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The Journal of Neuroscience, December 26, 2007, 27(52):14448-14458; doi:10.1523/JNEUROSCI.2279-07.2007

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Cellular/Molecular
A TAT–DEF–Elk-1 Peptide Regulates the Cytonuclear Trafficking of Elk-1 and Controls Cytoskeleton Dynamics

Jérémie Lavaur,^1,3 Frédéric Bernard,^2,3 Pierre Trifilieff,^1,3,4,5 Vincent Pascoli,^1,3 Vincent Kappes,^1,3 Christiane Pagès,^1,3 Peter Vanhoutte,^1,3 and Jocelyne Caboche^1,3

¹Signalisation Neuronale et Régulations Géniques and ²Développement Neuronal, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7102, 75005 Paris, France, ³Université Pierre et Marie Curie-Paris 6, 75005 Paris, France, ⁴CNRS, UMR 5106, 33405 Talence, France, and ⁵Université Bordeaux I, 33405 Talence, France

Correspondence should be addressed to Dr. Jocelyne Caboche, Université Pierre et Marie Curie-Paris 6, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7102, 9 quai Saint Bernard, 75005 Paris, France. Email: jocelyne.caboche{at}snv.jussieu.fr

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.

Key words: extracellular signal-regulated kinase (ERK); Elk-1; Elk-1 inhibitor; trafficking; gene regulations; neuronal differentiation; TAT–DEF–Elk-1 peptide

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Received May 18, 2007; revised Oct. 29, 2007; accepted Nov. 6, 2007.

Correspondence should be addressed to Dr. Jocelyne Caboche, Université Pierre et Marie Curie-Paris 6, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7102, 9 quai Saint Bernard, 75005 Paris, France. Email: jocelyne.caboche{at}snv.jussieu.fr

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