ETS domain transcription factor Elk-1 has been primarily Studied in the regulation of genes in response to mitogenic Stimuli, however the presence of Elk-1 in axonal projections of largely post-mitotic adult hippocampal sections has been reported. This finding has initially led LIS to a basic question: how is Elk-1 anchored to neuronal projections? To that end, we have investigated the intracellular localization of Elk-1 and its biochemical interactions with neuronal microtubules in model systems. Our results showed colocalization of Elk-1 With microtubules in hippocampal cultures and SH-SY5Y neuroblastoma cell lines, and have further demonstrated that Elk-1 protein can biochemically interact with microtubules in vitro. Analysis of the protein sequence has indicated many Putative microtubule binding domains, with the strongest binding prediction in amino acids 314-325, and Our results show that Elk-1 can bind to microtubules through most of these regions, but no interaction was observed through the DNA binding domain, where no putative binding motifs were predicted. We further show that upon serum induction, most of the phospho-Elk-1 translocates to the nucleus, which is independent of translation. We propose that Elk-1 is anchored to neuronal microtubules in resting or unstimulated cells, and upon Stimulation is phosphorylated, which relocalizes phospho-Elk-1 to the nucleus in neurons. (C) 2008 Elsevier Inc. All rights reserved.