptosis. This role is thought to arise from its phosphorylation by activated extracellular signal-regulated kinases (ERKs), a critical posttranslational event for the transcriptional activity of the ternary complex composed of Elk-1 and a dimer of serum response factor (SRF) at the serum response element (SRE) regulatory site of transcription. In addition to its nuclear localization, Elk-1 is found in the dendrites and soma of neuronal cells and recent evidence implicate a cytoplasmic proapoptotic function of Elk-1, via its association with the mitochondrial permeability transition pore complex. Thus, the nuclear versus cytoplasmic localization of Elk-1 seems to be crucial for its biological function. In this study we show that the excitatory neurotransmitter, glutamate, induces an ERK-dependent Elk-1 activation and nuclear relocalization. We demonstrate that Elk-1 phosphorylation on Ser383/389 has a dual function and triggers both Elk-1 nuclear translocation and SRE-dependent gene expression. Mutating these sites into inactive residues or using a synthetic penetrating peptide (TAT-DEF-Elk-1), which specifically interferes with the DEF docking domain of Elk-1, prevents Elk-1 nuclear translocation without interfering with ERK nor MSK1 (mitogen- and stress-activated protein kinase 1), a CREB kinase downstream from ERK- activation. This results in a differential regulation of glutamate-induced IEG regulation when compared with classical inhibitors of the ERK pathway. Using the TAT-DEF-Elk-1 peptide or the dominant-negative version of Elk-1, we show that Elk-1 phosphorylation controls dendritic elongation, SRF and Actin expression levels as well as cytoskeleton dynamics.
Lavaur
Jérémie
J
Signalisation Neuronale et Régulations Géniques, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7102, 75005 Paris, France.
Bernard
Frédéric
F
Trifilieff
Pierre
P
Pascoli
Vincent
V
Kappes
Vincent
V
Pagès
Christiane
C
Vanhoutte
Peter
P
Caboche
Jocelyne
J
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology; D003599:Cytoskeleton / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D012694:Serine / Q000378:metabolism / Q000494:pharmacology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014162:Transfection / Q000379:methods / Q000706:statistics & numerical data; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism*
D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D010455:Peptides; D050807:ets-Domain Protein Elk-1; D018698:Glutamic Acid; D012694:Serine; D020928:Mitogen-Activated Protein Kinases; D003042:Cocaine